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1

The autosomal dominant dystonias.  

PubMed

Dystonia is a term used to describe a specific set of abnormal movements that can occur as a symptom of a variety of neurologic disorders, but also as a disease entity in its own right. This review focuses on the primary dystonias and delineates the genetic contribution to these disorders. Included is a description of the well recognized forms of primary dystonias which manifest autosomal dominant inheritance, especially the "classic" type of early onset, generalized torsion dystonia, but also other clinically distinct forms such as myoclonic dystonia, paroxysmal dystonia, and DOPA-responsive dystonia. Also, a summary of the molecular genetic studies pertinent to these disorders and a discussion of the implications of recent genetic research for delineating the wide spectrum of this phenotypically and genetically heterogeneous group of diseases are forthcoming. PMID:1341964

Gasser, T; Fahn, S; Breakefield, X O

1992-10-01

2

Autosomal dominant burning feet syndrome  

PubMed Central

Familial burning feet syndrome inherited as an autosomal dominant trait has been described in only one family. Due to an associated sensory neuropathy the autosomal dominant burning feet syndrome was suggested to represent a variant form of hereditary sensory and autonomic neuropathy type I (HSAN I). Clinical, histopathological, and molecular genetic studies were performed in a large German kindred with autosomal dominant burning feet syndrome. The autosomal dominant burning feet syndrome was associated with a neuropathy predominantly affecting small unmyelinated nerve fibres. Linkage to the HSAN I locus on chromosome 9q22 and to the Charcot-Marie-Tooth disease type 2B (CMT 2B) locus on chromosome 3q13-q22 was excluded. The autosomal dominant burning feet syndrome is neither allelic to HSAN I nor to CMT 2B and thus represents a distinct genetic entity.??

Stogbauer, F.; Young, P.; Kuhlenbaumer, G.; Kiefer, R.; Timmerman, V.; Ringelstein, E; Wang, J.; Schroder, J; Van Broeckhoven, C.; Weis, J.

1999-01-01

3

[Autosomal dominant polycystic kidney disease].  

PubMed

Autosomal dominant polycystic kiney disease is a hereditary systemic disorder, characterized by the developement of cysts, mainly in the kidney and liver, also with gastrointestinal and cardiovascular abnormalities. It affects 4 to 6 million people wordwide and accounts for end-stage renal disease in 7-10% of dialysis patients. The genetic penetrance is 100%, all affected individuals develop renal cysts until 70 years of age, and because of a great renal function reserve only about 50% of patients develop some degree of renal failure until the age of 60. Autosomal dominant polycystic kiney disease is a heterogeneous disorder, from a clinical as well as from a genetic point of view. There are at least three genes responsible for the disease: PKD-1 gene localized on chromosome 16p in the 16p13.3 segment which encodes Polycystin 1 protein similar to membrane receptor, PKD-2 gene localized on chromosome 4q in 4q13-23 segment which encodes Polycystin 2 protein wery similar to voltage L type Ca++ channel as well as Na+ channel and PKD-3 gene of unknown localization. Specific proteins participate in regulation od cell proliferation, apoptosis, secretion, polarity, cell-matrix interactions as cell-cell interactions and lead to the developement of cystic kidney disease. Renal manifestations of disease include structural (cyst development), functional (concentration alility falls), endocrine (renin erythropoietin) abnormalities and extra- renal manifestations. A routine diagnostic methods are good case-history about cystic kidney disease in family, ultrasonographic examination of kidneys and computerized tomography. In therapy of autosomal dominant polycystic kiney disease, low protein diets may help, treatment of arterial hypertension with ACE inhibitors and angiotensin II receptor blockers, the vasopressin V2 antagonists (VSR), rapamycin and long-acting somatostatin analogue may have some benefit. PMID:20804105

2008-12-01

4

Hypertension in autosomal dominant polycystic kidney disease  

Microsoft Academic Search

Hypertension in autosomal dominant polycystic kidney disease. Autosomal dominant polycystic kidney disease (ADPKD) has been shown to be associated with a greater than 50 percent incidence of hypertension prior to deterioration in renal function as assessed by glomerular filtration rate. The present study provides evidence for increased cardiac pre-load, as assessed by plasma atrial natriuretic factor (ANF) and cardiac index,

Patricia E Bell; Kenneth F Hossack; Patricia A Gabow; Jacques A Durr; Ann M Johnson; Robert W Schrier

1988-01-01

5

New syndrome of mental retardation, Robin sequence, and brachydactyly.  

PubMed

We report on two sibs, brother and sister, affected with a multiple congenital anomalies/mental retardation (MCA/MR) syndrome, characterized by mild to moderate psychomotor delay, Robin sequence, peculiar facial appearance, and brachydactyly. To our knowledge, this combination of anomalies has not been reported previously. The occurrence of a similar pattern of anomalies in brother and sister suggests autosomal recessive inheritance; however, dominant transmission with reduced penetrance cannot be ruled out in our patients, since minor clinical signs, such as brachydactyly, are also present in the father. PMID:11337748

Gurrieri, F; Steindl, K; Giglio, S; Neri, G

2001-04-15

6

Autosomal dominant spinocerebellar ataxias: An Asian perspective  

Microsoft Academic Search

Autosomal dominant cerebellar ataxias, frequently referred to as spinocerebellar ataxias (SCAs) have been under intense scientific research limelight since expansions of coded CAG trinucleotide repeats were demonstrated to cause several dominantly inherited SCAs. The number of new SCA loci has expanded dramatically in recent years. At least ten genes have been identified for SCAs 1, 2, 3, 6, 7, 8,

Eng King TAN

2002-01-01

7

Autosomal dominant cerebellar ataxia deafness and narcolepsy  

Microsoft Academic Search

A new autosomal dominant syndrome in a Swedish pedigree is described. Five patients were affected with cerebellar ataxia and sensorineural deafness. Four of these patients had symptoms of narcolepsy. Optic atrophy, other neurological abnormalities and psychiatric symptoms developed with increasing disease duration. Three patients had non-neurological disease in addition, including diabetes mellitus in two and hypertrophic cardiomyopathy in one. Autopsy

Atle Melberg; Jerker Hetta; Niklas Dahl; Inger Nennesmo; Mats Bengtsson; Rolf Wibom; Crawford Grant; Karl Henrik Gustavson; Per Olov Lundberg

1995-01-01

8

Autosomal dominant juvenile amyotrophic lateral sclerosis  

Microsoft Academic Search

Summary Juvenile amyotrophic lateral sclerosis (ALS) is a form of chronic motor neuron disease characterized by combined upper and lower motor neuron symptoms and signs with onset prior to age 25 years. We report the clinical and electrodiagnostic findings in 49 affected family members and neuropathological findings from two autopsies of a Maryland kindred with autosomal dominant juvenile ALS linked

Bruce A. Rabin; John W. Griffin; Barbara J. Crain; Mena Scavina; Philip F. Chance; David R. Cornblath

1999-01-01

9

Pathogenesis of Osteoscierosis in Autosomal Dominant Osteopetrosis  

Microsoft Academic Search

OBJECTIVE. The purpose of this study was to determine if the generalized osteosclerosis seen on skeletal radiographs of patients with osteopetrosis is associated with an increase in bone density. SUBJECTS AND METHODS. Five children (three girls. two boys, 6-12 years old) with autosomal dominant osteopetrosis who had sustained a fracture with minimal trauma had the density and area of cortical

Arzu Kovanlikaya; M. LuizaLoro; Vicente Gilsanz

10

Autosomal dominant nocturnal frontal lobe epilepsy  

Microsoft Academic Search

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is an idiopathic epilepsy, with a spectrum of clinical manifestations, ranging from brief, stereotyped, sudden arousals to more complex dystonic–dyskinetic seizures. Video–polysomnography allows a correct differential diagnosis. There is no difference between sporadic nocturnal frontal lobe epilepsy (NFLE) and ADNFLE in the clinical and neurophysiological findings. ADNFLE is the first idiopathic epilepsy for

Romina Combi; Leda Dalprà; Maria Luisa Tenchini; Luigi Ferini-Strambi

2004-01-01

11

An autosomal dominant multiple pterygium syndrome.  

PubMed Central

Three sibs and their mother with features of a multiple pterygium syndrome are reported. Inheritance in this family is consistent with autosomal dominant inheritance with great variation in severity between affected subjects. The importance of examining other family members closely in cases of multiple pterygium is emphasised. Images

McKeown, C M; Harris, R

1988-01-01

12

Congenital hepatic fibrosis in autosomal-dominant polycystic kidney disease  

Microsoft Academic Search

Congenital hepatic fibrosis in autosomal-dominant polycystic kidney disease. Congenital hepatic fibrosis was found in four families with autosomal-dominant polycystic kidney disease. Congenital hepatic fibrosis is commonly thought to be characteristic for autosomal-recessive polycystic kidney disease, but the reported families show that it can also complicate autosomal-dominant polycystic kidney disease. In three families close linkage between the mutation causing the disease

Jan M Cobben; Martijn H Breuning; Coen Schoots; Leo P ten Kate; Klaus Zerres

1990-01-01

13

Mechanisms of Disease: autosomal dominant and recessive polycystic kidney diseases  

Microsoft Academic Search

Autosomal dominant polycystic kidney disease and autosomal recessive polycystic kidney disease are the best known of a large family of inherited diseases characterized by the development of renal cysts of tubular epithelial cell origin. Autosomal dominant and recessive polycystic kidney diseases have overlapping but distinct pathogeneses. Identification of the causative mutated genes and elucidation of the function of their encoded

Peter C Harris; Vicente E Torres

2006-01-01

14

A distinctive autosomal recessive syndrome of severe disproportionate short stature with short long bones, brachydactyly, and hypotrichosis in two consanguineous Arab families.  

PubMed

Disproportionate short stature is a heterogeneous group of hereditary disorders, which are classified according to their mode of inheritance, their clinical skeletal and non-skeletal manifestations, and their radiological characteristics. Herein, we inform on eight individuals with severe disproportionate short stature from two unrelated consanguineous families of Arab-Muslim ancestry. The adult height of the affected individuals is between 112 cm and 127 cm, and is due to pre- and post-natal growth retardation, which probably manifests as early as the second trimester of pregnancy. At a young age, the phenotype is characterized by a short stature, a relatively large head, and a long triangular face, and this phenotype later evolves to one with in which the head is relatively small, the mandible is large and pointy. The affected individuals have normal cognitive abilities and lack any neurological deficits. Other typical features include a prominent nose, a voice with an unusual high-pitched sound, relatively small ears, clinodactyly, brachydactyly, small hands, hypoplastic fingernails, a waddling gait, and sparse hair post-pubertally. Typical skeletal changes include short long bones, especially the femurs and humeri, with mild metaphyseal changes and very short femoral necks. After due consideration of the other hereditary causes of disproportionate short stature and close examination of the pedigrees of the two families, we concluded that these eight individuals have the same hitherto unreported form of severe disproportionate short stature that is inherited in the autosomal recessive mode. PMID:22440536

Shalev, Stavit A; Spiegel, Ronen; Borochowitz, Zvi U

2012-03-03

15

Autosomal dominant sacral agenesis: Currarino syndrome  

PubMed Central

Autosomal dominant sacral agenesis is characterised by a partial agenesis of the sacrum typically involving sacral vertebrae S2-S5 only. Associated features include anorectal malformation, a presacral mass, and urogenital malformation. Together, these features have been defined as the Currarino syndrome. Recently, HLXB9 has been identified as the major causative gene in Currarino syndrome allowing identification of asymptomatic heterozygotes. In this review, we have performed an analysis of medical publications, and our own additional cases, to identify the range of malformations and complications that occur. We have also estimated risks of malformation in heterozygotes by using Weinburg's proband method on families personally known to us in order to provide accurate genetic counselling information.???Keywords: sacral agenesis; presacral mass; anorectal malformation; Currarino triad

Lynch, S. A.; Wang, Y.; Strachan, T; Burn, J.; Lindsay, S.

2000-01-01

16

Epigenetics and autosomal dominant polycystic kidney disease.  

PubMed

The roles of epigenetic modulation of gene expression and protein functions in autosomal dominant polycystic kidney disease (ADPKD) have recently become the focus of scientific investigation. Evidence generated to date indicates that one of the epigenetic modifiers, histone deacetylases (HDACs), are important regulators of ADPKD. HDACs are involved in regulating the expression of the Pkd1 gene and are the target of fluid flow-induced calcium signal in kidney epithelial cells. Pharmacological inhibition of HDAC activity has been found to reduce the progression of cyst formation and slow the decline of kidney function in Pkd1 conditional knockout mice and Pkd2 knockout mice, respectively, implicating the potential clinical application of HDAC inhibitors on ADPKD. Since the expression of HDAC6 is upregulated in cystic epithelial cells, the potential roles of HDAC6 in regulating cilia resorption and epidermal growth factor receptor (EGFR) trafficking through deacetylating ?-tubulin and regulating Wnt signaling through deacetylating ?-catenin are also discussed. This article is part of a Special Issue entitled: Polycystic Kidney Disease. PMID:20970496

Li, Xiaogang

2010-10-20

17

[Autosomal dominant nocturnal frontal lobe epilepsy].  

PubMed

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a recently identified seizure disorder. The disease maps to the long arm of chromosome 20 and may be related in some families to a missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit. We describe one of the first European family with ADNFLE, including five affected individuals spanning four generations. In the most severely affected subject, the onset was during the second month of life and persisted through adult life. Seizures were very frequent during infancy, although long-term evolution was relatively benign. Ictal video-EEG studies showed that attacks occurred in clusters during sleep and were partial seizures that were consistent with a frontal origin. Neuro-imaging was normal. Carbamazepine had a dramatic effectiveness. Although recognition of this syndrome is important for appropriate therapy and genetic counselling, underestimation of cases is likely: the disease was in our family perceived like a hereditary curse, and subsequently concealed, including to medical attention. Relationships with other partial familial epilepsies and with idiopathic benign partial epilepsies of childhood are discussed. PMID:9773047

Thomas, P; Picard, F; Hirsch, E; Chatel, M; Marescaux, C

1998-04-01

18

Early onset autosomal dominant spinocerebellar ataxia with miosis: Four cases  

Microsoft Academic Search

Previously, at least 29 different forms of autosomal dominant spinocerebellar ataxias (SCAs) have been described. We describe a family with four members through three generations with autosomal dominant ataxia in combination with miosis and hyperreflexia. This family's ataxia does not match any of the previously described SCAs and is probably a novel form of SCA. To continue with the search

Niklas Timby; Eva-Lena Stattin; Ingela Kristiansen; Urban Eriksson; Anders Erikson

2008-01-01

19

Renal structure and hypertension in autosomal dominant polycystic kidney disease  

Microsoft Academic Search

Renal structure and hypertension in autosomal dominant polycystic kidney disease. Hypertension has been reported to occur in 50 to 75 percent of subjects with autosomal dominant polycystic kidney disease (ADPKD) prior to the onset of marked renal insufficiency but concurrent with cystic deformation of the renal parenchyma. The present study was undertaken to examine whether the renal structural abnormalities are

Patricia A Gabow; Arlene B Chapman; Ann M Johnson; Douglas J Tangel; Irene T Duley; William D Kaehny; Michael Manco-Johnson; Robert W Schrier

1990-01-01

20

Cyst formation and growth in autosomal dominant polycystic kidney disease  

Microsoft Academic Search

Cyst formation and growth in autosomal dominant polycystic kidney disease. Previous morphologic studies on kidneys from adult patients with autosomal dominant polycystic kidney disease (ADPKD) indicates that the cysts developed from nephrons and collecting ducts in association with hyperplasia of epithelial cells lining the cyst walls. In the present study, we systematically evaluated by scanning electron microscopy 387 cysts in

Jared J Grantham; James L Geiser; Andrew P Evan

1987-01-01

21

Treatment prospects for autosomal-dominant polycystic kidney disease  

Microsoft Academic Search

Treatment prospects for autosomal-dominant polycystic kidney disease. An increased understanding of the molecular genetic and cellular pathophysiologic mechanisms responsible for the development of autosomal-dominant polycystic kidney disease (ADPKD), made possible by the advances in molecular biology and genetics of the last three decades, has laid the foundation for the development of effective therapies. As the concept that a polycystic kidney

Qi Qian; Peter C. Harris; Vicente E. Torres

2001-01-01

22

EDS IV (acrogeria): new autosomal dominant and recessive types.  

PubMed

Evidence is presented that type IV of the Ehlers-Danlos syndrome (EDS IV) is genetically variable. A benign autosomal dominant form and two autosomal recessive variants are described with clinical and biochemical features that are distinct from classical acrogeria. PMID:7230200

Pope, F M; Nicholls, A C; Jones, P M; Wells, R S; Lawrence, D

1980-03-01

23

Familial hyperinsulinism with apparent autosomal dominant inheritance: Clinical and genetic differences from the autosomal recessive variant  

Microsoft Academic Search

We describe three families with hypoglycemia caused by familial hyperinsulinism (HI) in whom vertical transmission of the disorder occurred, suggesting autosomal dominant (AD) inheritance. We therefore examined the relationship between the apparent AD disorder and the more common autosomal recessive (AR) form of HI, which has recently been linked to the sulfonylurea receptor on chromosome 11p15.1. The clinical features of

Paul S. Thornton; Marta S. Satin-Smith; Kevan Herold; Benjamin Glaser; Ken C. Chiu; Ann Nestorowicz; M. Alan Permutt; Lester Baker; Charles A. Stanley

1998-01-01

24

Autosomal dominant polycystic kidney disease in childhood: A longitudinal study  

Microsoft Academic Search

Autosomal dominant polycystic kidney disease in childhood: A longitudinal study. One hundred fifty–four children aged eighteen years or younger from 83 families with autosomal–dominant polycystic kidney disease were studied by ultrasonography or excretory urography. Twenty–three children had bilateral renal involvement with at least five cysts (ADPKD), 28 children were classified as suspicious (SADPKD), and 103 children had no renal involvement

Aileen Sedman; Patricia Bell; Robert Schrier; Bradley A Warady; Edward O Heard; Patricia Gabow

1987-01-01

25

Angiogenesis in autosomal-dominant polycystic kidney disease  

Microsoft Academic Search

Angiogenesis in autosomal-dominant polycystic kidney disease.BackgroundAutosomal-dominant polycystic kidney disease (ADPKD) is a genetic disorder that is responsible for approximately 10% of all cases of end-stage renal disease (ESRD). It is characterized by the formation of epithelial cell cysts, an increase in the extracellullar matrix, and vascular alterations believed to be the result of compression by the cysts. Our recent observations

Elsa Bello-Reuss; Keith Holubec; Srinivasan Rajaraman

2001-01-01

26

Autosomal dominant palatal myoclonus and spinal cord atrophy  

Microsoft Academic Search

We report a new family with palatal myoclonus, pyramidal tract signs, cerebellar signs, marked atrophy of the medulla oblongata and spinal cord, and autosomal dominant inheritance. These findings were almost identical with those in patients previously reported to have histopathologically confirmed adult-onset Alexander disease. Recently, heterozygous point mutations in the coding region of glial fibrillary acidic protein (GFAP) in patients

Yuji Okamoto; Hideo Mitsuyama; Manabu Jonosono; Keiko Hirata; Kimiyoshi Arimura; Mitsuhiro Osame; Masanori Nakagawa

2002-01-01

27

Presymptomatic testing for autosomal dominant spinocerebellar ataxia type 1  

Microsoft Academic Search

Presymptomatic testing was done on four people from a large family in which an autosomal dominant form of spinocerebellar ataxia was segregating. Earlier genetic analysis had shown that in this family the disorder was tightly linked to an informative microsatellite polymorphism on chromosome 6p. Two subjects with prior risks of 50% of developing the disease had final risks after testing

A E Shrimpton; R Davidson; N MacDonald; D J Brock

1993-01-01

28

A “reverse genetic” approach to autosomal dominant polycystic kidney disease  

Microsoft Academic Search

Biochemical, anatomical, pathophysiological and clinical studies of autosomal dominant “adult-type” polycystic kidney disease have cast little light on the underlying biochemical defect which causes the disease. The advent of recombinant DNA technology permits a novel approach to its pathophysiology. In this approach, termed “reverse genetics”, the mutation which produces the disease is first localised by genetic linkage. This is followed

Stephen T. Reeders

1987-01-01

29

Haploinsufficiency of PAX9 is associated with autosomal dominant hypodontia  

Microsoft Academic Search

We recently identified a frame-shift mutation in the PAX9 gene as the underlying cause for hypodontia involving permanent molar teeth segregating in an autosomal dominant pattern in a single large family (Stockton et al. 2000). Here we report a small nuclear family in which a father and his daughter are affected with severe hypodontia, involving agenesis of all primary and

Parimal Das; David W. Stockton; Christopher Bauer; Lisa G. Shaffer; Rena N. D'Souza; Timothy J. Wright; Pragna I. Patel

2002-01-01

30

Cardiovascular abnormalities in autosomal-dominant polycystic kidney disease  

Microsoft Academic Search

Cardiovascular problems are a major cause of morbidity and mortality in patients with autosomal-dominant polycystic kidney disease (ADPKD). Hypertension is a common early symptom of ADPKD, and occurs in approximately 60% of patients before renal function has become impaired. Hypertension is associated with an increased rate of progression to end-stage renal disease and is the most important potentially treatable variable

Robert W. Schrier; Tevfik Ecder

2009-01-01

31

Retroperitoneoscopic Nephrectomy for Autosomal Dominant Polycystic Kidney Disease: Initial Experience  

Microsoft Academic Search

Introduction: Nephrectomy for autosomal dominant polycystic kidney disease (ADPKD) has been reported to have significant morbidity and mortality. Because of the large kidney size, laparoscopic nephrectomy is technically demanding and there have been only few reports on this subject. We describe our retroperitoneoscopic technique and review the literature. Methods: Retroperitoneoscopic nephrectomy was performed in 2 patients. A four-port retroperitoneal access

Stephen F. Wyler; Alexander Bachmann; Robin Ruszat; Thomas Forster; Tvrtko Hudolin; Thomas C. Gasser; Tullio Sulser

2007-01-01

32

Evidence for further genetic heterogeneity in autosomal dominant retinitis pigmentosa  

Microsoft Academic Search

We have investigated the possible involvement of further genetic heterogeneity in autosomal dominant retinitis pigmentosa using a previously unreported large Irish family with the disease. We have utilized polymorphic microsatellite markers to exclude the disease gene segregating in this family from 3q, 6p, and the pericentric region of 8, that is, each of the three chromosomal regions to which adRP

R. Kumar-Singh; P. F. Kenna; G. J. Farrar; P. Humphries

1993-01-01

33

Intracranial aneurysms and dolichoectasia in autosomal dominant polycystic kidney disease  

Microsoft Academic Search

Background. Intracranial saccular aneurysms (ICA) are a known extrarenal manifestation of autosomal dominant polycystic kidney disease (ADPKD). In order to facilitate the definition of subgroups who are at risk for ICA and to determine the prevalence of ICA in these subgroups we studied ADPKD patients with a positive family history for a cerebral event, including cerebral stroke (group I) and

Stefan Graf; Alexander Schischma; Knut E. Eberhardt; Roland Istel; Birgit Stiasny; Bernd D. Schulze

34

CADASIL (“cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy”)  

Microsoft Academic Search

CADASIL is a small artery disease of the brain responsible for migraine with aura, subcortical ischemic strokes, mood disturbances and dementia. The disease is transmitted with an autosomal dominant pattern and usually starts during midadulthood. On MRI, the presence of more or less diffuse signal abnormalities within the white-matter associated with typical lacunar infarcts are suggestive of the disorder. The

H Chabriat; M.-G Bousser

2004-01-01

35

Molecular diagnostics for autosomal dominant polycystic kidney disease  

Microsoft Academic Search

Autosomal dominant polycystic kidney disease (ADPKD) is a common nephropathy caused by mutations in either PKD1 or PKD2. Mutations in PKD1 account for ?85% of cases and cause more severe disease than mutations in PKD2. Diagnosis of ADPKD before the onset of symptoms is usually performed using renal imaging by either ultrasonography, CT or MRI. In general, these modalities are

Sandro Rossetti; Peter C. Harris

2010-01-01

36

Electromyography and nerve conduction study in autosomal dominant olivopontocerebellar atrophy  

Microsoft Academic Search

Electromyographic examination and studies of motor and sensory conduction velocities were performed in 11 patients with a presumptive diagnosis of olivopontocerebellar atrophy with autosomal dominant transmission. Peripheral nervous system involvement was shown in eight. In two patients with early onset of disease, electrophysiological alterations clearly pointed to severe axonal degeneration, whereas in six they were compatible with slight demyelination.

L. Carenini; G. Finocchiaro; S. Di Donato; A. Visciani; S. Negri

1984-01-01

37

Autosomal dominant polycystic kidney disease: the last 3 years  

Microsoft Academic Search

Autosomal dominant polycystic kidney disease is the most prevalent, potentially lethal monogenic disorder. It has large inter- and intra-familial variability explained to a large extent by its genetic heterogeneity and modifier genes. An increased understanding of its underlying genetic, molecular, and cellular mechanisms and a better appreciation of its progression and systemic manifestations have laid out the foundation for the

Vicente E Torres; Peter C Harris

2009-01-01

38

Homozygotes for the autosomal dominant neoplasia syndrome (MEN1)  

Microsoft Academic Search

Families in which both parents are heterozygotes for the same autosomal dominant neoplasia syndrome are extremely unusual. Recently, the authors had the unique opportunity to evaluate three symptomatic siblings from the union between two unrelated individuals affected by multiple endocrine neoplasia type 1 (MEN1). When the three siblings and their parents and relatives were genotyped for 12 markers tightly linked

M. L. Brandi; A. Falchetti; F. Tonelli; G. Weber; A. Svensson; C. Larsson; R. Castello; L. Furlani; S. Scappaticci; M. Fraccaro

1993-01-01

39

Autonomic nervous system function in patients with monogenic hypertension and brachydactyly: a field study in north-eastern Turkey  

Microsoft Academic Search

Laboratory studies in patients with autosomal-dominant hypertension and brachydactyly showed increased sensitivity to sympathetic stimuli and severe abnormalities in baroreflex buffering. To further elucidate the mechanisms by which impaired baroreflex sensitivity could influence blood pressure (BP), we conducted autonomic testing under field conditions. We studied 17 hypertensive affected (13 to 48 years, BMI 22.7 ± 6.5 kg\\/m2, 160 ± 23\\/98

J Tank; O Toka; HR Toka; J Jordan; A Diedrich; A Busjahn; FC Luft

2001-01-01

40

Autosomal dominant cerebellar ataxias in the Kinki area of Japan  

Microsoft Academic Search

Summary The autosomal dominant cerebellar ataxias are a heterogeneous group of neurodegenerative disorders characterized by slowly progressive cerebellar ataxia. Recently, among the ataxias, spinocerebellar ataxia type 1 (SCA1), Machado-Joseph disease (MJD) and dentatorubral-pallidoluysian atrophy have been found to be caused by expansion of a CAG trinucleotide repeat in the coding region of the disease genes. We have analyzed the CAG

Ryusuke Matsumura; Tetsuya Takayanagi; Kayoko Murata; Naonobu Futamura; Yasuyo Fujimoto

1996-01-01

41

Autosomal-dominant polycystic kidney disease in the rat  

Microsoft Academic Search

Autosomal-dominant polycystic kidney disease in the rat. Kaspareit-Rittinghausen described a rodent model of inherited polycystic kidney disease (PKD), the Han:SPRD rat [1, 2], in which heterozygotes develop renal cysts and renal failure (in males) over several months, whereas homozygous animals develop rapidly progressive renal enlargement that leads to death in a few weeks. In this study, we examined selected elements

Benjamin D Cowley; Seshagirirao Gudapaty; Amy L Kraybill; Brian D Barash; Michael A Harding; James P Calvet; Vincent H Gattone

1993-01-01

42

Molecular Cytogenetic Aberrations in Autosomal Dominant Polycystic Kidney Disease Tissue  

Microsoft Academic Search

Autosomal dominant polycystic kidney disease (AD- PKD) is a genetically heterogeneous disorder characterized by focal cyst formation from any part of the nephron. The molec- ular bases include germinal mutation of either PKD1 or PKD2 genes, enhanced expression of several protooncogenes, alter- ation of the TGF-\\/EGF\\/EGF receptor (EGFR) axis, and dis- turbed regulation of proliferative\\/apoptosis pathways. To iden- tify new

JEAN GOGUSEV; ICHIRO MURAKAMI; MIREILLE DOUSSAU; LOUISE TELVI; ALEXANDRE STOJKOSKI; PHILIPPE LESAVRE; DOMINIQUE DROZ

2003-01-01

43

Genotypes of autosomal dominant polycystic kidney disease in Japanese  

Microsoft Academic Search

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common hereditary disorders. The prevalence of the\\u000a ADPKD genotype in the Caucasian and Latin populations has been reported. Here, we used linkage analysis to demonstrate the\\u000a prevalence of the genotype and the correlation between phenotypes and genotypes among 21 Japanese ADPKD families consisting\\u000a of 96 individuals and including 57

Michiko Mizoguchi; Takashi Tamura; Akiko Yamaki; Eiji Higashihara; Yoshiko Shimizu

2002-01-01

44

Autosomal dominant hemolytic uremic syndrome: variable phenotypes and transplant results  

Microsoft Academic Search

Autosomal dominant hemolytic uremic syndrome (ADHUS) is a rare disorder with a poor prognosis that was considered to present\\u000a mainly in adults. Recurrent episodes of ADHUS were also thought to be uncommon. However, increasing reports suggest that children\\u000a are often affected, that recurrent episodes may occur pre-transplantation, and that post-transplant recurrences occur in about\\u000a 50% of cases. We describe the

B. S. Kaplan; M. B. Leonard

2000-01-01

45

Practical Genetics for Autosomal Dominant Polycystic Kidney Disease  

Microsoft Academic Search

Autosomal dominant polycystic kidney disease (ADPKD) is the most common mendelian disorder of the kidney and accounts for ?5% of end-stage renal disease in North America. It is characterized by focal development of renal cysts which increase in number and size with age. Mutations of PKD1 and PKD2 account for most cases. Although the clinical manifestations of both gene types

York Pei

2011-01-01

46

The clinical diagnosis of autosomal dominant spinocerebellar ataxias  

Microsoft Academic Search

The spinocerebellar ataxias (SCAs) are a heterogeneous group of autosomal dominantly inherited progressive ataxia diseases.\\u000a Up to now, almost 30 different gene loci have been found. In 14 of them, the underlying mutations have been identified. The\\u000a more common SCAs, SCA1, 2, 3 and 6 are due to translated CAG repeat expansions that code for an elongated polyglutamine tract\\u000a within

Thomas Klockgether

2008-01-01

47

Phenotypic Variation in a Large Family with Autosomal Dominant Hypocalcaemia  

Microsoft Academic Search

Background\\/Aims: Autosomal dominant hypocalcaemia (ADH) is caused by activating mutations in the calcium- sensing receptor (CASR). We aimed to describe the phenotypic variation within a large family with ADH, especially kidney and cerebral basal ganglia calcifications. Methods: Fifteen related subjects carrying the CASR mutation T151M participated in a cross-sectional study of calcium homeostasis, renal ultrasonography, cerebral CT, bone mineral density,

J. I. Sørheim; E. S. Husebye; B. G. Nedrebø; E. Svarstad; J. Lind; H. Boman; K. Løvås

2010-01-01

48

[Autosomal dominant spinocerebellar degeneration--new forms and pathomechanisms].  

PubMed

In our country, hereditary spinocerebellar degeneration accounted for approximately 30% of the total cases. Most of them are autosomal dominant and include more than 20 diseases. The outlines of some new members, namely autosomal dominant cortical cerebellar atrophy linked to chromosome 16 (16q-ADCCA), SCA14, an ataxia caused by FGF14 mutation and a form of neuroferritinopathy were described. The etiology of many autosomal dominant SCDs has been identified as the abnormal expansion of CAG repeat. The latter three diseases are caused by missense mutations of the causative genes, which clearly shows the presence of other new mechanisms of cerebellar degeneration than repeat expansion. 16q-ADCCA is the most frequent after Machado-Joseph disease and SCA6 according to our genetic diagnosis of 185 SCD patients. The disease is characterized by Purkinje cell degeneration and atrophy with somatic sprouts as well as the halo-like structure surrounding the soma. The halo is positive for synaptophysin. These features are so unique that 16q-ADCCA may be diagnosed by neuropathology alone. PMID:15651290

Mizusawa, Hidehiro

2004-11-01

49

Autosomal dominant polycystic kidney disease associated with familial sensorineural deafness.  

PubMed

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by both renal and non-renal disorders. Extrarenal involvement includes noncystic manifestations such as cardiovascular abnormalities, colonic diverticula and intracranial aneurysms. Familial sensorineural hearing loss (SNHL) has been included in the definition of Alport's syndrome. However, other types of nephropathy have been occasionally associated with hereditary deafness. The association of ADPKD with hereditary SNHL has not been previously documented. We report a family with ADPKD associated with bilateral sensorineural deafness in a pedigree of four affected members in four generations. PMID:10100367

Mora, C; Navarro, J F; García, J; Gallego, E; Macía, M; Méndez, M L; Chahin, J; Rivero, A

1999-02-01

50

Homozygotes for the autosomal dominant neoplasia syndrome (MEN1)  

SciTech Connect

Families in which both parents are heterozygotes for the same autosomal dominant neoplasia syndrome are extremely unusual. Recently, the authors had the unique opportunity to evaluate three symptomatic siblings from the union between two unrelated individuals affected by multiple endocrine neoplasia type 1 (MEN1). When the three siblings and their parents and relatives were genotyped for 12 markers tightly linked to the MEN1 locus, at 11q13, two of the siblings were found to be homozygotes, and one a heterozygote, for MEN1. With regard to the MEN1 syndrome, no phenotypic differences were observed between the two homozygotes and the heterozygotes. However, the two homozygotes showed unexplained infertility, which was not the case for any of the heterozygotes. Thus, MEN1 appears to be a disease with complete dominance, and the presence of two MEN1 alleles with mutations of the type that occur constitutionally may be insufficient for tumor development. 28 refs., 2 figs.

Brandi, M.L.; Falchetti, A.; Tonelli, F. (Univ. of Florence (Italy)); Weber, G.; Svensson, A.; Larsson, C. (Karolinska Hospital, Stockholm (Sweden)); Castello, R.; Furlani, L.; Scappaticci, S.; Fraccaro, M.

1993-12-01

51

Autosomal dominant nocturnal frontal lobe epilepsy. A distinctive clinical disorder.  

PubMed

The disorder of autosomal dominant nocturnal frontal lobe epilepsy has recently been identified, and is now delineated in detail. A phenotypically homogeneous group of five families from Australia, Britain and Canada, containing 47 affected individuals, was studied. The largest family contained 25 affected individuals spanning six generations. This disorder is characterized by clusters of brief nocturnal motor seizures, with hyperkinetic or tonic manifestations. Subjects often experienced an aura, and remained aware throughout the attacks. Seizures occurred in clusters (mean eight attacks/night) typically as the individual dozed, or shortly before awakening. The epilepsy usually began in childhood, and persisted through adult life, with considerable intra-family variation in severity. Seizures were often misdiagnosed as benign nocturnal parasomnias, psychiatric and medical disorders. Interictal EEG studies were unhelpful. Ictal video-EEG studies showed that the attacks were partial seizures with frontal lobe seizure semiology. Neuro-imaging was normal. Carbamazepine monotherapy was frequently effective. This disorder showed autosomal dominant inheritance. Recognition of this entity is clinically important for diagnosis, appropriate therapy and genetic counselling. Moreover, this disorder now offers an opportunity to identify a gene for partial epilepsy. PMID:7895015

Scheffer, I E; Bhatia, K P; Lopes-Cendes, I; Fish, D R; Marsden, C D; Andermann, E; Andermann, F; Desbiens, R; Keene, D; Cendes, F

1995-02-01

52

Autosomal-dominant Alzheimer's disease: a review and proposal for the prevention of Alzheimer's disease  

PubMed Central

Autosomal-dominant Alzheimer's disease has provided significant understanding of the pathophysiology of Alzheimer's disease. The present review summarizes clinical, pathological, imaging, biochemical, and molecular studies of autosomal-dominant Alzheimer's disease, highlighting the similarities and differences between the dominantly inherited form of Alzheimer's disease and the more common sporadic form of Alzheimer's disease. Current developments in autosomal-dominant Alzheimer's disease are presented, including the international Dominantly Inherited Alzheimer Network and this network's initiative for clinical trials. Clinical trials in autosomal-dominant Alzheimer's disease may test the amyloid hypothesis, determine the timing of treatment, and lead the way to Alzheimer's disease prevention.

2011-01-01

53

Autosomal-dominant Alzheimer's disease: a review and proposal for the prevention of Alzheimer's disease.  

PubMed

Autosomal-dominant Alzheimer's disease has provided significant understanding of the pathophysiology of Alzheimer's disease. The present review summarizes clinical, pathological, imaging, biochemical, and molecular studies of autosomal-dominant Alzheimer's disease, highlighting the similarities and differences between the dominantly inherited form of Alzheimer's disease and the more common sporadic form of Alzheimer's disease. Current developments in autosomal-dominant Alzheimer's disease are presented, including the international Dominantly Inherited Alzheimer Network and this network's initiative for clinical trials. Clinical trials in autosomal-dominant Alzheimer's disease may test the amyloid hypothesis, determine the timing of treatment, and lead the way to Alzheimer's disease prevention. PMID:21211070

Bateman, Randall J; Aisen, Paul S; De Strooper, Bart; Fox, Nick C; Lemere, Cynthia A; Ringman, John M; Salloway, Stephen; Sperling, Reisa A; Windisch, Manfred; Xiong, Chengjie

2011-01-06

54

LAMB3 Mutations Causing Autosomal-dominant Amelogenesis Imperfecta.  

PubMed

Amelogenesis imperfecta (AI) can be either isolated or part of a larger syndrome. Junctional epidermolysis bullosa (JEB) is a collection of autosomal-recessive disorders featuring AI associated with skin fragility and other symptoms. JEB is a recessive syndrome usually caused by mutations in both alleles of COL17A1, LAMA3, LAMB3, or LAMC2. In rare cases, heterozygous carriers in JEB kindreds display enamel malformations in the absence of skin fragility (isolated AI). We recruited two kindreds with autosomal-dominant amelogenesis imperfecta (ADAI) characterized by generalized severe enamel hypoplasia with deep linear grooves and pits. Whole-exome sequencing of both probands identified novel heterozygous mutations in the last exon of LAMB3 that likely truncated the protein. The mutations perfectly segregated with the enamel defects in both families. In Family 1, an 8-bp deletion (c.3446_3453del GACTGGAG) shifted the reading frame (p.Gly 1149Glufs*8). In Family 2, a single nucleotide substitution (c.C3431A) generated an in-frame translation termination codon (p.Ser1144*). We conclude that enamel formation is particularly sensitive to defects in hemidesmosome/basement-membrane complexes and that syndromic and non-syndromic forms of AI can be etiologically related. PMID:23958762

Kim, J W; Seymen, F; Lee, K E; Ko, J; Yildirim, M; Tuna, E B; Gencay, K; Shin, T J; Kyun, H K; Simmer, J P; Hu, J C-C

2013-08-19

55

Autosomal-dominant Alzheimer's disease: a review and proposal for the prevention of Alzheimer's disease  

Microsoft Academic Search

ABSTRACT: Autosomal-dominant Alzheimer's disease has provided significant understanding of the pathophysiology of Alzheimer's disease. The present review summarizes clinical, pathological, imaging, biochemical, and molecular studies of autosomal-dominant Alzheimer's disease, highlighting the similarities and differences between the dominantly inherited form of Alzheimer's disease and the more common sporadic form of Alzheimer's disease. Current developments in autosomal-dominant Alzheimer's disease are presented, including

Randall J Bateman; Paul S Aisen; Bart De Strooper; Nick C Fox; Cynthia A Lemere; John M Ringman; Stephen Salloway; Reisa A Sperling; Manfred Windisch; Chengjie Xiong

2011-01-01

56

Mitochondrial anomalies in a Swiss family with autosomal dominant myoglobinuria  

SciTech Connect

We report on a Swiss family in which 10 individuals of both sexes in 4 successive generations suffered from myoglobinuria, precipitated by febrile illness. It is the second family described with autosomal dominant inheritance of myoglobinuria. Four individuals suffered acute renal failure, which in two was reversible only after dialysis. In a recent case, a mitochondrial disorder was suspected because of an abnormal increase in lactate levels during an exercise test and because of a subsarcolemmal accumulation of mitochondria in a muscle biopsy, associated with a lack of cytochrome C oxidase in some muscle fibers. No mutation in the mitochondrial DNA was identified. Along with the inheritance pattern, these findings suggest that the myoglobinuria in this family is caused by a nuclear-encoded mutation affecting the respiratory chain. 22 refs., 2 figs.

Martin-du Pan, R.C. [Univ. Hospital, Geneva (Switzerland); Favre, H.; Junod, A. [Univ. Hospital, Geneva (Switzerland)] [and others

1997-04-14

57

Autism in siblings with autosomal dominant nocturnal frontal lobe epilepsy.  

PubMed

In 1999, Hirose et al. reported a Japanese family with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) associated with a neuronal nicotinic acetylcholine receptor ?4 subunit mutation (S252L). We followed the siblings of this family, and found that the elder brother had Asperger's disorder without mental retardation (MR) and the younger brother had autistic disorder with profound MR. The clinical epileptic features of the siblings were very similar, and both had deficits in socialization, but their cognitive development differed markedly. It thus seems that epilepsy is the direct phenotype of the S252L mutation, whereas other various factors modulate the cognitive and social development. No patients with ADNFLE have previously been reported to have autism spectrum disorder or profound MR. PMID:22883468

Miyajima, Tomoko; Kumada, Tomohiro; Saito, Keiko; Fujii, Tatsuya

2012-08-09

58

Autosomal dominant polycystic kidney disease: a case study.  

PubMed

Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent genetic cause of chronic kidney disease (CKD) and renal failure in adults. CKD is increasingly managed within a primary care setting, and thus, it is important for primary care providers (PCPs) to be aware of ADPKD. Diagnosis of ADPKD is usually made based on kidney imaging studies and genetic testing. Treatment of ADPKD is a challenge for PCPs and should be managed collaboratively with a nephrologist. This article describes a case study of a patient with ADPKD who is managed by a family nurse practitioner (FNP) and a nephrologist. Through the examination of this complex case, a continuum of care can be arranged for the patient through the end of life. PMID:19271623

Phillips, Angela

59

Mutations of DEPDC5 cause autosomal dominant focal epilepsies.  

PubMed

The main familial focal epilepsies are autosomal dominant nocturnal frontal lobe epilepsy, familial temporal lobe epilepsy and familial focal epilepsy with variable foci. A frameshift mutation in the DEPDC5 gene (encoding DEP domain-containing protein 5) was identified in a family with focal epilepsy with variable foci by linkage analysis and exome sequencing. Subsequent pyrosequencing of DEPDC5 in a cohort of 15 additional families with focal epilepsies identified 4 nonsense mutations and 1 missense mutation. Our findings provided evidence of frequent (37%) loss-of-function mutations in DEPDC5 associated with a broad spectrum of focal epilepsies. The implication of a DEP (Dishevelled, Egl-10 and Pleckstrin) domain-containing protein that may be involved in membrane trafficking and/or G protein signaling opens new avenues for research. PMID:23542701

Ishida, Saeko; Picard, Fabienne; Rudolf, Gabrielle; Noé, Eric; Achaz, Guillaume; Thomas, Pierre; Genton, Pierre; Mundwiller, Emeline; Wolff, Markus; Marescaux, Christian; Miles, Richard; Baulac, Michel; Hirsch, Edouard; Leguern, Eric; Baulac, Stéphanie

2013-03-31

60

Tobacco habits modulate autosomal dominant nocturnal frontal lobe epilepsy.  

PubMed

Mutations in neuronal nicotinic acetylcholine receptors have been demonstrated in autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). The beneficial effect of nicotine administration was previously reported in one single case. We investigated the influence of the tobacco habits of 22 subjects from two pedigrees with alpha4 mutations (776ins3 and S248F). Subjects were interviewed with respect to pattern of nicotine intake and seizures. Seizure freedom was significantly associated with tobacco use (P=0.024). All seven nonsmokers with manifest ADNFLE had persistent seizures. Seizure fluctuations, including long remissions, corresponded to changes in tobacco habits in several patients. One patient who recently had begun treatment with transdermal nicotine experienced improvement. We conclude that tobacco appears to be an environmental factor that influences seizure susceptibility in ADNFLE. Inactivation by desensitization of the mutant receptors by nicotine may explain the beneficial effect. The efficacy and safety of transdermal nicotine in ADNFLE should be further explored. PMID:16931165

Brodtkorb, Eylert; Picard, Fabienne

2006-08-22

61

[Autosomal dominant nocturnal frontal lobe epilepsy: the syndrome].  

PubMed

The identification of the autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) in 1994 was rapidly followed by that of other familial forms of non lesional partial epilepsies (familial temporal lobe epilepsy, autosomal dominant partial epilepsy with variable foci). Since then around forty families with ADNFLE have been described, most of them having only 3 or 4 affected individuals. The epilepsy usually begins during childhood (mean age at onset: 11 years). The seizures mainly consist of motor elements which can be dystonic, tonic or hyperkinetic (bipedal automatisms, pelvic thrashing movements...), often preceded by a non specific aura. They are brief and frequent, taking place at night, in clusters. Some patients also present some diurnal seizures. One third of the patients report the occurrence of rare secondarily generalized tonic-clonic seizures. There is a large intra-familial variability as to age of onset, intensity of the manifestations and the course of the epilepsy. During the period of highest frequency of seizures, some patients may present moderate neuropsychological disturbances concordant with frontal dysfunctioning, or transitory behavioral disorders. The seizures often subside with age and may even disappear at adulthood. The most effective antiepileptic drug is carbamazepine, however pharmacoresistance is seen in 20 to 30 p. 100 of the cases. Interictal EEG shows non specific epileptiform anomalies with a frontal predominance, often seen solely on sleep recording, in more than half of all patients. Ictal EEG does not always give evidence of definite ictal discharges. The clinical heterogeneity of ADNFLE as it is especially observed in very variable types of auras which are non localizing, aside form the EEG's own limits, makes it difficult to localize the primary epileptic focus with certainty in the frontal lobe in all cases. In all, the clinical and electrical spectrum of ADNFLE is large, and the topographical identification of these familial frontal lobe epilepsies sets the same problems as for sporadic, classical cryptogenic frontal lobe epilepsies. PMID:10472656

Picard, F; Chauvel, P

1999-07-01

62

Autosomal dominant diabetes arising from a wolfram syndrome 1 mutation.  

PubMed

We used an unbiased genome-wide approach to identify exonic variants segregating with diabetes in a multigenerational Finnish family. At least eight members of this family presented with diabetes with age of diagnosis ranging from 18 to 51 years and a pattern suggesting autosomal dominant inheritance. We sequenced the exomes of four affected members of this family and performed follow-up genotyping of additional affected and unaffected family members. We uncovered a novel nonsynonymous variant (p.Trp314Arg) in the Wolfram syndrome 1 (WFS1) gene that segregates completely with the diabetic phenotype. Multipoint parametric linkage analysis with 13 members of this family identified a single linkage signal with maximum logarithm of odds score 3.01 at 4p16.2-p16.1, corresponding to a region harboring the WFS1 locus. Functional studies demonstrate a role for this variant in endoplasmic reticulum stress, which is consistent with the ?-cell failure phenotype seen in mutation carriers. This represents the first compelling report of a mutation in WFS1 associated with dominantly inherited nonsyndromic adult-onset diabetes. PMID:23903355

Bonnycastle, Lori L; Chines, Peter S; Hara, Takashi; Huyghe, Jeroen R; Swift, Amy J; Heikinheimo, Pirkko; Mahadevan, Jana; Peltonen, Sirkku; Huopio, Hanna; Nuutila, Pirjo; Narisu, Narisu; Goldfeder, Rachel L; Stitzel, Michael L; Lu, Simin; Boehnke, Michael; Urano, Fumihiko; Collins, Francis S; Laakso, Markku

2013-07-31

63

Factors affecting the progression of renal disease in autosomal-dominant polycystic kidney disease  

Microsoft Academic Search

Factors affecting the progression of renal disease in autosomal-dominant polycystic kidney disease. Autosomal-dominant polycystic kidney disease results in renal failure at a varying age from childhood to old age. We postulated that factors other than the culprit gene alone contribute to the course of progression of the renal failure. We studied 580 subjects with autosomal-dominant polycystic kidney disease and 194

Patricia A Gabow; Ann M Johnson; William D Kaehny; William J Kimberling; Dennis C Lezotte; Irene T Duley; Richard H Jones

1992-01-01

64

Cardiovascular complications in autosomal dominant polycystic kidney disease.  

PubMed

Cardiovascular complications are a major cause of morbidity and mortality in patients with autosomal dominant polycystic kidney disease (ADPKD). Hypertension is a common finding of ADPKD occurring in 50-70% of patients before the impairment of renal function. Stimulation of the renin-angiotensin-aldosterone system plays a major role in the development of hypertension in ADPKD. Hypertension is associated with an increased rate of progression to end-stage renal disease and is the most important potentially treatable variable in these patients. Left ventricular hypertrophy, a major cardiovascular risk factor, is also common in patients with ADPKD. Both hypertension and left ventricular hypertrophy play a crucial role in the development of cardiovascular complications in these patients. Furthermore, endothelial dysfunction, impaired coronary flow velocity reserve, biventricular diastolic dysfunction, increased carotid intima-media thickness, and arterial stiffness are present even in young normotensive patients with ADPKD who have well-preserved renal function. These findings suggest that cardiovascular involvement starts very early in the course of ADPKD. Intracranial and extracranial aneurysms and cardiac valvular defects are other potential cardiovascular problems in patients with ADPKD. A multifactorial approach aiming at all cardiovascular risk factors, such as hypertension, smoking, dyslipidemia and obesity is extremely important in these patients. Early diagnosis and treatment of hypertension, with drugs that block the renin-angiotensin-aldosterone system, has the potential to decrease the cardiovascular complications and slow the progression of renal disease in ADPKD. PMID:23971638

Ecder, Tevfik

2013-02-01

65

Diagnosis and Screening of Autosomal Dominant Polycystic Kidney Disease  

PubMed Central

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited cause of kidney failure and accounts for ?5% of end-stage renal disease (ESRD) population in the United States. The disorder is characterized by the focal and sporadic development of renal cysts, which increase in size and number with age. Mutations of PKD1 and PKD2 account for most of the cases. Although the clinical manifestations of both gene types overlap completely, PKD1 is associated with more severe disease than PKD2, with larger kidneys and earlier onset of ESRD. In general, renal ultrasonography is commonly used for the diagnosis of ADPKD and age-dependent criteria have been defined for subjects at-risk of PKD1. However, the utility of the PKD1 ultrasound criteria in the clinic setting is unclear since their performance characteristics have not been defined for the milder PKD2 and the gene type for most test subjects is unknown. Recently, highly predictive ultrasound diagnostic criteria have been derived for at-risk subjects of unknown gene type. Additionally, both DNA linkage or gene-based direct sequencing are now available for the diagnosis of ADPKD, especially in subjects with equivocal imaging results, a negative or indeterminate family history, or in younger at-risk individuals being evaluated as potential living-related kidney donors. Here, we review the clinical utilities and limitations of both imaging- and molecular-based diagnostic tests, and outline our approach for the evaluation of individuals suspected to have ADPKD.

Pei, York; Watnick, Terry

2010-01-01

66

New treatments for autosomal dominant polycystic kidney disease.  

PubMed

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease and results from mutations in PKD1 or PKD2. Cyst initiation and expansion arise from a combination of abnormal cell proliferation, fluid secretion and extracellular matrix defects and results in kidney enlargement and interstitial fibrosis. Since its first description over 200 years ago, ADPKD has been considered an untreatable condition and its management is limited to blood pressure reduction and symptomatic treatment of disease complications. Results of the recently reported TEMPO 3/4 trial thus represent a paradigm shift in demonstrating for the first time that cystic disease and loss of renal function can be slowed in humans. In this paper, we review the major therapeutic strategies currently being explored in ADPKD including a range of novel approaches in preclinical models. It is anticipated that the clinical management of ADPKD will undergo a revolution in the next decade with the translation of new treatments into routine clinical use. PMID:23594398

Chang, Ming-Yang; Ong, Albert C M

2013-10-01

67

Molecular cytogenetic aberrations in autosomal dominant polycystic kidney disease tissue.  

PubMed

Autosomal dominant polycystic kidney disease (ADPKD) is a genetically heterogeneous disorder characterized by focal cyst formation from any part of the nephron. The molecular bases include germinal mutation of either PKD1 or PKD2 genes, enhanced expression of several protooncogenes, alteration of the TGF-alpha/EGF/EGF receptor (EGFR) axis, and disturbed regulation of proliferative/apoptosis pathways. To identify new locations of ADPKD related oncogenes and/or tumor suppressor genes (TSG), comparative genomic hybridization (CGH) and loss of heterozygosity (LOH) analyses were performed for a series of individual cysts (n = 24) from eight polycystic kidneys. By CGH, imbalances were detected predominantly on chromosomes 1p, 9q, 16p, 19, and 22q in all tissues. DNA copy number gain was seen on chromosomes 3q and 4q in five samples. The CGH data were supplemented by LOH analysis using 83 polymorphic microsatellite markers distributed along chromosomes 1, 9, 16, 19, and 22. The highest frequency of LOH was found on the 1p35-36 and 16p13.3 segments in cysts from seven samples. Allelic losses on 9q were detected in six, whereas deletions at 19p13 and 22q11 bands were observed in three polycystic kidneys. These results indicate that the deleted chromosomal regions may contain genes important in ADPKD initiation and progression. PMID:12538736

Gogusev, Jean; Murakami, Ichiro; Doussau, Mireille; Telvi, Louise; Stojkoski, Alexandre; Lesavre, Philippe; Droz, Dominique

2003-02-01

68

MECHANISMS OF EMPHYSEMA IN AUTOSOMAL DOMINANT CUTIS LAXA  

PubMed Central

Heterozygous elastin gene mutations cause autosomal dominant cutis laxa associated with emphysema and aortic aneurysms. To investigate the molecular mechanisms leading to cutis laxa in vivo, we generated transgenic mice by pronuclear injection of minigenes encoding normal human tropoelastin (WT) or tropoelastin with a cutis laxa mutation (CL). Three independent founder lines of CL mice showed emphysematous pulmonary airspace enlargement. No consistent dermatological or cardiovascular pathologies were observed. One CL and one WT line were selected for detailed studies. Both mutant and control transgenic animals showed elastin deposition into pulmonary elastic fibers, indicated by increased desmosine levels in the lung and by colocalization of transgenic and endogenous elastin by immunostaining. CL mice showed increased static lung compliance and decreased stiffness of lung tissue. In addition, markers of transforming growth factor-? (TGF?) signaling and the unfolded protein response (UPR) were elevated together with increased apoptosis in the lungs of CL animals. We conclude that the synthesis of mutant elastin in CL activates multiple downstream disease pathways by triggering a UPR, altered mechanical signaling, increased release of TGF? and apoptosis. We propose that the combined effects of these processes lead to the development of an emphysematous pulmonary phenotype in CL.

Hu, Qirui; Shifren, Adrian; Sens, Carla; Choi, Jiwon; Szabo, Zoltan; Starcher, Barry C.; Knutsen, Russell H.; Shipley, J. Michael; Davis, Elaine C.; Mecham, Robert P.; Urban, Zsolt

2012-01-01

69

Autosomal dominant cyclic hematopoiesis: Genetics, phenotype, and natural history  

SciTech Connect

Autosomal dominant cyclic hematopoiesis (ADCH; cyclic neutropenia) is a rare disorder manifested by transient neutropenia that recurs every three weeks. To facilitate mapping the ADCH gene by genetic linkage analysis, we studied 9 ADCH families with 42 affected individuals. Pedigrees revealed AD inheritance with no evidence for decreased penetrance. Similar intra- and interfamilial variable expression was observed, with no evidence to support heterogeneity. At least 3 families displayed apparent new mutations. Many adults developed chronic neutropenia, while offspring always cycled during childhood. Children displayed recurrent oral ulcers, gingivitis, lymphadenopathy, fever, and skin and other infections with additional symptoms. Interestingly, there were no cases of neonatal infection. Some children required multiple hospitalizations for treatment. Four males under age 18 died of Clostridium sepsis following necrotizing enterocolitis; all had affected mothers. No other deaths due to ADCH were found; most had improvement of symptoms and infections as adults. Adults experienced increased tooth loss prior to age 30 (16 out of 27 adults, with 9 edentulous). No increase in myelodysplasia, malignancy, or congenital anomalies was observed. Recombinant G-CSF treatment resulted in dramatic improvement of symptoms and infections. The results suggest that ADCH is not a benign disorder, especially in childhood, and abdominal pain requires immediate evaluation. Diagnosis of ADCH requires serial blood counts in the proband and at least one CBC in relatives to exclude similar disorders. Genetic counseling requires specific histories as well as CBCs of each family member at risk to determine status regardless of symptom history, especially to assess apparent new mutations.

Palmer, S.E.; Stephens, K.; Dale, D.C. [Univ. of Washington, Seattle, WA (United States)

1994-09-01

70

Familial central precocious puberty suggests autosomal dominant inheritance.  

PubMed

The prevalence of precocious puberty is higher in certain ethnic groups, and some cases may be familial. The aim of this study was to investigate the mode of inheritance of familial precocious puberty and to identify characteristics that distinguish familial from isolated precocious puberty. Of the 453 children referred to our center for suspected precocious puberty between January 1, 1997, and December 31, 2000, 156 (147 girls and 9 boys) were found to have idiopathic central precocious puberty, which was familial in 43 (42 girls and 1 boy) (27.5%). Data of the familial and sporadic cases were compared. The familial group was characterized by a significantly lower maternal age at menarche than the sporadic group (mean, 11.47 +/- 1.96 vs. 12.66 +/- 1.18 yr; P = 0.0001) and more advanced puberty at admission (Tanner stage 2, 56.5% vs. 78.1%; P = 0.006). Segregation analysis was used to study the mode of inheritance. The segregation ratio for precocious puberty was 0.38 (0.45 after exclusion of young siblings) assuming incomplete penetrance and 0.58 (0.65 after exclusion of young siblings) assuming complete ascertainment. These results suggest autosomal dominant transmission with incomplete, sex-dependent penetrance. PMID:15070947

de Vries, Liat; Kauschansky, Arieh; Shohat, Mordechai; Phillip, Moshe

2004-04-01

71

Autosomal dominant nocturnal frontal lobe epilepsy--a critical overview.  

PubMed

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is an idiopathic epilepsy, with a spectrum of clinical manifestations, ranging from brief, stereotyped, sudden arousals to more complex dystonic-dyskinetic seizures. Video-polysomnography allows a correct differential diagnosis. There is no difference between sporadic nocturnal frontal lobe epilepsy (NFLE) and ADNFLE in the clinical and neurophysiological findings. ADNFLE is the first idiopathic epilepsy for which a genetic basis has been identified. Mutations have been found in two genes (CHRNA4 and CHRNB2) coding for neuronal nicotinic receptor subunits (alpha4 and beta2, respectively). Contrasting data have been reported on the effect of these mutations on the functionality of the receptor.Moreover, the incomplete data on the neuronal network/s in which this receptor is involved, make difficult the understanding of the genotype-phenotype correlation. This is an overview on the clinical and genetic aspects of ADNFLE including a discussion of some open questions on the role of the neuronal nicotinic receptor subunit mutations in the pathogenesis of this form of epilepsy. PMID:15316796

Combi, Romina; Dalprà, Leda; Tenchini, Maria Luisa; Ferini-Strambi, Luigi

2004-08-01

72

Genetic basis of autosomal dominant nocturnal frontal lobe epilepsy.  

PubMed

In this review the current literature regarding autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is presented and discussed. This disease is caused by mutations of genes coding for subunits of neuronal acetylcholine receptor comprising the sodium/potassium ion channel. To date, three types of mutations of the gene encoding alpha4 subunit of acetylcholine receptor were described in multi-generation families in Australia, Spain, Norway and Japan. Two other types of mutations of the beta2 subunit were also reported in two families, one from Italy and the other from Scotland. Mutations were caused by substitutions of a single nucleotide or by several-nucleotide insertions and result in a decrease or an increase in the activity of the receptor, or its changes in the affinity to the ligand. Recent advances in molecular genetics have provided the means for a better understanding of human epileptogenesis at a molecular level, which facilitates clinical diagnosis and provides a more rational basis of therapy of this form of epilepsy. PMID:12773798

Rózycka, Agata; Trzeciak, Wies?aw H

2003-01-01

73

Detection of novel genetic variation in autosomal dominant retinitis pigmentosa.  

PubMed

We explored an approach to detect disease-causing sequence variants in 448 candidate genes from five index cases of autosomal dominant retinitis pigmentosa (adRP) by sequence DNA capture and next-generation DNA sequencing (NGS). Detection of sequence variants was carried out by sequence capture NimbleGen and NGS in a SOLiD platform. After filtering out variants previously reported in genomic databases, novel potential adRP-causing variants were validated by dideoxy capillary electrophoresis (Sanger) sequencing and co-segregation in the families. A total of 55 novel sequence variants in the coding or splicing regions of adRP candidate genes were detected, 49 of which were confirmed by Sanger sequencing. Segregation of these variants in the corresponding adRP families showed three variants present in all the RP-affected members of the family. A novel mutation, p.L270R in IMPDH1, was found to be disease causing in one family. In another family a variant, p.M96T in the NRL gene was detected; this variant was previously reported as probably causing adRP. However, the previously reported p.A76V mutation in NRL as a cause of RP was excluded by co-segregation in the family. We discuss the benefits and limitations of our approach in the context of mutation detection in adRP patients. PMID:23534816

Borràs, E; de Sousa Dias, M; Hernan, I; Pascual, B; Mañé, B; Gamundi, Mj; Delás, B; Carballo, M

2013-04-15

74

Developments in the management of autosomal dominant polycystic kidney disease  

PubMed Central

Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent life- threatening, hereditary disease. ADPKD is more common than sickle cell anemia, cystic fibrosis, muscular dystrophy, hemophilia, Down’s syndrome, and Huntington’s disease combined. ADPKD is a multisystemic disorder characterized by the progressive development of renal cysts and marked renal enlargement. Structural and functional renal deterioration occurs in ADPKD patients and is the fourth leading cause of end-stage renal disease (ESRD) in adults. Aside from the renal manifestations, extrarenal structural abnormalities, such as liver cysts, cardiovascular abnormalities, and intracranial aneurysms may lead to morbidity and mortality. Recent studies have identified prognostic factors for progressive renal impairment including gender, race, age, proteinuria, hematuria, hypertension and increased left ventricular mass index (LVMI). Early diagnosis and better understanding of the pathophysiology of the disease provides the opportunity to aggressivly treat hypertension with renin-angiotensin-aldosterone system inhibitors and thereby potentially reduce LVMI, prevent cardiovascular morbidity and mortality and slow progression of the renal disease.

Masoumi, Amirali; Reed-Gitomer, Berenice; Kelleher, Catherine; Bekheirnia, Mir Reza; Schrier, Robert W

2008-01-01

75

Cardiovascular abnormalities in autosomal-dominant polycystic kidney disease  

PubMed Central

Cardiovascular problems are a major cause of morbidity and mortality in patients with autosomal-dominant polycystic kidney disease (ADPKD). Hypertension is a common early symptom of ADPKD, and occurs in approximately 60% of patients before renal function has become impaired. Hypertension is associated with an increased rate of progression to end-stage renal disease and is the most important potentially treatable variable in ADPKD. Left ventricular hypertrophy, which is a powerful, independent risk factor for cardiovascular morbidity and mortality, also occurs frequently in patients with ADPKD. Both hypertension and left ventricular hypertrophy have important roles in cardiovascular complications in these individuals. Moreover, biventricular diastolic dysfunction, endothelial dysfunction, increased carotid intima-media thickness, and impaired coronary flow velocity reserve are present even in young patients with ADPKD who have normal blood pressure and well-preserved renal function. These findings suggest that cardiovascular involvement starts very early in the course of ADPKD. Intracranial and extracranial aneurysms and cardiac valvular defects are other potential cardiovascular problems in patients with ADPKD. Early diagnosis and treatment of hypertension, with drugs that block the renin-angiotensin-aldosterone system, has the potential to decrease the cardiovascular complications and slow the progression of renal disease in ADPKD.

Ecder, Tevfik; Schrier, Robert W.

2009-01-01

76

Renal, cardiovascular and hormonal characteristics of young adults with autosomal dominant polycystic kidney disease  

Microsoft Academic Search

Renal, cardiovascular and hormonal characteristics of young adults with autosomal dominant polycystic kidney disease. We studied young adults with autosomal dominant polycystic kidney disease (ADPKD) to determine the characteristics that precede renal impairment. Nineteen affected (A) and 20 unaffected (U) offspring from families with ADPKD showed no significant differences in basal glomerular filtration rate (A: mean 97, SD 19; U:

Stephen B Harrap; David L Davies; Ann M Macnicol; Anna F Dominiczak; Robert Fraser; Alan F Wright; Michael L Watson; J Douglas Briggs

1991-01-01

77

Linkage study of a large family with autosomal dominant polycystic kidney disease with reduced expression  

Microsoft Academic Search

We describe a large three generation family with autosomal dominant polycystic kidney disease (PKD). Ultrasonographic screening of 60 family members revealed 20 individuals, whose age ranged from ten to eighty years, with one or several cysts in only one kidney and 7 individuals with cysts in both kidneys. Transmission of unilateral cysts seems to be autosomal dominant, although there are

Lucien Bachner; Marie Claude Vinet; Roger Lacave; Marie Claude Babron; Eric Rondeau; Jean Daniel Sraer; Dominique Chevet; Jean-Claude Kaplan

1990-01-01

78

Connexin46 mutations in autosomal dominant congenital cataract.  

PubMed Central

Loci for autosomal dominant "zonular pulverulent" cataract have been mapped to chromosomes 1q (CZP1) and 13q (CZP3). Here we report genetic refinement of the CZP3 locus and identify underlying mutations in the gene for gap-junction protein alpha-3 (GJA3), or connexin46 (Cx46). Linkage analysis gave a significantly positive two-point LOD score (Z) at marker D13S175 (maximum Z [Zmax]=>7.0; maximum recombination frequency [thetamax] =0). Haplotyping indicated that CZP3 probably lies in the genetic interval D13S1236-D13S175-D13S1316-cen-13pter, close to GJA3. Sequencing of a genomic clone isolated from the CZP3 candidate region identified an open reading frame coding for a protein of 435 amino acids (47,435 D) that shared approximately 88% homology with rat Cx46. Mutation analysis of GJA3 in two families with CZP3 detected distinct sequence changes that were not present in a panel of 105 normal, unrelated individuals. In family B, an A-->G transition resulted in an asparagine-to-serine substitution at codon 63 (N63S) and introduced a novel MwoI restriction site. In family E, insertion of a C at nucleotide 1137 (1137insC) introduced a novel BstXI site, causing a frameshift at codon 380. Restriction analysis confirmed that the novel MwoI and BstXI sites cosegregated with the disease in families B and E, respectively. This study identifies GJA3 as the sixth member of the connexin gene family to be implicated in human disease, and it highlights the physiological importance of gap-junction communication in the development of a transparent eye lens.

Mackay, D; Ionides, A; Kibar, Z; Rouleau, G; Berry, V; Moore, A; Shiels, A; Bhattacharya, S

1999-01-01

79

Soluble Klotho and Autosomal Dominant Polycystic Kidney Disease  

PubMed Central

Summary Background and objectives Fibroblast growth factor 23 (FGF23) levels are elevated in patients with autosomal dominant polycystic kidney disease (ADPKD) and X-linked hypophosphatemia (XLH), but only the latter is characterized by a renal phosphate wasting phenotype. This study explored potential mechanisms underlying resistance to FGF23 in ADPKD. Design, setting, participants, & measurements FGF23 and Klotho levels were measured, and renal phosphate transport was evaluated by calculating the ratio of the maximum rate of tubular phosphate reabsorption to GFR (TmP/GFR) in 99 ADPKD patients, 32 CKD patients, 12 XLH patients, and 20 healthy volunteers. ADPKD and CKD patients were classified by estimated GFR (CKD stage 1, ?90 ml/min per 1.73 m2; CKD stage 2, 60–89 ml/min per 1.73 m2). Results ADPKD patients had 50% higher FGF23 levels than did XLH patients; TmP/GFR was near normal in most ADPKD patients and very low in XLH patients. Serum Klotho levels were lowest in the ADPKD group, whereas the CKD and XLH groups and volunteers had similar levels. ADPKD patients with an apparent renal phosphate leak had two-fold higher Klotho levels than those without. Serum Klotho values correlated inversely with cyst volume and kidney growth. Conclusions Loss of Klotho might be a consequence of cyst growth and constrain the phosphaturic effect of FGF23 in most patients with ADPKD. Normal serum Klotho levels were associated with normal FGF23 biologic activity in all XLH patients and a minority of ADPKD patients. Loss of Klotho and FGF23 increase appear to exceed and precede the changes that can be explained by loss of GFR in patients with ADPKD.

Pavik, Ivana; Jaeger, Philippe; Ebner, Lena; Poster, Diane; Krauer, Fabienne; Kistler, Andreas D.; Rentsch, Katharina; Andreisek, Gustav; Wagner, Carsten A.; Devuyst, Olivier; Wuthrich, Rudolf P.; Schmid, Christoph; Serra, Andreas L.

2012-01-01

80

Transperitoneal Laparoscopic Nephrectomy for Autosomal Dominant Polycystic Kidney Disease  

PubMed Central

Objective: This study focuses on laparoscopic nephrectomy for autosomal dominant polycystic kidney disease (ADPKD). Material and Methods: We retrospectively reviewed 21 consecutive patients who had previously undergone laparoscopy between 2007 and 2010. Data were compared to that obtained from 19 consecutive patients who had open surgery between 2004 and 2007. Clinical parameters, operative data, perioperative mortality, postoperative complications, and length of hospital stay were compared using ?2 and Student t tests for qualitative and quantitative variables, respectively. Results: Nephrectomy is usually performed to create space for renal transplantation (81% and 79%, respectively). Operating time was longer with the laparoscopic approach (180 min vs. 128 min, P = .001). Blood loss was comparable in the 2 groups (154 vs. 222 ml, P = .359) but 3 patients were transfused in the open surgery group as compared with 1 patient in the laparoscopic group. No conversion was needed. There was a trend in the laparoscopic group with respect to lower consumption of analgesics in the postoperative period (P = .06). Delay to transit recovery (2.1 d vs 4.1 d, P < .001) and hospital stay (5.2 d vs. 8.28 d, P = .002) were significantly decreased in the laparoscopic group. The interval from surgery to renal transplantation was lower in patients operated on laparoscopically (3.1 vs. 12 mo). Complications occurred in 33% of the patients in the laparoscopic group as compared with 68% in the open surgery group (P = .22). Severe complications were less frequent in the laparoscopic group (9.5% vs. 37%, P = .04). Conclusion: Laparoscopic nephrectomy is a feasible and safe procedure for ADPKD. Morbidity is significantly reduced compared with the open approach.

Delreux, Arnaud; Mathieu, Romain; Patard, Jean-Jacques; Vigneau, Cecile; Rioux-Leclercq, Nathalie; Bensalah, Karim

2012-01-01

81

Tolvaptan in Autosomal Dominant Polycystic Kidney Disease: Three Years' Experience  

PubMed Central

Summary Background and objectives Autosomal dominant polycystic kidney disease (ADPKD), a frequent cause of end-stage renal disease, has no cure. V2-specific vasopressin receptor antagonists delay disease progression in animal models. Design, setting, participants, and measurements This is a prospectively designed analysis of annual total kidney volume (TKV) and thrice annual estimated GFR (eGFR) measurements, from two 3-year studies of tolvaptan in 63 ADPKD subjects randomly matched 1:2 to historical controls by gender, hypertension, age, and baseline TKV or eGFR. Prespecified end points were group differences in log-TKV (primary) and eGFR (secondary) slopes for month 36 completers, using linear mixed model (LMM) analysis. Sensitivity analyses of primary and secondary end points included LMM using all subject data and mixed model repeated measures (MMRM) of change from baseline at each year. Pearson correlation tested the association between log-TKV and eGFR changes. Results Fifty-one subjects (81%) completed 3 years of tolvaptan therapy; all experienced adverse events (AEs), with AEs accounting for six of 12 withdrawals. Baseline TKV (controls 1422, tolvaptan 1635 ml) and eGFR (both 62 ml/min per 1.73 m2) were similar. Control TKV increased 5.8% versus 1.7%/yr for tolvaptan (P < 0.001, estimated ratio of geometric mean 0.96 [95% confidence interval 0.95 to 0.97]). Corresponding annualized eGFR declined: ?2.1 versus ?0.71 ml/min per 1.73 m2/yr (P = 0.01, LMM group difference 1.1 ml/min per 1.73 m2/yr [95% confidence interval 0.24 to 1.9]). Sensitivity analyses including withdrawn subjects were similar, whereas MMRM analyses were significant at each year for TKV and nonsignificant for eGFR. Increasing TKV correlated with decreasing eGFR (r = ?0.21, P < 0.01). Conclusion ADPKD cyst growth progresses more slowly with tolvaptan than in historical controls, but AEs are common.

Higashihara, Eiji; Chapman, Arlene B.; Grantham, Jared J.; Bae, Kyongtae; Watnick, Terry J.; Horie, Shigeo; Nutahara, Kikuo; Ouyang, John; Krasa, Holly B.; Czerwiec, Frank S.

2011-01-01

82

Pseudoxanthoma Elasticum: the End of the Autosomal Dominant Segregation Myth  

Microsoft Academic Search

Pseudoxanthoma elasticum (PXE) is a heritable connective-tissue disorder affecting the eye, skin, and vascular system. Recent publications show that PXE exclusively segregates in an autosomal recessive fashion. However, the lack of an internationally accepted clinical “gold standard” for PXE, our incomplete knowledge of PXE etiology, and the incomplete nature of some molecular, clinical, and environmental studies warrant further investigation.

Arthur A B Bergen

2006-01-01

83

Two Iranian Families with a Novel Mutation in GJB2 Causing Autosomal Dominant Nonsyndromic Hearing Loss  

PubMed Central

Mutations in GJB2, encoding connexin 26 (Cx26), cause both autosomal dominant and autosomal recessive nonsyndromic hearing loss at the DFNA3 and DFNB1 loci, respectively. Most of the over 100 described GJB2 mutations cause autosomal recessive nonsyndromic hearing loss. Only a minority has been associated with autosomal dominant hearing loss. In this study, we present two families with autosomal dominant nonsyndromic hearing loss caused by a novel mutation in GJB2 (p.Asp46Asn). Both families were ascertained from the same village in northern Iran consistent with a founder effect. This finding implicates the D46N missense mutation in Cx26 as a common cause of deafness in this part of Iran mandating mutation screening of GJB2 for D46N in all persons with hearing loss who originate from this geographic region.

Bazazzadegan, Niloofar; Sheffield, Abraham M.; Sobhani, Masoomeh; Kahrizi, Kimia; Meyer, Nicole C; Van Camp, Guy; Hilgert, Nele; Abedini, Seyedeh Sedigheh; Habibi, Farkhondeh; Daneshi, Ahmad; Nishimura, Carla; Avenarius, Matthew R.; Farhadi, Mohammad; Smith, Richard J.H.; Najmabadi, Hossein

2009-01-01

84

Scanning Electron Microscopy of Teeth in Autosomal Dominant Osteogenesis Imperfecta: Support for Genetic Heterogeneity.  

National Technical Information Service (NTIS)

SEM studies were performed on 25 deciduous and permanent teeth from members of seven kindreds with autosomal dominant osteogenesis imperfecta (O.I.). Two families had normal teeth on clinical and radiological examination; five families had blue or brown o...

J. M. Brady L. S. Levin M. Melnick

1979-01-01

85

New Therapeutic Strategy for Autosomal Dominant Polycystic Kidney Disease: Activation of AMP Kinase by Metformin.  

National Technical Information Service (NTIS)

Autosomal dominant polycystic kidney disease is a common inherited disorder. Patients are born with normal kidneys but, over the course of decades, they develop large fluid filled cysts that damage the normal kidney tissue. The damage caused by these cyst...

M. J. Caplan

2011-01-01

86

Autosomal dominant polycystic kidney disease with congenital absence of contralateral kidney  

Microsoft Academic Search

Autosomal dominant polycystic kidney disease is the most frequent hereditary kidney disorder, accounting for 8–10% of the\\u000a cases of end-stage renal disease. It is characterized by bilateral multiple renal cysts, nevertheless, asymmetric enlargement\\u000a of the kidneys is frequently observed, and this can lead to diagnostic confusion. We report the rare occurrence of autosomal\\u000a dominant polycystic disease confined to a right

A. E. Sirvent; R. Enríquez; F. Ardoy; F. Amorós; C. González; A. Reyes

2006-01-01

87

Synthesis of renin by tubulocystic epithelium in autosomal-dominant polycystic kidney disease  

Microsoft Academic Search

Synthesis of renin by tubulocystic epithelium in autosomal-dominant polycystic kidney disease. Evidence suggests an important role for the renin-angiotensin system in the pathogenesis of autosomal-dominant polycystic kidney disease (ADPKD). Therefore, we studied the presence of immunoreactive renin in renal biopsies and measured the concentrations of renin in cyst fluids. Normal kidneys and kidneys with renal artery stenosis were used for

Vicente E Torres; Kathleen A Donovan; Gloria Scicli; Keith E Holley; Stephen N Thibodeau; Oscar A Carretero; Tadashi Inagami; James A McAteer; Christopher M Johnson

1992-01-01

88

Epidemiological study of kidney survival in autosomal dominant polycystic kidney disease  

Microsoft Academic Search

Epidemiological study of kidney survival in autosomal dominant polycystic kidney disease.BackgroundIt is unknown whether the substantial increase in research, identification of risk factors for renal progression, greater antihypertensive armamentarium including inhibitors of the renin-angiotensin-aldosterone system (RAAS) and enhanced educational information have impacted the progression of autosomal dominant polycystic kidney disease (ADPKD) renal disease.MethodsAn epidemiological study involving 513 ADPKD subjects was

Robert W Schrier; Kimberly K McFann; Ann M Johnson

2003-01-01

89

Seven novel mutations of the PKD2 gene in families with autosomal dominant polycystic kidney disease  

Microsoft Academic Search

Seven novel mutations of thePKD2gene in families with autosomal dominant polycystic kidney disease.BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is genetically heterogeneous, with at least three chromosomal loci accounting for the disease. Mutations in the PKD2 gene on the long arm of chromosome 4 are expected to be responsible for approximately 15% of cases of ADPKD.MethodsWe report a systematic screening for

Roser Torra; Miguel Viribay; Dolores Tellería; Cèlia Badenas; Michael Watson; Peter Harris; Alejandro Darnell; José L San Millán

1999-01-01

90

Autosomal-dominant polycystic kidney disease as a risk factor for diabetes mellitus following renal transplantation  

Microsoft Academic Search

Autosomal-dominant polycystic kidney disease as a risk factor for diabetes mellitus following renal transplantation.BackgroundPosttransplant diabetes mellitus is an important complication of renal transplantation that is associated with a significant impact on quality of life and an increase in long-term morbidity and mortality. Autosomal-dominant polycystic kidney disease (ADPKD) is a hereditary disease that commonly leads to end-stage renal disease (ESRD) in

Angelo M. de Mattos; Ali J. Olyaei; Jonathan C. Prather; Muralikrishna S. Golconda; John M. Barry; Douglas J. Norman

2005-01-01

91

Is there evidence for anticipation in autosomal-dominant polycystic kidney disease?  

Microsoft Academic Search

Is there evidence for anticipation in autosomal-dominant polycystic kidney disease? The heritability of autosomal-dominant polycystic kidney disease (ADPKD) is marked by an apparent high mutation rate, neonatal onset of disease in some patients and intrafamily variability. These findings raise the possibility of genetic anticipation in ADPKD as has been observed in fragile-X syndrome, myotonic dystrophy and Huntington's disease. We reviewed

Godela M Fick; Ann M Johnson; Patricia A Gabow

1994-01-01

92

Randomized Clinical Trial of Long-Acting Somatostatin for Autosomal Dominant Polycystic Kidney and Liver Disease  

Microsoft Academic Search

There are no proven, effective therapies for polycystic kidney disease (PKD) or polycystic liver disease (PLD). We enrolled 42 patients with severe PLD resulting from autosomal dominant PKD (ADPKD) or autosomal dominant PLD (ADPLD) in a randomized, double-blind, placebo-controlled trial of octreotide, a long-acting somatostatin analogue. We randomly assigned 42 patients in a 2:1 ratio to octreotide LAR depot (up

Marie C. Hogan; Tetyana V. Masyuk; Linda J. Page; Vickie J. Kubly; Eric J. Bergstralh; Xujian Li; Bohyun Kim; Bernard F. King; James Glockner; David R. Holmes; Sandro Rossetti; Peter C. Harris; Nicholas F. LaRusso; Vicente E. Torres

2010-01-01

93

An 11-Year-Old Child with Autosomal Dominant Polycystic Kidney Disease Who Presented with Nephrolithiasis  

PubMed Central

Patients with autosomal dominant polycystic kidney disease become symptomatic and are diagnosed usually at adulthood. The rate of nephrolithiasis in these patients is 5–10 times the rate in the general population, and both anatomic and metabolic abnormalities play role in the formation of renal stones. However, nephrolithiasis is rare in childhood age group. In this paper, an 11-year-old child with autosomal dominant polycystic kidney disease presenting with nephrolithiasis is discussed.

Firinci, Fatih; Soylu, Alper; Kasap Demir, Belde; Turkmen, Mehmet; Kavukcu, Salih

2012-01-01

94

Follow-up of intracranial aneurysms in autosomal-dominant polycystic kidney disease  

Microsoft Academic Search

Follow-up of intracranial aneurysms in autosomal-dominant polycystic kidney disease.BackgroundApproximately 8% of autosomal-dominant polycystic kidney disease (ADPKD) patients have intracranial aneurysms. The risk of growth and rupture of those discovered by presymptomatic screening is key to the feasibility and success of a screening program. This study was initiated to ascertain this risk.MethodsADPKD patients were offered screening with magnetic resonance (MR) imaging

Gordon F. Gibbs; John Huston; Qi Qian; Vickie Kubly; Peter C. Harris; Robert D. Brown; Vicente E. Torres

2004-01-01

95

Autosomal-dominant familial hematuria with retinal arteriolar tortuosity and contractures: A novel syndrome  

Microsoft Academic Search

Autosomal-dominant familial hematuria with retinal arteriolar tortuosity and contractures: A novel syndrome.BackgroundAutosomal-dominant forms of hematuria have been mostly related to mutations in the COL4A3\\/COL4A4 genes. Patients with thin basement membrane (BM) disease do not have extrarenal manifestations, while those with Alport syndrome often present with hearing loss, anterior lenticonus, and dot-and-fleck retinopathy.MethodsWe performed a phenotypic study and a candidate gene

EMMANUELLE PLAISIER; SONIA ALAMOWITCH; OLIVIER GRIBOUVAL; BÉATRICE MOUGENOT; ALAIN GAUDRIC; CORINNE ANTIGNAC; ETIENNE ROULLET; PIERRE RONCO

2005-01-01

96

A gene for autosomal dominant congenital nystagmus localizes to 6p12  

SciTech Connect

Congenital nystagmus is an idiopathic disorder characterized by bilateral ocular oscillations usually manifest during infancy. Vision is typically decreased due to slippage of images across the fovea. As such, visual acuity correlates with nystagmus intensity, which is the amplitude and frequency of eye movements at a given position of gaze. X-linked, autosomal dominant, and autosomal recessive pedigrees have been described, but no mapping studies have been published. We recently described a large pedigree with autosomal dominant congenital nystagmus. A genome-wide search resulted in six markers on 6p linked by two-point analysis at {theta} = 0 (D6S459, D6S452, D6S465, FTHP1, D6S257, D6S430). Haplotype analysis localizes the gene for autosomal dominant congenital motor mystagmus to an 18-cM region between D6S271 and D6S455. 16 refs., 1 fig., 1 tab.

Kerrison, J.B.; Arnould, V.J.; Koenekoop, R.K. [Johns Hopkins Hospital, Baltimore, MD (United States)] [and others

1996-05-01

97

An operated case of Holt-Oram syndrome with autosomal dominant inheritance  

Microsoft Academic Search

Summary This report is concerned with a patient successfully operated forHolt-Oram syndrome. The disorder is inherited dominantly with complete penetrance and variable expressivity. It is pointed out that in cases of congenital heart disease familial cumulation must be borne in mind which can easily be verified by pedigree investigation. After demonstrating autosomal dominant inheritance, suitable inferences must be drawn for

Z. Czakó; A. Gömöry; P. Homolay; S. Bacsa; S. Kiss; F. Móricz; F. Fülöp; Z. Papp

1976-01-01

98

Autosomal Dominant Hypoparathyroidism Associated with Short Stature and Premature Osteoarthritis  

Microsoft Academic Search

Familial hypoparathyroidism is an unusual and genetically het- erogeneous group of disorders that may be isolated or may be asso- ciated with congenital or acquired abnormalities in other organs or glands. We have evaluated a family with a novel syndrome of auto- somal dominant hypoparathyroidism, short stature, and premature osteoarthritis. A 74-yr-old female (generation I) presented with hypoparathyroid- ism, a

JOHN L. STOCK; ROSALIND S. BROWN; JEFFREY BARON; JAMES A. CODERRE; EDNA MANCILLA; FRANCESCO DE LUCA; KAUSIK RAY; MARIA VERONICA MERICQ

99

Mutations of the LMNA gene can mimic autosomal dominant proximal spinal muscular atrophy  

Microsoft Academic Search

The molecular basis of autosomal dominant spinal muscular atrophy (AD-SMA) is largely unknown. Because the phenotypic spectrum\\u000a of diseases caused by LMNA mutations is extremely broad and includes myopathies, neuropathies, and cardiomyopathies designated as class 1 laminopathies,\\u000a we sequenced the LMNA gene in index patients with the clinical picture of proximal SMA, who had a family history suggestive of autosomal

Sabine Rudnik-Schöneborn; Elke Botzenhart; Thomas Eggermann; Jan Senderek; Benedikt G. H. Schoser; Rolf Schröder; Manfred Wehnert; Brunhilde Wirth; Klaus Zerres

2007-01-01

100

Fibrosis and progression of autosomal dominant polycystic kidney disease (ADPKD).  

PubMed

The age on onset of decline in renal function and end-stage renal disease (ESRD) in autosomal polycystic kidney disease (ADPKD) is highly variable and there are currently no prognostic tools to identify patients who will progress rapidly to ESRD. In ADPKD, expansion of cysts and loss of renal function are associated with progressive fibrosis. Similar to the correlation between tubulointerstitial fibrosis and progression of chronic kidney disease (CKD), in ADPKD, fibrosis has been identified as the most significant manifestation associated with an increased rate of progression to ESRD. Fibrosis in CKD has been studied extensively. In contrast, little is known about the mechanisms underlying progressive scarring in ADPKD although some commonality may be anticipated. Current data suggest that fibrosis associated with ADPKD shares at least some of the "classical" features of fibrosis in CKD (increased interstitial collagens, changes in matrix metalloproteinases (MMPs), over-expression of tissue inhibitor of metalloproteinase-1 (TIMP-1), over-expression of plasminogen activator inhibitor-1 (PAI-1) and increased transforming growth factor beta (TGF?) but that there are also some unique and stage-specific features. Epithelial changes appear to precede and to drive interstitial changes leading to the proposal that development of fibrosis in ADPKD is biphasic with alterations in cystic epithelia precipitating changes in interstitial fibroblasts and that reciprocal interactions between these cell types drives progressive accumulation of extracellular matrix (ECM). Since fibrosis is a major component of ADPKD it follows that preventing or slowing fibrosis should retard disease progression with obvious therapeutic benefits. The development of effective anti-fibrotic strategies in ADPKD is dependent on understanding the precise mechanisms underlying initiation and progression of fibrosis in ADPKD and the role of the intrinsic genetic defect in these processes. This article is part of a Special Issue entitled: Polycystic Kidney Disease. PMID:21745567

Norman, Jill

2011-07-01

101

Fibrosis and progression of Autosomal Dominant Polycystic Kidney Disease (ADPKD)  

PubMed Central

The age on onset of decline in renal function and end-stage renal disease (ESRD) in autosomal polycystic kidney disease (ADPKD) is highly variable and there are currently no prognostic tools to identify patients who will progress rapidly to ESRD. In ADPKD, expansion of cysts and loss of renal function is associated with progressive fibrosis. Similar to the correlation between tubulointerstitial fibrosis and progression of CKD, in ADPKD, fibrosis has been identified as the most significant manifestation associated with an increased rate of progression to ESRD. Fibrosis in CKD has been studied extensively. In contrast, little is known about the mechanisms underlying progressive scarring in ADPKD although some commonality may be anticipated. Current data suggest that fibrosis associated with ADPKD shares at least some of the “classical” features of fibrosis in CKD (increased interstitial collagens, changes in MMPs, over-expression of TIMP-1, over-expression of PAI-1 and increased TGF?) but that there are also some unique and stage-specific features. Epithelial changes appear to precede and to drive interstitial changes leading to the proposal that development of fibrosis in ADPKD is biphasic with alterations in cystic epithelia precipitating changes in interstitial fibroblasts and that reciprocal interactions between these cell types drives progressive accumulation of ECM. Since fibrosis is a major component of ADPKD it follows that preventing or slowing fibrosis should retard disease progression with obvious therapeutic benefits. The development of effective anti-fibrotic strategies in ADPKD is dependent on understanding the precise mechanisms underlying initiation and progression of fibrosis in ADPKD and the role of the intrinsic genetic defect in these processes.

Norman, Jill

2011-01-01

102

Autosomal dominant nocturnal frontal lobe epilepsy: demonstration of focal frontal onset and intrafamilial variation.  

PubMed

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a newly recognized autosomal dominant partial epilepsy. We studied seizure localization and intrafamilial variation using video-EEG monitoring (VEM) and functional neuroimaging in two pairs of subjects from unrelated families. The clinical features of seizures were similar from seizure to seizure in each individual, but varied between individuals. As is often found in frontal lobe epilepsies, ictal EEG localization was imprecise in three of four cases. One patient showed a consistent left fronto-polar onset that was corroborated by congruent focal hypometabolism on interictal PET and focal hyperperfusion on ictal single photon emission computed tomography (SPECT). A second case studied with ictal SPECT showed a right parasagittal, midfrontal focus. We conclude that this autosomal dominant epilepsy syndrome, which in one of the two families was due to a known neuronal nicotinic acetylcholine receptor mutation, causes frontal lobe foci that are unilateral and in variable locations in different individuals. PMID:9339675

Hayman, M; Scheffer, I E; Chinvarun, Y; Berlangieri, S U; Berkovic, S F

1997-10-01

103

[Hypo-/aplasia of the nasal bones--an autosomal dominant inherited anomaly].  

PubMed

We report a family with isolated hypo- or aplasia of the nasal bones as an autosomal dominant trait. The conspicuous shape of the nose resembled that of "potato nose". This anomaly is caused by a specific developmental field defect of the medial nasal processes with no genetic relation to frontonasal "dysplasia". The minimal intrafamilial variation suggests a monogenic trait with an autosomal dominant mode of transmission. For the ENT practitioner it may be added that patients with hypo- or aplasia need no treatment unless a septal deviation causes nasal obstruction. PMID:3692934

Ernst, M; Schilbach, U

1987-11-01

104

Evidence of autosomal dominant mutations in childhood-onset proximal spinal muscular atrophy  

SciTech Connect

Autosomal recessive and dominant inheritance of proximal spinal muscular atrophy (SMA) are well documented. Several genetic studies found a significant deviation from the assumption of recessive inheritance in SMA, with affected children in one generation. The existence of new autosomal dominant mutations has been assumed as the most suitable explanation, which is supported by three observations of this study: (1) The segregation ratio calculated in 333 families showed a significant deviation from autosomal recessive inheritance in the milder forms of SMA (= .09[+-].06 for onset at 10-36 mo and .13[+-].07 for onset at >36 mo; and P = .09[+-]0.7 for SMA IIIa and .12[+-].07 for SMA IIIb). (2) Three families with affected subjects in two generations are reported, in whom the disease could have started as an autosomal dominant mutation. (3) Linkage studies with chromosome 5q markers showed that in 5 (5.4%) of 93 informative families the patient shared identical haplotypes with at least one healthy sib. Other mechanisms, such as the existence of phenocopies, pseudodominance, or a second autosomal recessive gene locus, cannot be excluded in single families. The postulation of spontaneous mutations, however, is a suitable explanation for all three observations. Estimated risk figures for genetic counseling are given. 29 refs., 2 figs., 5 tabs.

Rudnik-Schoeneborn, S.; Wirth, B.; Zerres, K. (Univ. of Bonn (Germany))

1994-07-01

105

Autosomal dominant epidermodysplasia verruciformis lacking a known EVER1 or EVER2 mutation  

PubMed Central

Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by abnormal susceptibility to infection with specific human papillomavirus (HPV) serotypes. EV is a genetically heterogeneous disease, and autosomal recessive and X-linked inheritance patterns have been reported. Nonsense mutations in the genes EVER1 and EVER2 have been identified in over 75% of cases. We present EV in a father and son with typical histologic and clinical findings that occur in the absence of mutations in EVER1 or EVER2. EV in this father/son pair in a non-consanguinous pedigree is consistent with autosomal dominant inheritance. This is the first report of autosomal dominant transmission of EV, providing further evidence of the genetic heterogeneity of EV.

McDermott, David H.; Gammon, Bryan; Snijders, Peter J.; Mbata, Ihunanya; Phifer, Beth; Hartley, A. Howland; Lee, Chyi-Chia Richard; Murphy, Philip M.; Hwang, Sam T.

2012-01-01

106

Autosomal recessive polycystic kidney disease does not map to the second gene locus for autosomal dominant polycystic kidney disease on chromosome 4  

Microsoft Academic Search

Linkage analysis in 19 families with autosomal recessive polycystic kidney disease (ARPKD) has shown that ARPKD is not linked to the recently assigned second gene locus for autosomal dominant polycystic kidney disease (ADPKD) on chromosome 4q (PKD2). Thus, there is strong evidence that ADPKD and ARPKD have different gene loci.

Klaus Zerres; Gabi Miicher; Sabine Rudnik-Schöneborn

1994-01-01

107

CAG repeat expansion in the TATA box-binding protein gene causes autosomal dominant cerebellar ataxia  

Microsoft Academic Search

Summary At least 13 loci responsible for autosomal dominant cerebellar ataxia (ADCA) have been identified. Spinocerebellar ataxia 1, 2, 3, 6 and 7 are caused by translated CAG repeat expansions. However, in France, >30% of ADCAs are not explained by the known genes. Recently, analysis of the TATA box-binding protein (TBP) gene, one of the transcription factors known to contain

Hiroto Fujigasaki; Jean-Jacques Martin; Peter Paul De Deyn; Agnes Camuzat; Didier Deffond; Giovanni Stevanin; Bart Dermaut; Christine Van Broeckhoven; Alexandra Durr; Alexis Brice

2001-01-01

108

Neuronal nicotinic acetylcholine receptors and autosomal dominant nocturnal frontal lobe epilepsy: a critical review  

Microsoft Academic Search

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a distinct human epileptic syndrome. In some families, it is associated with mutations of the Ŏ or the Š subunit of the neuronal nicotinic acetylcholine receptor (nAChR). It has been suggested that these mutations are the causative factors responsible for the induction and expression of this syndrome. However, the pathogenic mechanisms leading

Bernd Sutor; Gerd Zolles

2001-01-01

109

Familial congenital hydrocephalus and aqueduct stenosis with probably autosomal dominant inheritance and variable expression  

Microsoft Academic Search

A kindred is reported on with suspected autosomal dominant congenital hydrocephalus and aqueduct stenosis. In contrast to patients with X-linked congenital hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS) our patients were not mentally retarded and they did not show any pyramidal tract dysfunction or clasped thumbs; the pyramids were not affected either, as was confirmed by autopsy, CT

Wim I. M Verhagen; Ronald H. A. M Bartels; Erik Fransen; Guy van Camp; Willy O Renier; J. André Grotenhuis

1998-01-01

110

Laparoscopic nephrectomy in patients with end-stage renal disease and autosomal dominant polycystic kidney disease  

Microsoft Academic Search

Autosomal dominant polycystic kidney disease (ADPKD) is often characterized by end-stage renal disease (ESRD) and problems including pain, hematuria, and infection. Open nephrectomy is curative; however, the morbidity of the procedure is considerable. Between 1995 and 1998, 11 laparoscopic nephrectomies were performed on nine symptomatic patients (five men and four women) with ESRD and ADPKD. Two patients underwent a staged

Matthew D. Dunn; Andrew J. Portis; Abdelhamid M. Elbahnasy; Arieh L. Shalhav; Marcos Rothstein; Elspeth M. McDougall; Ralph V. Clayman

2000-01-01

111

The Molecular Basis of Focal Cyst Formation in Human Autosomal Dominant Polycystic Kidney Disease Type I  

Microsoft Academic Search

Autosomal dominant polycystic kidney disease (ADPKD) is a common disease and an important cause of renal failure. It is characterized by considerable intrafamilial phenotypic variation and focal cyst formation. To elucidate the molecular basis for these observations, we have developed a novel method for isolating renal cystic epithelia from single cysts and have used it to show that individual renal

Feng Qian; Terry J Watnick; Luiz F Onuchic; Gregory G Germino

1996-01-01

112

Evidence for a third genetic locus for autosomal dominant polycystic kidney disease  

Microsoft Academic Search

Autosomal dominant polycystic kidney disease (ADPKD) is a genetically heterogeneous disease with loci on chromosomes 16p and 4q. It has a moderately high spontaneous mutation rate, although the relative frequency of such mutations at each gene locus is unknown. In studying genetic heterogeneity in the French-Canadian population, we identified a family in which a classical clinical presentation of ADPKD resulted

Martin C. Daoust; David M. Reynolds; Daniel G. Bichet; Stefan Somlo

1995-01-01

113

Familial Paroxysmal Exercise-Induced Dystonia: Atypical Presentation of Autosomal Dominant GTP-Cyclohydrolase 1 Deficiency  

ERIC Educational Resources Information Center

|Paroxysmal exercise-induced dystonia (PED) is one of the rarer forms of paroxysmal dyskinesia, and can occur in sporadic or familial forms. We report a family (male index case, mother and maternal grandfather) with autosomal dominant inheritance of paroxysmal exercise-induced dystonia. The dystonia began in childhood and was only ever induced…

Dale, Russell C.; Melchers, Anna; Fung, Victor S. C.; Grattan-Smith, Padraic; Houlden, Henry; Earl, John

2010-01-01

114

Autosomal Dominant Retinitis Pigmentosa in a Large Family: A Clinical and Molecular Genetic Study  

Microsoft Academic Search

Purpose. To characterize the pedigree, visual function phenotype, and responsible mutation in a large family with autosomal dominant retinitis pigmentosa. Methods. Pedigree data were obtained by personal interviews and corroborated with commu- nity records. One hundred twenty-eight members of the family were examined clinically, and a subset of 12 affected subjects was further studied with dark- and light-adapted static perimetry

Delia J. Rosas; Jennifer P. Macke; Jeremy Nathans

1994-01-01

115

Genetics and phenotypic characteristics of autosomal dominant polycystic kidney disease in Finns  

Microsoft Academic Search

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease, leading to renal insufficiency and renal transplantation. Mutation screening in the major gene for ADPKD, the polycystic kidney disease type 1 (PKD1) gene, has often been incomplete because of multiple homologous copies of this gene elsewhere on chromosome 16. Furthermore, there are only a few studies investigating

Paula Peltola; Anne Lumiaho; Raija Miettinen; Jussi Pihlajamäki; Richard Sandford; Markku Laakso

2005-01-01

116

Molecular diagnostics in autosomal dominant polycystic kidney disease: Utility and limitations  

Microsoft Academic Search

Background and objectives: Gene-based mutation screening is now available and has the potential to provide diagnostic confirmation or exclusion of autosomal dominant polycystic kidney disease. This study illustrates its utility and limitations in the clinical setting. Design, setting, participants, & measurements: Using a molecular diagnostic service, genomic DNA of one affected individual from each study family was screened for pathologic

Xiao Zhao; Andrew D. Paterson; Alireza Zahirieh; Ning He; Kairong Wang; York Pei; Rachel Karchin

2008-01-01

117

A ‘two-hit’ model of cystogenesis in autosomal dominant polycystic kidney disease?  

Microsoft Academic Search

An intriguing feature of autosomal dominant polycystic kidney disease (ADPKD) is the focal and sporadic nature of individual cyst formation. Typically, only a few renal cysts are detectable in an affected individual during the first two decades of life. By the fifth decade, however, hundreds to thousands of renal cysts can be found in most patients. Additionally, significant intra-familial variability

York Pei

2001-01-01

118

Detection of autosomal dominant polycystic kidney disease by NMR spectroscopic fingerprinting of urine  

Microsoft Academic Search

Autosomal dominant polycystic kidney disease (ADPKD) is a frequent cause of kidney failure; however, urinary biomarkers for the disease are lacking. In a step towards identifying such markers, we used multidimensional-multinuclear nuclear magnetic resonance (NMR) spectroscopy with support vector machine-based classification and analyzed urine specimens of 54 patients with ADPKD and slightly reduced estimated glomerular filtration rates. Within this cohort,

Wolfram Gronwald; Matthias Klein; Raoul Zeltner; Bernd-Detlef Schulze; Stephan W Reinhold; Markus Deutschmann; Ann-Kathrin Immervoll; Carsten A Böger; Bernhard Banas; Kai-Uwe Eckardt; Peter J Oefner

2011-01-01

119

Volume Progression in Autosomal Dominant Polycystic Kidney Disease: The Major Factor Determining Clinical Outcomes  

Microsoft Academic Search

Autosomal dominant polycystic kidney disease (PKD) is a hereditary condition characterized by the progressive enlargement of innumerable renal cysts that contribute to life-altering morbidity early in the course of the disease. Evidence indicates that the rate of increase in kidney volume can be reliably measured by magnetic resonance or computed tomography imaging, thus providing objective means to judge the effectiveness

Jared J. Grantham; Arlene B. Chapman; Vicente E. Torres

2006-01-01

120

Cystic fibrosis and the phenotypic expression of autosomal dominant polycystic kidney disease  

Microsoft Academic Search

Recent experiments in cultured cyst epithelial cells from kidneys of patients with autosomal dominant polycystic kidney disease (ADPKD) have shown that the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) is present in the apical surface of these cells and mediates chloride (Cl-) and fluid secretion in vitro. To determine whether the presence of CF with the expression of mutated CFTR

DA O'Sullivan; VE Torres; PA Gabow; SN Thibodeau; BF King; EJ Bergstralh

1998-01-01

121

Olfactory Identification Deficits in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy  

Microsoft Academic Search

Background\\/Aims: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited angiopathy caused by mutations of the Notch 3 gene. Olfactory identification deficits are present in a number of neurodegenerative disorders. However, olfaction has not been investigated in CADASIL. The aim of the present study was to assess olfactory identification in CADASIL and to determine whether there

Jung Seok Lee; Jay Chol Choi; Sa-Yoon Kang; Ji-Hoon Kang; Sang Hun Lee; Jeong Hong Kim; SangYun Kim

2010-01-01

122

Familial Paroxysmal Exercise-Induced Dystonia: Atypical Presentation of Autosomal Dominant GTP-Cyclohydrolase 1 Deficiency  

ERIC Educational Resources Information Center

Paroxysmal exercise-induced dystonia (PED) is one of the rarer forms of paroxysmal dyskinesia, and can occur in sporadic or familial forms. We report a family (male index case, mother and maternal grandfather) with autosomal dominant inheritance of paroxysmal exercise-induced dystonia. The dystonia began in childhood and was only ever induced…

Dale, Russell C.; Melchers, Anna; Fung, Victor S. C.; Grattan-Smith, Padraic; Houlden, Henry; Earl, John

2010-01-01

123

SETX gene mutation in a family diagnosed autosomal dominant proximal spinal muscular atrophy  

Microsoft Academic Search

Autosomal dominant proximal spinal muscular atrophy (ADSMA) is a rare disorder with unknown gene defects in the majority of families. Here we describe a family where the diagnosis of juvenile and adult onset ADSMA was made in three individuals. Because of retained tendon reflexes an atypical course of juvenile amyotrophic lateral sclerosis (ALS4) was considered. SETX gene sequencing revealed the

Sabine Rudnik-Schöneborn; Larissa Arning; Jörg T. Epplen; Klaus Zerres

124

Familial clustering of ruptured intracranial aneurysms in autosomal dominant polycystic kidney disease  

Microsoft Academic Search

Ruptured intracranial aneurysm (RICA) is a life-threatening complication of autosomal dominant polycystic kidney disease (ADPKD). A family history of RICA may be a risk factor for RICA. Six hundred eight adult members of 199 ADPKD families were interviewed, and family pedigrees were constructed. Individuals were classified as having definite, probable, or possible RICAs from evidence and history obtained in interviews.

Mark M. Belz; Richard L. Hughes; William D. Kaehny; Ann M. Johnson; Godela M. Fick-Brosnahan; Michael P. Earnest; Patricia A. Gabow

2001-01-01

125

Autosomal Dominant Polycystic Kidney Disease: New Treatment Options and How to Test Their Efficacy  

Microsoft Academic Search

Autosomal dominant polycystic kidney disease (ADPKD) represents a slowly progressing cystic kidney disorder which evolves into end-stage renal disease in the majority of patients. Currently, there are no established treatments to retard the progression of the disease, but several promising therapeutic options are being tested in ongoing clinical trials. An inherent dilemma for the investigation of therapies in ADPKD is

Rudolf P. Wüthrich; Andreas L. Serra; Andreas D. Kistler

2009-01-01

126

X-linked adrenoleukodystrophy presenting as autosomal dominant pure hereditary spastic paraparesis  

Microsoft Academic Search

We present a family in which an initial clinical diagnosis of autosomal dominant pure hereditary spastic paraparesis (HSP) was made on the basis of a three generation pedigree in which both males and females presented with a spastic paraparesis. Subsequent biochemical and genetic analysis revealed that the family was in fact affected by the adrenomyeloneuropathy subtype of X-linked adrenoleukodystrophy. In

C J Shaw-Smith; S J G Lewis; E Reid

2004-01-01

127

Secretion of cytokines and growth factors into autosomal dominant polycystic kidney disease liver cyst fluid  

Microsoft Academic Search

The principal extrarenal manifestation of autosomal dominant polycystic kidney disease (ADPKD) involves formation of liver cysts derived from intrahepatic bile ducts. Autocrine and paracrine factors secreted into the cyst would be positioned to modulate the rate of hepatic cyst growth. The aim of this study was to identify potential growth factors present in human ADPKD liver cyst fluid. Cytokine array

Matthew T. Nichols; Elsa Gidey; Tom Matzakos; Rolf Dahl; Greg Stiegmann; Raj J. Shah; Jared J. Grantham; J. Gregory Fitz; R. Brian

2004-01-01

128

Spontaneous vertebral artery dissection as a complication of autosomal dominant polycystic kidney disease  

Microsoft Academic Search

Autosomal dominant polycystic kidney disease (ADPKD) may be associated with a variety of cardiovascular complications, including intracranial saccular aneurysms. In ADPKD, intracranial saccular aneurysms tend to rupture more frequently and earlier than the sporadic variety with a tendency to cluster in families. In contrast, dissecting intracranial aneurysms are rarely associated with either intracranial saccular aneurysms or ADPKD. We describe an

Jorge Larranaga; Gregory W. Rutecki; Frederick C. Whittier

1995-01-01

129

Cortical bone remodeling in autosomal dominant osteopetrosis: A study of two different phenotypes  

Microsoft Academic Search

Previous analyses of cancellous bone remodeling in autosomal dominant osteopetrosis (ADO) have suggested a diminished osteoclastic resorption at the endocortical surface. Consequently, cortical width increases with age in both ADO type I and II. By means of histomorphometric methods, the remodeling cycle of the Haversian surface in the iliac crest has recently been reconstructed in normal individuals. The aim of

H. Brockstedt; J. Bollerslev; F. Melsen; L. Mosekilde

1996-01-01

130

Rapamycin Inhibits Cystogenesis by Cystic Epithelial Cells Derived from Human Autosomal Dominant Polycystic Kidneys  

Microsoft Academic Search

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common genetic disorders and carries a high health burden since it progresses to renal failure in half of the afflicted individuals by the 6 th decade of life. Currently, there is no effective treatment to slow the progression of ADPKD. Rapamycin, a drug most commonly used as an immunosuppressive

Gerard Elberg; Teresa V. Lewis; Lijuan Chen; Martin A. Turman

2006-01-01

131

Autosomal dominant pure spastic paraplegia: a clinical, paraclinical, and genetic study  

Microsoft Academic Search

OBJECTIVESAt least three clinically indistinguishable but genetically different types of autosomal dominant pure spastic paraplegia (ADPSP) have been described. In this study the clinical, genetic, neurophysiological, and MRI characteristics of ADPSP were investigated.METHODSSixty three at risk members from five families were clinically evaluated. A diagnostic index was constructed for the study. Microsatellite genotypes were determined for chromosomes 2p, 14q, and

J E Nielsen; K Krabbe; P Jennum; P Koefoed; L Neerup Jensen; K Fenger; H Eiberg; L Hasholt; L Werdelin; S A Sørensen

1998-01-01

132

Autosomal dominant polycystic kidney disease with anticipation and Caroli's disease associated with a PKD1 mutation Rapid Communication  

Microsoft Academic Search

Autosomal dominant polycystic kidney disease with anticipation and Caroli's disease associated with a PKD1 mutation. Autosomal dominant polycystic kidney disease (ADPKD) is the most common renal hereditary disorder. Clinical expression of ADPKD shows interfamilial and intrafamilial variability. We screened for mutations the 3? region of the PKD1 gene, from exon 43 to exon 46, in a family showing anticipation and

Roser Torra; Cèlia Badenas; Alejandro Darnell; Concepció Brú; Angels Escorsell; Xavier Estivill; Dra Roser Torra

1997-01-01

133

Evaluation of candidate genes for familial brachydactyly  

Microsoft Academic Search

Type A1 brachydactyly in humans is a recognisable syndrome characterised by shortening of the middle phalanx of all digits with occasional fusion of the middle and terminal phalanges. The purpose of this study was to evaluate candidate genes for type A1 brachydactyly in two families with multiple affected members. Several classes of genes have been implicated in the control of

J M Mastrobattista; P Dollé; S H Blanton; H Northrup

1995-01-01

134

Localization of a gene for autosomal dominant amelogenesis imperfecta (ADAI) to chromosome 4q  

SciTech Connect

Amelogenesis imperfecta (AI), a disorder affecting the formation of enamel, is significantly more common in Northern Sweden than in other parts of the world. The disease is genetically and clinically heterogenous, and autosomal dominant, autosomal recessive and X-linked inheritance patterns have been recognized. Linkage analysis has identified two different loci for X-linked AI, one of which is identical to the gene encoding the enamel protein amelogenin. However, in families with an autosomal inheritance pattern for AI, the genetic basis of the disease still remains unknown. We report a linkage analysis study performed on three Swedish families where the affected members had an autosomal dominant variant of AI (ADAI) clinically characterized as local hypoplastic. Significant linkage to microsatellite markers on chromosome 4q were obtained, with a maximum lod score of 5.55 for the marker D4S428. Recombinations in the family localized the ADAI locus to the interval between D4S392 and D4S395. This chromosome region contains both a locus for the dental disorder dentinogenesis imperfecta and the albumin gene. Serum albumin has been suggested to play a role in enamel formation, and the albumin gene is therefore a candidate gene for this genetic disease.

Forsman, K.; Lind. L.; Westermark, E. [Univ. of Umea (Sweden)] [and others

1994-09-01

135

Benign neonatal sleep myoclonus: an autosomal dominant form not allelic to KCNQ2 or KCNQ3.  

PubMed

Benign neonatal sleep myoclonus is an uncommon, nonepileptic disorder characterized by myoclonic jerks appearing in the neonatal period that occur predominantly during sleep. Although self-limiting, the disorder is frequently confused with epileptic neonatal seizures. A few familial cases have been reported; however the genetics has not been studied. We ascertained 3 families with 2 or more affected individuals and analyzed the pedigrees. We used microsatellite markers to determine if the disorder was possibly linked to KCNQ2 or KCNQ3, the 2 genes that cause most cases of benign familial neonatal seizures, a disorder that it could be easily confused with. The 3 pedigrees, including one with 4 affected individuals, were suggestive of autosomal dominant inheritance. The loci for KCNQ2 and KCNQ3 were excluded in the 2 larger families. We conclude that benign neonatal sleep myoclonus can show autosomal dominant inheritance and is not allelic with benign familial neonatal seizures. PMID:22447848

Afawi, Zaid; Bassan, Haim; Heron, Sarah; Oliver, Karen; Straussberg, Rachel; Scheffer, Ingrid; Leventer, Richard; Korczyn, Amos; Berkovic, Samuel

2012-03-23

136

Genetic linkage studies in autosomal dominant ataxia families with an MJD phenotype  

Microsoft Academic Search

Machado-Joseph disease (MJD) is an autosomal dominant spinocerebellar degeneration which was originally described in patients originating from the Portuguese islands of the Azores. The first non-Portuguese kindred was described in 1979 and was an American black family originating from North Carolina. Since then the number of pedigrees of non-Azorean, non-Portuguese origin has increased with families being reported from other European

I. Silveira; I. Lopes-Cendes; P. Paciel

1994-01-01

137

Fluorescent Multiplex PCR: Fast Method for Autosomal Dominant Spinocerebellar Ataxias Screening  

Microsoft Academic Search

Expansion of CAG trinucleotide repeats has been shown to cause a number of autosomal dominant spinocerebellar ataxias such as SCA1, SCA2, SCA3\\/MJD, SCA6, and SCA7. These disorders are characterized by a wide inter- and intrafamiliar variation in clinical features. The same mutation can result in different phenotypes and the very similar phenotypes can be caused by different mutations. Therefore it

P. O. Bauer; S. E. Kotliarova; V. Matoska; Z. Musova; P. Hedvicakova; A. Boday; A. Tomek; N. Nukina; P. Goetz

2005-01-01

138

Clinical features and neuropathology of autosomal dominant spinocerebellar ataxia (SCA17)  

Microsoft Academic Search

Autosomal dominant spinocerebellar ataxias (SCAs) are a group of neurodegenerative disorders clinically characterized by late-onset ataxia and variable other manifestations. Genetically and clinically, SCA is highly heterogeneous. Recently, CAG repeat expansions in the gene encoding TATA-binding protein (TBP) have been found in a new form of SCA, which has been designated SCA17. To estimate the frequency of SCA17 among white

Arndt Rolfs; Arnulf H. Koeppen; Ingrid Bauer; Peter Bauer; Sven Buhlmann; Helge Topka; Olaf Riess

2003-01-01

139

Locus heterogeneity in autosomal dominant spinocerebellar ataxia: Evidence for the existence of a fifth locus  

Microsoft Academic Search

The autosomal dominantly inherited spinocerebellar ataxias (SCAs) are a heterogeneous group of neurodegenerative disorders. To date, four loci have been identified: the SCA-1 locus (on chromosome (chr) 6p), the SCA-2 locus (on chr 12q), the SCA-3\\/MJD locus (on chr 14q), and more recently an SCA-4 locus was described (chr 16q) in a Utah kindred. We have studied one large French

J. Sarrazin; G. A. Rouleau; E. Andermann

1994-01-01

140

A new locus for autosomal dominant amelogenesis imperfecta on chromosome 8q24.3  

Microsoft Academic Search

Amelogenesis imperfecta (AI) is a collective term used to describe phenotypically diverse forms of defective tooth enamel\\u000a development. AI has been reported to exhibit a variety of inheritance patterns, and several loci have been identified that\\u000a are associated with AI. We have performed a genome-wide scan in a large Brazilian family segregating an autosomal dominant\\u000a form of AI and mapped

Gustavo Mendoza; Trevor J. Pemberton; Kwanghyuk Lee; Raquel Scarel-Caminaga; Ruty Mehrian-Shai; Catalina Gonzalez-Quevedo; Vasiliki Ninis; Jaana Hartiala; Hooman Allayee; Malcolm L. Snead; Suzanne M. Leal; Sergio R. P. Line; Pragna I. Patel

2007-01-01

141

A New bA1Crystallin Splice Junction Mutation in Autosomal Dominant Cataract  

Microsoft Academic Search

PURPOSE. To map the locus for autosomal dominant cataracts (ADCs) in a Brazilian family using candidate gene linkage analyses, describe the clinical variability, and identify potential mutations in the human bA1-crystallin gene (CRYBA1), a candidate gene identified through linkage studies demonstrating cosegregation with markers on chromosome 17. METHODS. Members of a Brazilian family with ADC were studied. Clinical examinations and

J. Bronwyn Bateman; David D. Geyer; Pamela Flodman; Meriam Johannes; James Sikela; Nicole Walter; Ana Teresa Moreira; Kevin Clancy; M. Anne Spence

2000-01-01

142

The etiology, pathogenesis, and treatment of autosomal dominant polycystic kidney disease: Recent advances  

Microsoft Academic Search

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in at least three different genes: PKD1, PKD2, and PKD3. ADPKD1 is an inherited disorder that has led to the discovery of a novel protein, polycystin. Polycystin, a 460 kd protein with a host of domains implicating a potential role in cell-cell and cell-matrix regulation, is encoded by a 52

Jared J. Grantham

1996-01-01

143

Autosomal dominant polycystic kidney disease: Genetics, mutations and microRNAs  

Microsoft Academic Search

Autosomal dominant polycystic kidney disease (ADPKD) is a common, monogenic multi-systemic disorder characterized by the development of renal cysts and various extrarenal manifestations. Worldwide, it is a common cause of end-stage renal disease. ADPKD is caused by mutation in either one of two principal genes, PKD1 and PKD2, but has large phenotypic variability among affected individuals, attributable to PKD genic

Ying-Cai Tan; Jon Blumenfeld; Hanna Rennert

2011-01-01

144

The Effect of Caffeine on Renal Epithelial Cells from Patients with Autosomal Dominant Polycystic Kidney Disease  

Microsoft Academic Search

Autosomal dominant polycystic kidney disease (AD- PKD) is a hereditary disorder characterized by the progressive enlargement of cysts derived from tubules. Tubule cell prolif- eration and chloride-dependent fluid accumulation, mecha- nisms underlying cyst expansion, are accelerated by adenosine 3':5'-cyclic monophosphate (cAMP). This study examined the extent to which caffeine may stimulate the production of cAMP by cyst epithelial cells, thereby

FRANCK A. BELIBI; DARREN P. WALLACE; TAMIO YAMAGUCHI; MARCY CHRISTENSEN; GAIL REIF; JARED J. GRANTHAM

2002-01-01

145

Autosomal Dominant Inheritance of Centrotemporal Sharp Waves in Rolandic Epilepsy Families  

PubMed Central

SUMMARY Purpose: Centrotemporal sharp (CTS) waves, the electroencephalogram (EEG) hallmark of rolandic epilepsy, are found in approximately 4% of the childhood population. The inheritance of CTS is presumed autosomal dominant but this is controversial. Previous studies have varied considerably in methodology, especially in the control of bias and confounding. We aimed to test the hypothesis of autosomal dominant inheritance of CTS in a well-designed family segregation analysis study. Methods: Probands with rolandic epilepsy were collected through unambiguous single ascertainment. Siblings in the age range 4–16 years underwent sleep-deprived EEG; observations from those who remained awake were omitted. CTS were rated as present or absent by two indepen-dent observers blinded to the study hypothesis and subject identities. We computed the segregation ratio of CTS, corrected for ascertainment. We tested the segregation ratio estimate for consistency with dominant and recessive modes of inheritance, and compared the observed sex ratio of those affected with CTS for consistency with sex linkage. Results: Thirty siblings from 23 families under-went EEG examination. Twenty-three showed evidence of sleep in their EEG recordings. Eleven of 23 recordings demonstrated CTS, yielding a corrected segregation ratio of 0.48 (95% CI: 0.27–0.69). The male to female ratio of CTS affectedness was approximately equal. Conclusions: The segregation ratio of CTS in rolandic epilepsy families is consistent with a highly penetrant autosomal dominant inheritance, with equal sex ratio. Autosomal recessive and X-linked inheritance are rejected. The CTS locus might act in combination with one or more loci to produce the phenotype of rolandic epilepsy.

Bali, Bhavna; Kull, Lewis L.; Strug, Lisa J.; Clarke, Tara; Murphy, Peregrine L.; Akman, Cigdem I.; Greenberg, David A.; Pal, Deb K.

2007-01-01

146

Mutations in LRRK2 Cause Autosomal-Dominant Parkinsonism with Pleomorphic Pathology  

Microsoft Academic Search

We have previously linked families with autosomal-dominant, late-onset parkinsonism to chromosome 12p11.2-q13.1 (PARK8). By high-resolution recombination mapping and candidate gene sequencing in 46 families, we have found six disease-segregating mutations (five missense and one putative splice site mutation) in a gene encoding a large, multifunctional protein, LRRK2 (leucine-rich repeat kinase 2). It belongs to the ROCO protein family and includes

Alexander Zimprich; Saskia Biskup; Petra Leitner; Peter Lichtner; Matthew Farrer; Sarah Lincoln; Jennifer Kachergus; Mary Hulihan; Ryan J. Uitti; Donald B. Calne; A. Jon Stoessl; Ronald F. Pfeiffer; Nadja Patenge; Iria Carballo Carbajal; Peter Vieregge; Friedrich Asmus; Bertram Müller-Myhsok; Dennis W. Dickson; Thomas Meitinger; Tim M. Strom; Zbigniew K. Wszolek; Thomas Gasser

2004-01-01

147

Fine mapping and genetic heterogeneity in the pure form of autosomal dominant familial spastic paraplegia  

Microsoft Academic Search

.   We evaluated seven families segregating pure, autosomal dominant familial spastic paraplegia (SPG) for linkage to four recently\\u000a identified SPG loci on chromosomes 2q (1), 8q (2), 12q (3), and 19q (4). These families were previously shown to be unlinked\\u000a to SPG loci on chromosomes 2p, 14q, and 15q. Two families demonstrated linkage to the new loci. One family (family

Allison Ashley-Koch; Erin R. Bonner; P. Craig Gaskell; Sandra G. West; Richard Tim; Chantelle M. Wolpert; Rodney Jones; Carolyn D. Farrell; Martha Nance; Ingrid K. Svenson; Douglas A. Marchuk; Rose-Mary N. Boustany; Jeffery M. Vance; William K. Scott; Margaret A. Pericak-Vance

2001-01-01

148

Autosomal dominant cerebellar ataxia type I: A review of the phenotypic and genotypic characteristics  

Microsoft Academic Search

Type I autosomal dominant cerebellar ataxia (ADCA) is a type of spinocerebellar ataxia (SCA) characterized by ataxia with\\u000a other neurological signs, including oculomotor disturbances, cognitive deficits, pyramidal and extrapyramidal dysfunction,\\u000a bulbar, spinal and peripheral nervous system involvement. The global prevalence of this disease is not known. The most common\\u000a type I ADCA is SCA3 followed by SCA2, SCA1, and SCA8,

Nathaniel Robb Whaley; Shinsuke Fujioka; Zbigniew K Wszolek

2011-01-01

149

Evidence for Pathogenicity of Atypical Splice Mutations in Autosomal Dominant Polycystic Kidney Disease  

Microsoft Academic Search

Background and objectives: Mutation-based molecular diagnostics of autosomal dominant polycystic kidney disease (ADPKD) is complicated by locus and allelic heterogeneity, large multi-exon gene structure and duplication in PKD1, and a high level of unclassified variants. Comprehensive screening of PKD1 and PKD2 by two recent studies have shown that atypical splice mutations account for 3.5% to 5% of ADPKD. We evaluated

Kiarong Wang; Xiao Zhao; Shelly Chan; Onur Cil; Ning He; Xuewen Song; Andrew D. Paterson; York Pei

2009-01-01

150

The enigma of 7q36 linked autosomal dominant limb girdle muscular dystrophy  

Microsoft Academic Search

IntroductionTwo families with autosomal dominant limb girdle muscular dystrophy (LGMD) have previously been linked to a locus on chromosome 7q36 10 years ago. The locus has been termed both LGMD1D and 1E, but because of lack of additional families to narrow down the linked region of interest, this disease has remained elusive.MethodsA large Finnish family was clinically and genetically investigated.

Satu Sandell; Sanna Huovinen; Jaakko Sarparanta; Helena Luque; Olayinka Raheem; Hannu Haapasalo; Peter Hackman; Bjarne Udd

2010-01-01

151

Redefining the disease locus of 16q22.1-linked autosomal dominant cerebellar ataxia  

Microsoft Academic Search

The 16q22.1-linked autosomal dominant cerebellar ataxia (16q-ADCA; Online Mendelian Inheritance in Man [OMIN] #117210) is\\u000a one of the most common ADCAs in Japan. Previously, we had reported that the patients share a common haplotype by founder effect\\u000a and that a C-to-T substitution (?16C>T) in the puratrophin-1 gene was strongly associated with the disease. However, recently, an exceptional patient without the

Takeshi Amino; Kinya Ishikawa; Shuta Toru; Taro Ishiguro; Nozomu Sato; Taiji Tsunemi; Miho Murata; Kazuhiro Kobayashi; Johji Inazawa; Tatsushi Toda; Hidehiro Mizusawa

2007-01-01

152

Comparison of Intracerebral Hemorrhage and Subarachnoid Hemorrhage in Patients with Autosomal-Dominant Polycystic Kidney Disease  

Microsoft Academic Search

Background\\/Aims: Subarachnoid hemorrhage (SAH) and intracerebral hemorrhage (ICH) are two subtypes of hemorrhagic stroke that may cause severe complications in patients with autosomal-dominant polycystic kidney disease (ADPKD). The differences in clinical features between SAH and ICH associated with ADPKD are not known. Methods: Among 647 ADPKD patients hospitalized between 1997 and 2007 in our hospital, 11 with ICH (1.7%) and

Ming-Yang Chang; Chi-Man Kuok; Yung-Cheng Chen; Shan-Jin Ryu; Ya-Chung Tian; Yah-Huei Wu-Chou; Fang-Ji Tseng; Chih-Wei Yang

2010-01-01

153

Hyperbaric oxygen therapy in a patient with autosomal dominant polycystic kidney disease with a perinephritic abscess  

Microsoft Academic Search

A 68-year-old female in hemodialysis due to autosomal dominant polycystic kidney disease underwent resection of cysts in her\\u000a right kidney via a laparoscopic approach due to abdominal pain. Three weeks after surgery, she was admitted with sepsis. A\\u000a CT scan showed a large abscess around the right kidney. Percutaneous drainage of abscess was performed. The pus smear showed\\u000a Gram-positive cocci

Jorge Vega; Helmuth Goecke; Francisco Manriquez; Carlos Escobar; Max Escobar; Christian Videla; Mario Santamarina; Carlos Echeverria; Francisco Javier Guarda

2011-01-01

154

Influence of Endothelin1 Gene Polymorphisms on the Progression of Autosomal Dominant Polycystic Kidney Disease  

Microsoft Academic Search

Background\\/Aim:A significant phenotypical variability is observed in autosomal dominant polycystic kidney disease (ADPKD). The variability cannot be fully explained by the genetic heterogeneity of the disease. Endothelin-1 (ET-1) has been suggested to be a major promoting factor in renal diseases. The role of the ET-1 gene locus (EDN1) in the renal function in the general nondiabetic population was evaluated. We

J. Reiterová; M. Merta; J. Štekrová; R. Cibulka; D. Maixnerová; R. Ryšavá

2006-01-01

155

FGF23 analysis of a Chinese family with autosomal dominant hypophosphatemic rickets  

Microsoft Academic Search

Autosomal dominant hypophosphatemic rickets (ADHR; MIM 193100) is a hereditary disorder characterized by isolated renal phosphate\\u000a wasting, hypophosphatemia, and inappropriately normal 1,25-dihydroxyvitamin D3 levels. Recent studies have shown that the fibroblast growth factor 23 (FGF23) gene is responsible for this disease. FGF23\\u000a protein is a phosphaturic factor that is elevated in several diseases associated with hypophosphatemia and rickets but varies

Yue Sun; Ou Wang; Weibo Xia; Yan Jiang; Mei Li; Xiaoping Xing; Yingying Hu; Huaicheng Liu; Xunwu Meng; Xueying Zhou

156

Metabolomic profiling of the autosomal dominant polycystic kidney disease rat model  

Microsoft Academic Search

Background  Autosomal dominant polycystic kidney disease (ADPKD) is an inherited systemic disease characterized by renal cyst expansion,\\u000a resulting in renal failure. With the progression of renal damage, the accumulation of uremic compounds is recently reported\\u000a to subsequently cause further renal damage and hypertension. Finding uremic toxins and sensitive markers for detecting the\\u000a early stage of ADPKD is necessary to clarify its

Takafumi Toyohara; Takehiro Suzuki; Yasutoshi Akiyama; Daisuke Yoshihara; Yoichi Takeuchi; Eikan Mishima; Koichi Kikuchi; Chitose Suzuki; Masayuki Tanemoto; Sadayoshi Ito; Shizuko Nagao; Tomoyoshi Soga; Takaaki Abe

157

FOXC2 haploinsufficient mice are a model for human autosomal dominant lymphedema-distichiasis syndrome  

Microsoft Academic Search

Lymphedema-distichiasis (LD) (OMIM 153400) is a rare autosomal-dominant condition characterized by pubertal onset of lower limb lymphedema and an aberrant second row of eyelashes arising from the meibomian glands. In some patients cardiac, skeletal and other defects coexist. We previously identified inactivating, nonsense and frameshift mutations in the forkhead transcription factor FOXC2 in affected members of LD families. To further

Benjamin M. Kriederman; Teressa L. Myloyde; Marlys H. Witte; Susan L. Dagenais; Charles L. Witte; Margaret Rennels; Michael J. Bernas; Michelle T. Lynch; Robert P. Erickson; Mark S. Caulder; Naoyuki Miura; David Jackson; Brian P. Brooks; Thomas W. Glover

2003-01-01

158

Metaphyseal dysplasia: a new autosomal dominant type in a large German kindred.  

PubMed

We describe a new autosomal dominant type of metaphyseal dysplasia (MD) in five generations of a German kindred. The main characteristics are metaphyseal widening and undermodeling of the tubular bones with Erlenmeyer flask-like appearance of the distal femora (typical of MD), with unusually severe varus deformity of the radii and flat exostoses of the long bones localized in the metaphyses. The skull is unaffected. Allelism with craniometaphyseal dysplasia (CMD) was excluded by linkage analysis. PMID:11343343

Braun, H S; Nürnberg, P; Tinschert, S

2001-06-01

159

Impaired TH17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome  

Microsoft Academic Search

The autosomal dominant hyper-IgE syndrome (HIES, `Job's syndrome') is characterized by recurrent and often severe pulmonary infections, pneumatoceles, eczema, staphylococcal abscesses, mucocutaneous candidiasis, and abnormalities of bone and connective tissue. Mutations presumed to underlie HIES have recently been identified in stat3, the gene encoding STAT3 (signal transducer and activator of transcription 3) (refs 3, 4). Although impaired production of interferon-gamma

Joshua D. Milner; Jason M. Brenchley; Arian Laurence; Alexandra F. Freeman; Brenna J. Hill; Kevin M. Elias; Yuka Kanno; Christine Spalding; Houda Z. Elloumi; Michelle L. Paulson; Joie Davis; Amy Hsu; Ava I. Asher; John O'Shea; Steven M. Holland; William E. Paul; Daniel C. Douek

2008-01-01

160

Percutaneous Treatment of Pyocystis in Patients with Autosomal Dominant Polycystic Kidney Disease  

Microsoft Academic Search

The course of autosomal dominant polycystic kidney disease (ADPKD) is frequently complicated by infection of a cyst within\\u000a a polycystic kidney, which is a diagnostic and therapeutic dilemma damaging the clinical course of patients. The aim of this\\u000a study was to demonstrate the safety and efficacy of percutaneous drainage in management of infected cysts in ADPKD patients.\\u000a Between May 2003

Devrim Akinci; Baris Turkbey; Rahmi Yilmaz; Erhan Akpinar; Mustafa N. Ozmen; Okan Akhan

2008-01-01

161

The KBG syndrome: confirmation of autosomal dominant inheritance and further delineation of the phenotype.  

PubMed

We report on a Turkish family in which the father and his two sons were diagnosed as having the KBG syndrome. Large upper central incisors were the diagnostic finding in all three patients along with mental retardation, cryptorchidism, skeletal abnormalities, and short stature. Our report clearly confirms that the inheritance is autosomal dominant in KBG syndrome, although a high male to female ratio has been observed in published cases. PMID:15378538

Tekin, Mustafa; Kavaz, Asli; Berbero?lu, Merih; Fitoz, Suat; Ekim, Mesiha; Ocal, Gönül; Akar, Nejat

2004-10-15

162

Autosomal Dominant Polycystic Kidney Disease: Recent Advances in Pathogenesis and Treatment  

Microsoft Academic Search

Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder affecting 1 in 1,000 people in the general population and accounts for up to 10% of all patients on renal replacement therapy. Numerous fluid-filled epithelial cysts arise from different nephron segments as spherical dilatations or small out-pouchings, enlarge progressively and eventually become disconnected from the rest of the renal

Ming-Yang Chang; Albert C. M. Ong

2008-01-01

163

The macrostructure and microstructure of sleep in patients with autosomal dominant nocturnal frontal lobe epilepsy.  

PubMed

The electroclinical features of autosomal dominant nocturnal frontal lobe epilepsy have been recently described. Although some patients reported a poor quality of sleep, daytime tiredness, and sleepiness, their sleep macrostructure appeared to be indistinguishable from those of the control group. The aim of this study was to evaluate the macro- and microstructure of sleep in a sample of autosomal dominant nocturnal frontal lobe epilepsy patients, diagnosed by videopolysomnography. The authors selected 16 patients, 8 with daytime complaints (morning tiredness and/or excessive sleepiness) (group 1) and 8 without those complaints (group 2). The classical macrostructure of sleep and the microstructure, according to the cyclic alternating pattern (CAP) scoring rules, were compared with another group of 8 healthy controls. In group 1 the motor attacks during sleep took place more frequently during CAP and were significantly related to phase A of the CAP cycle in comparison to group 2 (P = 0.04). Group 2 had a sleep microstructure similar to the controls, whereas group 1 showed higher CAP/nonrapid eye movement sleep (CAP rate) and a higher number of CAP cycles with respect to controls (P = 0.012 and P = 0.001) and to group 2 (P = 0.05 and P = 0.04). The analysis of sleep microstructure showed an increase in sleep instability in patients with autosomal dominant nocturnal frontal lobe epilepsy and daytime sleep complaints and indicated the relationship between sleep fragmentation, nocturnal motor seizures, and daytime symptoms. PMID:10709813

Zucconi, M; Oldani, A; Smirne, S; Ferini-Strambi, L

2000-01-01

164

Evidence for locus heterogeneity in autosomal dominant limb-girdle muscular dystrophy  

SciTech Connect

Limb-girdle muscular dystrophy (LGMD) is a diagnostic classification encompassing a broad group of proximal myopathies. A gene for the dominant form of LGMD (LGMD1A) has recently been localized to a 7-cM region of chromosome 5q between D5S178 and IL9. We studied three additional dominant LGMD families for linkage to these two markers and excluded all from localization to this region, providing evidence for locus heterogeneity within the dominant form of LGMD. Although the patterns of muscle weakness were similar in all families studied, the majority of affected family members in the chromosome 5-linked pedigree have a dysarthric speech pattern, which is not present in any of the five unlinked families. The demonstration of heterogeneity within autosomal dominant LGMD is the first step in attempting to subclassify these families with similar clinical phenotypes on a molecular level. 33 refs., 1 fig., 2 tabs.

Speer, M.C.; Stajich, J.M.; Gaskell, P.C. [Duke Univ. Medical School, Durham, NC (United States)] [and others

1995-12-01

165

Autosomal dominant cornea plana: clinical findings in a Cuban family and a review of the literature.  

PubMed

Cornea plana may occur in connection with malformations of the eye or of other parts of the body. As an isolated ocular anomaly, it may be inherited in an autosomal recessive or in an autosomal dominant fashion. We have previously mapped genes for both forms of the disease to 12q21. We studied 36 members of three generations of a Black Cuban family with autosomal dominant cornea plana. Three affected males and 11 affected females were examined. Corneal refraction varied between 37.50 and 42.75 diopters. Horizontal corneal diameter ranged from 8.75 to 11.25 mm. The cornea was clear and the limbal zone only occasionally widened. A marked arcus senilis was present in six patients aged 30 to 58 years, but in none of their healthy relatives. The anterior chamber was shallow in those affected, varying in depth from 1.68 to 2.38 mm. One woman was blind from closed-angle glaucoma. The axial length was within normal limits in all patients. PMID:9228241

Sigler-Villanueva, A; Tahvanainen, E; Lindh, S; Dieguez-Lucena, J; Forsius, H

1997-06-01

166

A nonsense mutation in the enamelin gene causes local hypoplastic autosomal dominant amelogenesis imperfecta (AIH2).  

PubMed

Amelogenesis imperfecta (AI) is an inherited tooth disorder affecting tooth enamel formation only. A gene for autosomal dominant AI, the local hypoplastic form, has been localized to a 4 Mb region on chromosome 4q (AIH2). The enamelin gene (ENAM ), has been mapped to chromosome 4q21, to the same region as AIH2, and was recently shown to be mutated in patients with smooth and thin hypoplastic autosomal dominant AI (ADAI). In this study, we describe an ENAM mutation causing the local hypoplastic form of ADAI, a phenotype that accounts for 27% of the autosomally inherited cases in Northern Sweden. This nonsense mutation in the enamelin gene results in a truncated peptide of 52 amino acids as compared with 1142 amino acids of the normal protein. Our results show that while a splice site mutation is associated with smooth and thin hypoplastic AI, a base substitution resulting in a shorter peptide causes local hypoplasia of the enamel, a milder form of AI. These findings support ENAM as a disease gene, and shed new light on the molecular mechanism of the disease and to the function of the enamelin protein in enamel formation. PMID:11978766

Mårdh, Carina K; Bäckman, Birgitta; Holmgren, Gösta; Hu, Jan C-C; Simmer, James P; Forsman-Semb, Kristina

2002-05-01

167

Mutation of the gene encoding the enamel-specific protein, enamelin, causes autosomal-dominant amelogenesis imperfecta  

Microsoft Academic Search

Amelogenesis imperfecta (AI) is a group of inherited defects of dental enamel formation that shows both clinical and genetic heterogeneity. To date, mutations in the gene encoding amelogenin have been shown to underlie a subset of the X-linked recessive forms of AI. Although none of the genes underlying autosomal- dominant or autosomal-recessive AI have been identified, a locus for a

M. Helen Rajpar; Kathryn Harley; Chris Laing; M. Davies; Michael J. Dixon

2001-01-01

168

Mutations in the chloride-bicarbonate exchanger gene AE1 cause autosomal dominant but not autosomal recessive distal renal tubular acidosis  

PubMed Central

Primary distal renal tubular acidosis (dRTA) is characterized by reduced ability to acidify urine, variable hyperchloremic hypokalemic metabolic acidosis, nephrocalcinosis, and nephrolithiasis. Kindreds showing either autosomal dominant or recessive transmission are described. Mutations in the chloride-bicarbonate exchanger AE1 have recently been reported in four autosomal dominant dRTA kindreds, three of these altering codon Arg589. We have screened 26 kindreds with primary dRTA for mutations in AE1. Inheritance was autosomal recessive in seventeen kindreds, autosomal dominant in one, and uncertain due to unknown parental phenotype or sporadic disease in eight kindreds. No mutations in AE1 were detected in any of the autosomal recessive kindreds, and analysis of linkage showed no evidence of linkage of recessive dRTA to AE1. In contrast, heterozygous mutations in AE1 were identified in the one known dominant dRTA kindred, in one sporadic case, and one kindred with two affected brothers. In the dominant kindred, the mutation Arg-589/Ser cosegregated with dRTA in the extended pedigree. An Arg-589/His mutation in the sporadic case proved to be a de novo mutation. In the third kindred, affected brothers both have an intragenic 13-bp duplication resulting in deletion of the last 11 amino acids of AE1. These mutations were not detected in 80 alleles from unrelated normal individuals. These findings underscore the key role of Arg-589 and the C terminus in normal AE1 function, and indicate that while mutations in AE1 cause autosomal dominant dRTA, defects in this gene are not responsible for recessive disease.

Karet, F. E.; Gainza, F. J.; Gyory, A. Z.; Unwin, R. J.; Wrong, O.; Tanner, M. J. A.; Nayir, A.; Alpay, H.; Santos, F.; Hulton, S. A.; Bakkaloglu, A.; Ozen, S.; Cunningham, M. J.; di Pietro, A.; Walker, W. G.; Lifton, R. P.

1998-01-01

169

Recessive versus imprinted disorder: consanguinity can impede establishing the diagnosis of autosomal dominant pseudohypoparathyroidism type Ib  

PubMed Central

Hypocalcemia and hyperphosphatemia with low/normal parathyroid hormone (PTH) levels can be observed in hypoparathyroidism (HP), a disorder that may follow an autosomal dominant (AD) or autosomal recessive (AR) mode of inheritance. Similar biochemical changes are also observed in pseudohypoparathyroidism (PHP) type Ia and Ib, but affected patients usually show elevated PTH levels indicative of hormonal resistance. Features of Albright’s hereditary osteodystrophy (AHO) are typically not observed in patients affected by familial forms of PHP-Ib, which are most frequently caused by maternally inherited, heterozygous microdeletions within STX16 and are associated with isolated loss of methylation at GNAS exon A/B. We established the molecular defect in two children of consanguineous Turkish parents, who presented with hypocalcemia, hyperphosphatemia, and low 25-OH vitamin D levels, but initially normal or only mildly elevated PTH levels, i.e. findings that do not readily exclude HP. After normalizing serum magnesium levels, hypocalcemia and hyperphosphatemia persisted, and PTH levels increased, suggesting PTH-resistance rather than PTH-deficiency. Because of the absence of AHO and parental consanguinity, an AR form of PHP-Ib appeared plausible, which had previously been suggested for sporadic cases. However, loss of GNAS methylation was restricted to exon A/B, which led to the identification of the 3-kb STX16 microdeletion. The same mutation was also detected in the healthy mother, who did not show any GNAS methylation abnormality, indicating that her deletion resides on the paternal allele. Our findings emphasize the importance of considering a parentally imprinted, autosomal dominant disorder even if consanguinity suggests an autosomal recessive mode of inheritance.

Turan, Serap; Akin, Leyla; Akcay, Teoman; Adal, Erdal; Sarikaya, Sevil; Bastepe, Murat; Juppner, Harald

2010-01-01

170

Genetic linkage studies in autosomal dominant ataxia families with an MJD phenotype  

SciTech Connect

Machado-Joseph disease (MJD) is an autosomal dominant spinocerebellar degeneration which was originally described in patients originating from the Portuguese islands of the Azores. The first non-Portuguese kindred was described in 1979 and was an American black family originating from North Carolina. Since then the number of pedigrees of non-Azorean, non-Portuguese origin has increased with families being reported from other European countries, as well as Brazil, Japan, India, The United States and Australia. The autosomal dominant ataxias are a clinically and genetically heterogeneous group of disorders. To date, genetic analysis of families with autosomal dominant ataxias has permitted the identification of four loci, the SCA1 (spinocerebellar ataxia type 1) locus on chromosome 6p, the SCA2 locus on chromosome 12q, a third locus on chromosome 14q, the MJD/SCA3 and, more recently, the DRPLA (Dentatorubral-pallidoluysian atrophy) locus on chromosome 12p. We ascertained a total of 181 individuals with 60 affected from eight Indian, two Brazilian and one Sicilian-American family; all of them have received the clinical diagnosis of MJD. Recently, we have begun molecular genetic studies in these families in order to test these four candidate regions. The SCA1 mutation and the DRPLA mutation has been found to be an expansion of a CAG repeat. Direct analysis of the SCA1 and DRPLA expansion has been performed in all families and no expansion was found in the affected individuals. We are now running flanking markers for the SCA2 and MJD/SCA3 loci. These results will also be presented.

Silveira, I.; Lopes-Cendes, I.; Paciel, P. [McGill Univ., Montreal (Canada)] [and others

1994-09-01

171

Autosomal Dominant Inheritance of a Predisposition to Thoracic Aortic Aneurysms and Dissections and Intracranial Saccular Aneurysms  

PubMed Central

A genetic predisposition for thoracic aortic aneurysms and dissections (TAAD) can be inherited in an autosomal dominant manner with decreased penetrance and variable expression. Four genes identified to date for familial TAAD account for approximately 20% of the heritable predisposition. In a cohort of 514 families with two or more members with presumed autosomal dominant TAAD, 48 (9.3%) families have one or more members who were at 50% risk to inherit the presumptive gene causing TAAD had an intracranial vascular event. In these families, gender is significantly associated with disease presentation (p <0.001), with intracranial events being more common in women (65.4%) while TAAD events occurred more in men (64.2%,). Twenty-nine of these families had intracranial aneurysms (ICA) that could not be designated as saccular or fusiform due to incomplete data. TGFBR1, TGFBR2, and ACTA2 mutations were found in 4 families with TAAD and predominantly fusiform ICAs. In 15 families, of which 14 tested negative for 3 known TAAD genes, 17 family members who were at risk for inheriting TAAD had saccular ICAs. In 2 families, women who harbored the genetic mutation causing TAAD had ICAs. In 2 additional families, intracranial, thoracic and abdominal aortic aneurysms were observed. This study documents the autosomal dominant inheritance of TAADs with saccular ICAs, a previously recognized association that has not been adequately characterized as heritable.I these families, routine cerebral and aortic imaging for at risk members could prove beneficial for timely medical and surgical management to prevent a cerebral hemorrhage or aortic dissection.

Regalado, Ellen; Medrek, Sarah; Tran-Fadulu, Van; Guo, Dong-Chuan; Pannu, Hariyadarshi; Golabbakhsh, Hossein; Smart, Suzanne; Chen, Julia H.; Shete, Sanjay; Kim, Dong H.; Stern, Ralph; Braverman, Alan C.; Milewicz, Dianna M.

2013-01-01

172

Renal activation of extracellular signal-regulated kinase in rats with autosomal-dominant polycystic kidney disease  

Microsoft Academic Search

Renal activation of extracellular signal-regulated kinase in rats with autosomal-dominant polycystic kidney disease.BackgroundAbnormal proliferation of renal tubule epithelial cells is a central factor in the biogenesis and sustained expansion of cysts in autosomal-dominant polycystic kidney disease (ADPKD). Recent evidence from in vitro studies of human cyst wall epithelial cells has implicated a role for the mitogen-activated protein (MAP) kinase pathway

Shizuko Nagao; Tamio Yamaguchi; Masatomo Kusaka; Robin L Maser; Hisahide Takahashi; Benjamin D Cowley; Jared J Grantham

2003-01-01

173

Classification and identification of inherited brachydactylies  

PubMed Central

A search for patterns of malformation in the brachydactylies has resulted in new ways to identify the different types. Type A-1 can be characterised by a proportionate reduction of the middle phalanges. Type B is thought to be an amputation-like defect. In type C the fourth middle phalanx is usually the longest, and type E (Riccardi and Holmes, 1974) is characterised by short metacarpals and short distal phalanges. Short stature is usually present in type A-1 and type E brachydactyly (Riccardi and Holmes, 1974) and it may be present in some individuals with brachydactyly C. As short children have short hands, it is possible that in patients with very mild expressions of brachydactyly the cause of the short stature may be overlooked. It is suggested that in every child with proportionate short stature the hands should be carefully examined. If the hands are disproportionately short, if any distal creases are missing, if there is a shortening, however mild, of any finger, if any metacarpals are short, then it is important to have ?-rays to look for brachydactyly A-1, C, or E. Much information is still needed. It is important in future reports to have skeletal surveys, pattern profile analyses, and to note the height of children with brachydactyly C. Most interesting of all will be when fetal limbs of each type become available for study. Images

Fitch, Naomi

1979-01-01

174

A transducin-like gene maps to the autosomal dominant polycystic kidney disease gene region  

SciTech Connect

A novel human gene (sazD) that maps to the autosomal dominant polycystic kidney disease region shares sequence similarity with members of the [beta]-transducin superfamily. The cDNA sazD-c predicts an [approximately]58-kDa protein (sazD) with seven internal repeats, similar to the WD-40 motif of the transducin family. The size of this protein family has been expanding rapidly; however, neither the structure nor the function of this repeated motif is known. Preliminary data do not suggest that sazD is mutated in patients with polycystic kidney disease. 13 refs., 2 figs.

Weinstat-Saslow, D.L.; Reeders, S.T.; Germino, G.G.; Somlo, S. (Yale Univ. School of Medicine, New Haven, CT (United States))

1993-12-01

175

Evidence for a third genetic locus for autosomal dominant polycystic kidney disease  

SciTech Connect

Autosomal dominant polycystic kidney disease (ADPKD) is a genetically heterogeneous disease with loci on chromosomes 16p and 4q. It has a moderately high spontaneous mutation rate, although the relative frequency of such mutations at each gene locus is unknown. In studying genetic heterogeneity in the French-Canadian population, we identified a family in which a classical clinical presentation of ADPKD resulted from a mutation at a locus genetically distinct from either of the previously described loci for this disease. This suggests the existence of a third genetic locus for ADPKD. 21 refs., 1 fig., 1 tab.

Daoust, M.C.; Bichet, D.G. [Universite de Montreal, Quebec (Canada); Reynolds, D.M. [Albert Einstein College of Medicine, Bronx, NY (United States)] [and others

1995-02-10

176

SPECT Myocardial Perfusion in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy.  

PubMed

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare hereditary small vessel disease. Although the symptoms are exclusively neurological, arteriopathy is generalized. We performed cardiac evaluation using myocardial perfusion single photon emission computed tomography (SPECT), dual-source 128-channel multidetector computed tomography (MDCT) angiogram, echocardiogram, and electrocardiogram (ECG) in a 46-year-old woman with CADASIL. No abnormal findings were observed on MDCT angiogram, echocardiogram, or ECG. However, SPECT demonstrated reversible perfusion defects in the left anterior descending artery territory. We suggest that myocardial perfusion SPECT is a valuable tool to identify risk from cardiovascular accident in CADASIL patients. PMID:23603583

Park, Soon-Ah; Cho, Kwang Ho; Kim, Nam-Ho; Yang, Chung-Yong; Park, Seong Hoon

2013-11-01

177

CHRNB2 is the second acetylcholine receptor subunit associated with autosomal dominant nocturnal frontal lobe epilepsy.  

PubMed

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is an uncommon, idiopathic partial epilepsy characterized by clusters of motor seizures occurring in sleep. We describe a mutation of the beta2 subunit of the nicotinic acetylcholine receptor, effecting a V287M substitution within the M2 domain. The mutation, in an evolutionary conserved region of CHRNB2, is associated with ADNFLE in a Scottish family. Functional receptors with the V287M mutation are highly expressed in Xenopus oocytes and characterized by an approximately 10-fold increase in acetylcholine sensitivity. CHRNB2 is a new gene for idiopathic epilepsy, the second acetylcholine receptor subunit implicated in ADNFLE. PMID:11104662

Phillips, H A; Favre, I; Kirkpatrick, M; Zuberi, S M; Goudie, D; Heron, S E; Scheffer, I E; Sutherland, G R; Berkovic, S F; Bertrand, D; Mulley, J C

2000-12-05

178

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL): a patient from Sri Lanka.  

PubMed

We report the first patient from Sri Lanka (the third patient from the Indian subcontinent) with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). The patient experienced a young onset familial stroke with an 856T>G missense mutation in exon 5 of the NOTCH3 gene resulting in a C260G mutation in the sixth epidermal growth factor-like repeat. We believe this is the first reported Sri Lankan patient. CADASIL is probably underdiagnosed in the region. PMID:19683925

De Silva, K R D; Gamage, R; Dunuwille, Janavi; Gunarathna, D; Sirisena, D; Weerasinghe, A; Amarasinghe, P H; Hosomi, Akiko; Mizuno, Toshiki

2009-08-15

179

COL4A3\\/COL4A4 mutations: From familial hematuria to autosomal-dominant or recessive Alport syndrome  

Microsoft Academic Search

COL4A3\\/COL4A4 mutations: From familial hematuria to autosomal-dominant or recessive Alport syndrome.BackgroundMutations of the type IV collagen COL4A5 gene cause X-linked Alport syndrome (ATS). Mutations of COL4A3 and COL4A4 have been reported both in autosomal-recessive and autosomal-dominant ATS, as well as in benign familial hematuria (BFH). In the latter conditions, however, clinical features are less defined, few mutations have been reported,

Ilaria Longo; Paola Porcedda; Francesca Mari; Daniela Giachino; Ilaria Meloni; Carla Deplano; Alfredo Brusco; Maurizio Bosio; Laura Massella; Giancarlo Lavoratti; Dario Roccatello; Giovanni Frascá; Gianna Mazzucco; Andrea Onetti Muda; Maura Conti; Federica Fasciolo; Christelle Arrondel; Laurence Heidet; Alessandra Renieri; Mario De Marchi

2002-01-01

180

Randomized Clinical Trial of Long-Acting Somatostatin for Autosomal Dominant Polycystic Kidney and Liver Disease  

PubMed Central

There are no proven, effective therapies for polycystic kidney disease (PKD) or polycystic liver disease (PLD). We enrolled 42 patients with severe PLD resulting from autosomal dominant PKD (ADPKD) or autosomal dominant PLD (ADPLD) in a randomized, double-blind, placebo-controlled trial of octreotide, a long-acting somatostatin analogue. We randomly assigned 42 patients in a 2:1 ratio to octreotide LAR depot (up to 40 mg every 28 ± 5 days) or placebo for 1 year. The primary end point was percent change in liver volume from baseline to 1 year, measured by MRI. Secondary end points were changes in total kidney volume, GFR, quality of life, safety, vital signs, and clinical laboratory tests. Thirty-four patients had ADPKD, and eight had ADPLD. Liver volume decreased by 4.95% ± 6.77% in the octreotide group but remained practically unchanged (+0.92% ± 8.33%) in the placebo group (P = 0.048). Among patients with ADPKD, total kidney volume remained practically unchanged (+0.25% ± 7.53%) in the octreotide group but increased by 8.61% ± 10.07% in the placebo group (P = 0.045). Changes in GFR were similar in both groups. Octreotide was well tolerated; treated individuals reported an improved perception of bodily pain and physical activity. In summary, octreotide slowed the progressive increase in liver volume and total kidney volume, improved health perception among patients with PLD, and had an acceptable side effect profile.

Masyuk, Tetyana V.; Page, Linda J.; Kubly, Vickie J.; Bergstralh, Eric J.; Li, Xujian; Kim, Bohyun; King, Bernard F.; Glockner, James; Holmes, David R.; Rossetti, Sandro; Harris, Peter C.; LaRusso, Nicholas F.; Torres, Vicente E.

2010-01-01

181

Autosomal dominant and sporadic monocytopenia with susceptibility to mycobacteria, fungi, papillomaviruses, and myelodysplasia  

PubMed Central

We identified 18 patients with the distinct clinical phenotype of susceptibility to disseminated nontuberculous mycobacterial infections, viral infections, especially with human papillomaviruses, and fungal infections, primarily histoplasmosis, and molds. This syndrome typically had its onset in adulthood (age range, 7-60 years; mean, 31.1 years; median, 32 years) and was characterized by profound circulating monocytopenia (mean, 13.3 cells/?L; median, 14.5 cells/?L), B lymphocytopenia (mean, 9.4 cells/?L; median, 4 cells/?L), and NK lymphocytopenia (mean, 16 cells/?L; median, 5.5 cells/?L). T lymphocytes were variably affected. Despite these peripheral cytopenias, all patients had macrophages and plasma cells at sites of inflammation and normal immunoglobulin levels. Ten of these patients developed 1 or more of the following malignancies: 9 myelodysplasia/leukemia, 1 vulvar carcinoma and metastatic melanoma, 1 cervical carcinoma, 1 Bowen disease of the vulva, and 1 multiple Epstein-Barr virus+ leiomyosarcoma. Five patients developed pulmonary alveolar proteinosis without mutations in the granulocyte-macrophage colony-stimulating factor receptor or anti–granulocyte-macrophage colony-stimulating factor autoantibodies. Among these 18 patients, 5 families had 2 generations affected, suggesting autosomal dominant transmission as well as sporadic cases. This novel clinical syndrome links susceptibility to mycobacterial, viral, and fungal infections with malignancy and can be transmitted in an autosomal dominant pattern.

Vinh, Donald C.; Patel, Smita Y.; Uzel, Gulbu; Anderson, Victoria L.; Freeman, Alexandra F.; Olivier, Kenneth N.; Spalding, Christine; Hughes, Stephen; Pittaluga, Stefania; Raffeld, Mark; Sorbara, Lynn R.; Elloumi, Houda Z.; Kuhns, Douglas B.; Turner, Maria L.; Cowen, Edward W.; Fink, Danielle; Long-Priel, Debra; Hsu, Amy P.; Ding, Li; Paulson, Michelle L.; Whitney, Adeline R.; Sampaio, Elizabeth P.; Frucht, David M.; DeLeo, Frank R.

2010-01-01

182

A Greek-American kindred with autosomal dominant, levodopa-responsive parkinsonism and anticipation.  

PubMed

Interest is increasing concerning the role of genetic factors in the etiology of Parkinson's disease. We report the analysis of a Greek-American kindred with levodopa-responsive parkinsonism. Of the 98 individuals present in six generations of this pedigree, 16 individuals in three successive generations have developed parkinsonism. Affected members were examined both in Greece and in the United States. The clinical presentation consisted of asymmetric rigidity, resting tremor, bradykinesia, and postural instability, and symptoms were responsive to levodopa. The disease appears to be inherited in an autosomal dominant manner. The inheritance pattern and the development of parkinsonism in successive generations on two continents challenges environmental factors as the primary cause in the pathogenesis of parkinsonism in this kindred. Anticipation is present in this pedigree. The affected members in the third generation developed symptoms at ages 50 to 71, in the fourth at ages 40 to 55, and in the fifth at age 31 years. This is another example of a neurodegenerative disease with autosomal dominant inheritance and anticipation. A molecular genetic analysis of this pedigree is in progress. PMID:7668822

Markopoulou, K; Wszolek, Z K; Pfeiffer, R F

1995-09-01

183

A novel mutation in CRYAB associated with autosomal dominant congenital nuclear cataract in a Chinese family  

PubMed Central

Purpose To identify the genetic defects associated with autosomal dominant congenital nuclear cataract in a Chinese family. Methods Clinical data were collected, and the phenotypes of the affected members in this family were recorded by slit-lamp photography. Genomic DNA was isolated from peripheral blood. Mutations were screened in cataract-associated candidate genes through polymerase chain reaction (PCR) analyses and sequencing. Structural models of the wild-type and mutant ?B-crystallin were generated and analyzed by SWISS-MODEL. Results Mutation screening identified only one heterozygous G?A transition at nucleotide 32 in the first exon of ?B-crystallin (CRYAB), resulting in an amino acid change from arginine to histidine at codon 11 (R11H). This mutation segregated in all available affected family members but was not observed in any of the unaffected persons of the family. The putative mutation disrupted a restriction site for the enzyme, Fnu4HI, in the affected family members. The disruption, however, was not found in any of the randomly selected ophthalmologically normal individuals or in 40 unrelated senile cataract patients. Computer-assisted prediction suggested that this mutation affected the biochemical properties as well as the structure of ?B-crystallin. Conclusions These results supported the idea that the novel R11H mutation was responsible for the autosomal dominant nuclear congenital cataract in this pedigree.

Chen, Qiang; Ma, Junjie; Yan, Ming; Mothobi, Maneo Emily; Liu, Yuanyuan

2009-01-01

184

A novel nonsense mutation in CRYGC is associated with autosomal dominant congenital nuclear cataracts and microcornea  

PubMed Central

Purpose To report the identification of a novel nonsense mutation in CRYGC in a Chinese family with autosomal dominant congenital nuclear cataracts and microcornea. Methods We investigated a four-generation Chinese family with six members affected with nuclear cataracts and microcornea. The family resides in a relatively isolated region of northern China. Genomic DNA was isolated from blood leucocytes, genotyping was performed using more than 100 microsatellite markers for the known cataract candidate gene loci, and LOD scores were calculated using the LINKAGE programs. Mutations were detected by DNA sequence analysis of the candidate genes. Results Evidence for linkage was detected at marker D2S325 (LOD score [Z]=2.29, recombination fraction [?]=0.0), which closely flanks the ?-crystallin gene cluster (CRYGA-CRYGD) on chromosome 2q32.3-q35. Direct sequencing of the candidate CRYGA-CRYGD gene cluster revealed a c.470G>A transversion in exon 3 of CRYGC, which cosegregated with cataracts in the family and was not observed in 100 normal controls. This single nucleotide change was predicted to introduce a translation stop codon at tryptophan 157 (W157X). Conclusions The present study has identified a novel nonsense mutation in CRYGC associated with autosomal dominant cataracts and microcornea in a Chinese family. Our finding expands the spectrum of CRYGC mutations associated with congenital cataract and confirms the role of ?-crystallin in the pathogenesis of congenital nuclear cataracts.

Zhang, Lu; Fu, Songbin; Ou, Yangshan; Zhao, Tingting; Su, Yunjuan

2009-01-01

185

Autosomal dominant oculoauriculovertebral spectrum and 14q23.1 microduplication.  

PubMed

Oculoauriculovertebral spectrum (OAVS; OMIM 164210) is characterized by anomalies derived from an abnormal development of the first and second branchial arches, with marked inter and intra-familial phenotypic variability. Main clinical features are defects on aural, oral, mandibular, and vertebral development. Cardiac, pulmonary, renal, skeletal, and central nervous system anomalies have also been described. Most affected individuals are isolated cases in otherwise normal families. Autosomal dominant inheritance has been observed in about 2-10% of cases and linkage analysis as well as array-CGH analysis have detected candidate loci for OAVS offering new insights into the understanding of pathogenesis of this entity. We describe a family with clinical diagnosis of OAVS, autosomal dominant inheritance pattern, and detection of a 14q23.1 duplication of 1.34 Mb in size which segregates with the phenotype. This region contains OTX2, which is involved in the development of the forebrain, eyes, and ears, and appears to be a good candidate gene for OAVS. PMID:23794319

Ballesta-Martínez, Maria Juliana; López-González, Vanesa; Dulcet, Lluis Armengol; Rodríguez-Santiago, Benjamín; Garcia-Miñaúr, Sixto; Guillen-Navarro, Encarna

2013-06-21

186

Inheritance pattern of familial moyamoya disease: autosomal dominant mode and genomic imprinting  

PubMed Central

Background Although the aetiology of moyamoya disease (MMD) has not been fully clarified, genetic analysis of familial MMD (F?MMD) has considerable potential to disclose it. Objective To determine the inheritance pattern and clinical characteristics of F?MMD to enable precise genetic analyses of the disease. Methods 15 highly aggregated Japanese families (52 patients; 38 women and 14 men) with three or more affected members were examined. The difference in categories of age at onset (child onset, adult onset and asymptomatic) between paternal and maternal transmission was compared by ?2 statistics. Results In all families there had been three or more generations without consanguinity, and all types of transmission, including father?to?son, were observed. Among a total of 135 offspring of affected people, 59 (43.7%) were patients with MMD or obligatory carriers. Affected mothers were more likely to produce late?onset (adult?onset or asymptomatic) female offspring (p?=?0.007). Conclusions The mode of inheritance of F?MMD is autosomal dominant with incomplete penetrance. Thus, in future genetic studies on F?MMD, parametric linkage analyses using large families with an autosomal dominant mode of inheritance are recommended. Genomic imprinting may be associated with the disease.

Mineharu, Y; Takenaka, K; Yamakawa, H; Inoue, K; Ikeda, H; Kikuta, K-I; Takagi, Y; Nozaki, K; Hashimoto, N; Koizumi, A

2006-01-01

187

A nonsense mutation in CRYGC associated with autosomal dominant congenital nuclear cataract in a Chinese family  

PubMed Central

Purpose To identify the genetic defect associated with autosomal dominant congenital nuclear cataract in a Chinese family. Methods Family history and phenotypic data were recorded, and the phenotypes were documented by slit lamp photography. The genomic DNA was extracted from peripheral blood leukocytes. All the exons and flanking intronic sequences of CRYGC and CRYGD were amplified by polymerase chain reaction (PCR) and screened for mutation by direct DNA sequencing. Structural models of the wild type and mutant ?C-crystallin were generated and analyzed by SWISS-MODEL. Results Sequencing of the coding regions of CRYGC and CRYGD showed the presence of a heterozygous C>A transversion at c.327 of the coding sequence in exon 3 of CRYGC (c.327C>A), which results in the substitution of a wild type cysteine to a nonsense codon (C109X). One and a half Greek key motifs at the COOH-terminus were found to be absent in the structural model of the mutant truncated ?C-crystallin. Conclusions A novel nonsense mutation in CRYGC was detected in a Chinese family with consistent autosomal dominant congenital nuclear cataract, providing clear evidence of a relationship between the genotype and the corresponding cataract phenotype.

Jin, Chongfei; Zhu, Ning; Wang, Wei; Wu, Renyi; Jiang, Jin; Shentu, Xingchao

2008-01-01

188

Gamma-D crystallin gene (CRYGD) mutation causes autosomal dominant congenital cerulean cataracts  

PubMed Central

Congenital cataracts are a major cause of bilateral visual impairment in childhood. We mapped the gene responsible for autosomal congenital cerulean cataracts to chromosome 2q33–35 in a four generation family of Moroccan descent. The maximum lod score (7.19 at recombination fraction ?=0) was obtained for marker D2S2208 near the ?-crystallin gene (CRYG) cluster. Sequencing of the coding regions of the CRYGA, B, C, and D genes showed the presence of a heterozygous C>A transversion in exon 2 of CRYGD that is associated with cataracts in this family. This mutation resulted in a proline to threonine substitution at amino acid 23 of the protein in the first of the four Greek key motifs that characterise this protein. We show that although the x ray crystallography modelling does not indicate any change of the backbone conformation, the mutation affects a region of the Greek key motif that is important for determining the topology of this protein fold. Our data suggest strongly that the proline to threonine substitution may alter the protein folding or decrease the thermodynamic stability or solubility of the protein. Furthermore, this is the first report of a mutation in this gene resulting in autosomal dominant congenital cerulean cataracts.

Nandrot, E; Slingsby, C; Basak, A; Cherif-Chefchaoun..., M; Benazzouz, B; Hajaji, Y; Boutayeb, S; Gribouval, O; Arbogast, L; Berraho, A; Abitbol, M; Hilal, L

2003-01-01

189

A case of autosomal dominant osteopetrosis type II with a novel TCIRG1 gene mutation.  

PubMed

Osteopetrosis is a rare genetic disorder characterized by increased bone mineral density (BMD) due to osteoclast failure. T-cell immune regulator 1 (TCIRG1) plays crucial roles on osteoclast function, and its mutation causes autosomal recessive osteopetorosis. However, mutations in TCIRG1 have never been identified in autosomal dominant osteopetrosis (ADO). A 3-year-old boy was first presented to the clinic because of spontaneous radius and femur fractures. He has optic atrophy. The areal BMD at the lumbar spine was 1274 g/cm2 (233% of normal). Laboratory tests revealed no remarkable abnormal findings, including anemia, except for extremely elevated serum tartrate-resistant acid phosphatase-5b (14,600 mU/dL). Radiographically, the skull base, pelvis, and vertebrae showed a focal sclerosis. Genetic analysis revealed a novel de novo heterozygous missense mutation (His242Arg). Taken together with the mutation, his mild clinical features were diagnosed as ADO. This case implies that TCIRG1 could become a genetic candidate for ADO in addition to malignant forms such as ARO. PMID:23412864

Wada, Keiko; Harada, Daisuke; Michigami, Toshimi; Tachikawa, Kanako; Nakano, Yukako; Kashiwagi, Hiroko; Yamashita, Sumie; Sano, Tetsuya; Seino, Yoshiki

2013-01-01

190

Refined localisation of the second gene for autosomal dominant polycystic kidney disease  

SciTech Connect

The PKD1-gene responsible for autosomal dominant polycystic kidney disease in 85% of the families maps to chromosome 16q13. Last year the PKD2-gene was localized on chromosome 4q21-23 between the markers D4S231 and D4S231 and D4S423, an interval of about 8cM. In a collaborative effort to narrow down the PKD2-region, families with recombinants have been analyzed with several markers within the interval. First, an integrated map had to be constructed which contains previously published markers of different sources. To construct this map, cosmids and/or YACs isolated with the markers have been mapped by two-color FISH and were screened with the other markers. Affected recombinants localize the disease between D4S1534 and D4S1544.

Peters, D.J.M.; Saris, J.J.; Spruit, L. [Wassenaaseweg, Leiden (Netherlands)] [and others

1994-09-01

191

High-density renal cysts in autosomal dominant polycystic kidney disease demonstrated by CT  

SciTech Connect

Unenhanced abdominal CT scans of 35 patients with autosomal dominant polycystic kidney disease (ADPKD) showed multiple high-density (58-84 HU) renal cysts in 42.9% of patients, occasional high-density cysts in 25.7%, and no high-density cysts in 31.4%. These high-density cysts were usually subcapsular and were more frequent in patients with markedly enlarged kidneys and flank pain at the time of CT. Follow-up CT often showed a reduction in cyst densities, although some cysts developed mural calcification and calcification of their contents. Renal carcinomas occur rarely in ADPKD and may occasionally be hyperdense. However, high-density cysts may usually be distinguished from carcinomas on CT by their smooth contours, sharp interfaces with renal parenchyma, homogeneity, and lack of contrast enhancement.

Levine, E.; Grantham, J.J.

1985-02-01

192

Linkage disequilibrium in the region of the autosomal dominant polycystic kidney disease gene (PKD1)  

SciTech Connect

The gene for autosomal dominant polycystic kidney disease (PKD1) is located on chromosome 16p, between the flanking markers D16S84 and D16S125 (26.6 prox). This region is 750 kb long and has been cloned. The authors have looked at the association of 10 polymorphic markers from the region, with the disease and with each other. This was done in a set of Scottish families that had previously shown association with D16S94, a marker proximal to the PKD1 region. They report significant association between two CA repeat markers and the disease but have not found evidence for a single founder haplotype in these families, indicating the presence of several mutations in this population. Their results favor a location of the PKD1 gene in the proximal part of the candidate region. 25 refs., 1 fig., 4 tabs.

Snarey, A. (Imperial Cancer Research Fund, London (United Kingdom)); Thomas, S.; Harris, P.C. (Institute of Molecular Medicine, Oxford (United Kingdom)); Schneider, M.C. (Brigham and Women's Hospital, Boston, MA (United States)); Pound, S.E.; Wright, A.F. (Western General Hospital, Edinburgh (United Kingdom)); Barton, N.; Somlo, S.; Germino, G.G.; Reeders, S.T. (and others)

1994-08-01

193

Novel ophthalmic pathology in an autopsy case of autosomal dominant retinal vasculopathy with cerebral leukodystrophy.  

PubMed

Autosomal dominant retinocerebral vasculopathy with cerebral leukodystrophy (RVCL) is a rare neurovascular syndrome causing retinal and central nervous system vasculopathy often recognized as contrast-enhancing white matter changes or pseudotumors on imaging. Heterozygous frameshift mutations in the 3-prime repair exonuclease 1 gene have been identified in families affected by RVCL. Variable light microscopic findings and a characteristic ultrastructural appearance of the vasculature in the brain have been reported. Description of the ophthalmic histopathology is exceedingly rare. Here, we report previously undescribed bilateral eye findings in a patient diagnosed with RVCL. The ophthalmic pathology includes thickening and reduplication of the retinal capillary basal lamina demonstrated by electron microscopy. These findings expand what is known about this disease and help further delineate its phenotype. PMID:21131853

Gruver, Aaron M; Schoenfield, Lynn; Coleman, Joshua F; Hajj-Ali, Rula; Rodriguez, E Rene; Tan, Carmela D

2011-03-01

194

Autosomal dominant polycystic kidney disease with ectopic unilateral multicystic dysplastic kidney  

PubMed Central

Background Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disorder. In most cases, ADPKD similarly affects bilateral kidneys. Case presentation Among the 605 ADPKD patients that were followed up by our center, we identified two male patients with unilateral ADPKD. The cases were remarkable because the patients also had ectopia and multicystic dysplasia in the contralateral kidney, which are generally sporadic disease conditions. Both patients tested positive for polycystic kidney disease 1 mutation, but negative for hepatocyte nuclear factor 1 beta mutation. Moreover, the deterioration of their kidney function seemed to be quicker than their age- and sex-matched controls and siblings. Both patients had started a long-term hemodialysis in their 40s. Conclusion Anatomical and genetic abnormality in patients with ADPKD may be more frequent and complex than previously believed. The compensatory capacity in patients with ADPKD is fragile, and missing one kidney could accelerate the deterioration of renal function.

2013-01-01

195

Dissecting aneurysm in a patient with autosomal dominant polycystic kidney disease.  

PubMed

Autosomal dominant polycystic kidney disease (ADPKD) is primarily associated with renal failure, but it also causes systemic diseases, including cysts of other systemic organs and cerebral or visceral aneurysm. To make matters worse, life-threatening aortic diseases are associated with ADPKD in some cases. However, only a few reports of ADPKD-associated with thoracic aortic dissection have been published. Herein, we present a case of dissecting aneurysm in a patient with hypertension and ADPKD. He had been followed up for type B aortic dissection for six years. Preoperative creatinine level ranged from 2.1 to 2.4 mg/dl. We performed replacement of the thoracic aorta with prosthetic graft successfully, and postoperatively, dialysis was not required.It is very important for us to recognize the relationship between ADPKD and thoracic aortic dissection, which can cause high mortality and morbidity rates. PMID:22293308

Fukunaga, Naoto; Yuzaki, Mitsuru; Nasu, Michihiro; Okada, Yukikatsu

2012-01-31

196

The LRRK2 gene is mutated in a Chinese autosomal-dominant Parkinson's disease family.  

PubMed

The mutation of the leucine-rich repeat kinase2 gene (LRRK2) is the most commonly detected genetic determinant of Parkinson's disease (PD). However, the specific role of the LRRK2 mutation in the occurrence of the autosomal-dominant family PD remains to be elucidated. In this study, we report a large Chinese LRRK2-related PD family with 33 members of four generations. Genomic DNA was isolated from peripheral blood specimens of 11 family members. The common LRRK2 mutations were screened by polymerase chain reaction, followed by polymorphic restriction enzyme digestion or direct DNA sequencing. We detected the G2385R mutation, a substitution at codon 2385 to produce a glycine-to-arginine phenotype, in two affected cases and one suspected case. Our data support the concept that the LRRK2 G2385R mutation may be involved in the pathogenesis of PD in this family. PMID:23268655

Guo, Rui; Hu, Xinyu; Chen, Qiuhui; Zhang, Ying; Zhang, Yizhi; Sun, Yajuan; Hu, Guohua

2012-12-26

197

SETX gene mutation in a family diagnosed autosomal dominant proximal spinal muscular atrophy.  

PubMed

Autosomal dominant proximal spinal muscular atrophy (ADSMA) is a rare disorder with unknown gene defects in the majority of families. Here we describe a family where the diagnosis of juvenile and adult onset ADSMA was made in three individuals. Because of retained tendon reflexes an atypical course of juvenile amyotrophic lateral sclerosis (ALS4) was considered. SETX gene sequencing revealed the previously reported heterozygous missense mutation c.1166T

Rudnik-Schöneborn, Sabine; Arning, Larissa; Epplen, Jörg T; Zerres, Klaus

2011-11-15

198

Severe autosomal dominant nocturnal frontal lobe epilepsy associated with psychiatric disorders and intellectual disability.  

PubMed

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a relatively benign epilepsy syndrome with few comorbidities. Here we describe two families with unusually severe ADNFLE, with associated psychiatric, behavioral, and cognitive features. Detailed clinical data on 17 affected individuals were obtained, and genotyping of microsatellite markers, linkage analysis, and sequencing of candidate genes was performed. The severe ADNFLE phenotype in these families was often refractory to treatment, with status epilepticus occurring in 24% of subjects. Psychiatric or behavioral disorders occurred in 53%, with intellectual disability in 24%, and developmental regression in two individuals. No mutations were identified in alpha4, alpha2, or beta2 nAChR subunits. In one family there was evidence of linkage to a region of 15q24 without nAChR subunit genes. In conclusion, severe ADNFLE has significant medical, psychiatric, and intellectual morbidity. The molecular basis of severe ADNFLE is unknown but may involve non-nAChR-related mechanisms. PMID:18479385

Derry, Christopher P; Heron, Sarah E; Phillips, Fiona; Howell, Stephen; MacMahon, Jacinta; Phillips, Hilary A; Duncan, John S; Mulley, John C; Berkovic, Samuel F; Scheffer, Ingrid E

2008-05-09

199

Autosomal Dominant Cataract: Intrafamilial Phenotypic Variability, Interocular Asymmetry, and Variable Progression in Four Chilean Families  

PubMed Central

PURPOSE To document intrafamilial and interocular phenotypic variability of autosomal dominant cataract (ADC). DESIGN Prospective observational case series. METHODS We performed ophthalmologic examination in four Chilean ADC families. RESULTS The families exhibited variability with respect to morphology, location with the lens, color and density of cataracts among affected members. We documented asymmetry between eyes in the morphology, location within the lens, color and density of cataracts, and a variable rate of progression. CONCLUSIONS The cataracts in these families exhibit wide intrafamilial and interocular phenotypic variability, supporting the premise that the mutated genes are expressed differentially in individuals and between eyes; other genes or environmental factors may be the bases for this variability. Marked progression among some family members underscores the variable clinical course of a common mutation within a family. Like retinitis pigmentosa, classification of ADC will be most useful if based on the gene and specific mutation.

Shafie, Suraiya M.; Barria von-Bischhoffshausen, Fernando R.; Bateman, J. Bronwyn

2006-01-01

200

A Tumor Necrosis Factor-Alpha-Mediated Pathway Promoting Autosomal Dominant Polycystic Kidney Disease  

PubMed Central

Autosomal dominant polycystic kidney disease (ADPKD) is caused by heterozygous mutations in either PKD1 or PKD2, genes that encode polycystin (PC) -1 and -2, respectively 1. We show here that tumor necrosis factor-alpha (TNF-?), an inflammatory cytokine present in human ADPKD cystic fluid, disrupts the localization of PC2 to the plasma membrane and primary cilia through a scaffold protein, FIP2, which is induced by TNF-?. Treatment of mouse embryonic kidney organ cultures with TNF-? resulted in formation of cysts, and this effect was exacerbated in the Pkd2+/? kidneys. TNF-? also stimulated cyst formation in vivo in Pkd2+/? mice. In contrast, treatment of Pkd2+/? mice with the TNF-? inhibitor, etanercept, prevented cyst formation. These data reveal a pathway connecting TNF-? signaling, polycystins and cystogenesis, the activation of which may reduce functional PC2 below a critical threshold, precipitating the ADPKD cellular phenotype.

Li, Xiaogang; Magenheimer, Brenda S.; Xia, Sheng; Johnson, Teri; Wallace, Darren P.; Calvet, James P.; Li, Rong

2012-01-01

201

Autosomal dominant transmission of gouty arthritis with renal disease in a large Japanese family.  

PubMed Central

Six generations of a Japanese family had gouty arthritis and progressive nephropathy. Data on nine of 51 women (18%) and 15 of 66 men (23%) with either asymptomatic hyperuricaemia, gouty arthritis, or renal insufficiency were obtained. Renal function in four men and one woman with hyperuricaemia or gouty arthritis was also examined. Urinary excretion of uric acid was decreased in all subjects examined, including the young. Erythrocyte phosphoribosylpyrophosphate synthetase and hypoxanthine-guanine phosphoribosyltransferase activities determined in 10 patients were normal. Some patients had been treated with allopurinol to reduce serum uric acid concentrations, but the treatment did not prevent progression of renal impairment. Transmission of the disease in this large family is considered to be autosomal dominant. The data suggest that the disease in this family is the same entity as that described by other workers--that is, familial urate nephropathy. As far as is known this is the largest family with this disease so far reported.

Yokota, N; Yamanaka, H; Yamamoto, Y; Fujimoto, S; Eto, T; Tanaka, K

1991-01-01

202

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy syndrome mutations increase susceptibility to spreading depression.  

PubMed

Migraine with aura is often the first manifestation of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy syndrome (CADASIL), a disorder caused by NOTCH3 gene mutations expressed predominantly in vascular smooth muscle. Here, we report that cortical spreading depression (CSD), the electrophysiological substrate of migraine aura, is enhanced in mice expressing a vascular Notch 3 CADASIL mutation (R90C) or a Notch 3 knockout mutation. The phenotype was stronger in Notch 3 knockout mice, implicating both loss of function and neomorphic mutations in its pathogenesis. Our results link vascular smooth muscle Notch 3 mutations to enhanced spreading depression susceptibility, implicating the neurovascular unit in the development of migraine aura. PMID:21387384

Eikermann-Haerter, Katharina; Yuzawa, Izumi; Dilekoz, Ergin; Joutel, Anne; Moskowitz, Michael A; Ayata, Cenk

2011-02-01

203

Autosomal dominant zonular cataract with sutural opacities localized to chromosome 17q11-12  

SciTech Connect

Congenital cataracts constitute a morphologically and genetically heterogeneous group of diseases that are a major cause of childhood blindness. Different loci for hereditary congenital cataracts have been mapped to chromosomes 1, 2, 16, and 17q24. We report linkage of a gene causing a unique form of autosomal dominant zonular cataracts with Y-sutural opacities to chromosome 17q11-12 in a three-generation family exhibiting a maximum lod score of 3.9 at D17S805. Multipoint analysis gave a Mod confidence interval of 17 cM. This interval is bounded by the markers D17S799 and D17S798, a region that would encompass a number of candidate genes including that coding for {Beta}A3/A1-crystallin. 30 refs., 2 figs., 1 tab.

Padma, T.; Ayyagari, R.; Murty, J.S. [and others

1995-10-01

204

Further screening of the rhodopsin gene in patients with autosomal dominant retinitis pigmentosa  

SciTech Connect

Here the authors report 8 novel mutations and 8 previously reported mutations found from further analysis of the rhodopsin gene in a large set of additional patients with autosomal dominant retinitis pigmentosa. Leukocyte DNA was purified from 122 unrelated patients with autosomal dominant retinitis pigmentosa who were not included in previous analyses. The coding region and splice donor and acceptor sites of the rhodopsin gene were screened for mutations using single-strand conformation polymorphism analysis and direct genomic sequencing. They found 29 patients with varient bands that were due to mutations. Sequence analysis showed that 20 cases each had 1 of 9 previously published mutations: Pro23His, Thr58Arg, Gly89Asp, Pro171Leu, Glu181Lys, Pro347Leu, Phe45Leu, Arg135Trp, and Lys296Glu. In 9 other cases, they found 8 novel mutations. One was a 3-bp deletion (Cys264-del), and the rest were point mutations resulting in an altered amino acid: Gly51Arg (GGC [yields] CGC), Cys110Tyr (TCG [yields] TAC), Gly114Asp (GGC [yields] GAC), Ala164Glu (GCG [yields] GAG), Pro171Ser (CCA [yields] TCA), Val345Leu (GTG [yields] CTG), and Pro347Gln (CCG [yields] CAG). Each of these novel mutations was found in only one family except for Gly51Arg, which was found in two. In every family tested, the mutation cosegregated with the disease. However, in pedigree D865 only one affected member was available for analysis. About two-thirds of the mutations affect amino acids in transmembrane domains, yet only one-half of opsin's residues are in these regions. One-third of the mutations alter residues in the extracellular/intradiscal space, which includes only 25% of the protein.

Vaithinathan, R.; Berson, E.L.; Dryja, T.P. (Harvard Medical School, Boston, MA (United States))

1994-05-15

205

A novel nonsense mutation in CRYBB1 associated with autosomal dominant congenital cataract  

PubMed Central

Purpose To identify the molecular defect underlying an autosomal dominant congenital nuclear cataract in a Chinese family. Methods Twenty-two members of a three-generation pedigree were recruited, clinical examinations were performed, and genomic DNA was extracted from peripheral blood leukocytes. All members were genotyped with polymorphic microsatellite markers adjacent to each of the known cataract-related genes. Linkage analysis was performed after genotyping. Candidate genes were screened for mutation using direct sequencing. Individuals were screened for presence of a mutation by restriction fragment length polymorphism (RFLP) analysis. Results Linkage analysis identified a maximum LOD score of 3.31 (recombination fraction [?]=0.0) with marker D22S1167 on chromosome 22, which flanks the ?-crystallin gene cluster (CRYBB3, CRYBB2, CRYBB1, and CRYBA4). Sequencing the coding regions and the flanking intronic sequences of these four candidate genes identified a novel, heterozygous C?T transition in exon 6 of CRYBB1 in the affected individuals of the family. This single nucleotide change introduced a novel BfaI site and was predicted to result in a nonsense mutation at codon 223 that changed a phylogenetically conserved amino acid to a stop codon (p.Q223X). RFLP analysis confirmed that this mutation co-segregated with the disease phenotype in all available family members and was not found in 100 normal unrelated individuals from the same ethnic background. Conclusions This study has identified a novel nonsense mutation in CRYBB1 (p.Q223X) associated with autosomal dominant congenital nuclear cataract.

Yang, Juhua; Zhu, Yihua; Gu, Feng; He, Xiang; Cao, Zongfu; Li, Xuexi; Tong, Yi

2008-01-01

206

Localization of genes for autosomal dominant congenital cataracts to chromosomes 2 and 17  

SciTech Connect

Linkage analysis was performed in a seven generation family in which 28 of 52 individuals examined had autosomal dominant congenital pulverulent cataracts and a five generation family in which 10 of 17 individuals examined had autosomal dominant congenital zonular cataracts with sutural opacities. Initial analysis with 21 microsatellite markers in 7 candidate gene regions localized the pulverulent cataract locus to the long arm of chromosome 2 near the {beta}B2-crystallin gene. A lod score of 3.6 was obtained with D2S72 ({theta}=0.12), 3.5 with CRYG ({theta}=0.06), 3.4 with ({theta}=0.05), 2.0 with D2S117 ({theta}=0.22) and 6.6 with D2S128 ({theta}=0.05). Multipoint linkage analysis gave Zmax=4.2 at D2S157 with a one lod confidence interval covering 19 cM. The closest flanking markers showing obligate recombinants are D2S157 and D2S173. The zonular cataract locus was mapped to chromosome 2 near the {gamma}-crystallin gene cluster. A maximum lod score of 3.8 was obtained with D17S805 ({theta}=0.0), 2.1 with D17S798 ({theta}=0.60), and 3.7 with NF1 ({theta}=0.0). Multipoint analysis showed Zmax=3.81 at D17S805 with a one lod confidence interval covering 17 cM based on the Genethon map, localizing cataracts between markers D17S799 and D17S800. Further efforts are being directed at refining the localization of these cataract loci and examining the nearby crystallin genes for possible mutations.

Ayyagari, R.; Scott, M.; Wozencraft, L. [National Eye Institute, Bethesda, MD (United States)] [and others

1994-09-01

207

Autosomal dominant frontonasal dysplasia (atypical Greig syndrome): Lessons from the Xt mutant mouse  

SciTech Connect

Greig syndrome is the autosomal dominant association of mild hypertelorism, variable polysyndactyly, and normal intelligence. Several families have been found to have translocations or deletions of 7p13 interrupting the normal expression of GLI3 (a zinc finger, DNA binding, transcription repressor). Recently, a mutation in the mouse homologue of GLI3 was found in the extra-toes mutant mouse (Xt). The phenotypic features of this mouse model include mild hypertelorism, postaxial polydactyly of the forelimbs, preaxial polydactyly of the hindlimbs, and variable tibial hemimelia. The homozygous mutant Xt/Xt have severe frontonasal dysplasia (FND), polysyndactyly of fore-and hindlimbs and invariable tibial hemimelia. We have recently evaluated a child with severe (type D) frontonasal dysplasia, fifth finger camptodactyly, preaxial polydactyly of one foot, and ispilateral tibial hemimelia. His father was born with a bifid nose, broad columnella, broad feet, and a two centimeter leg length discrepancy. The paternal grandmother of the proband is phenotypically normal; however, her fraternal twin died at birth with severe facial anomalies. The paternal great-grandmother of the proband is phenotypically normal however her niece was born with moderate ocular hypertelorism. This pedigree is suggestive of an autosomal dominant form of frontonasal dysplasia with variable expressivity. The phenotypic features of our case more closely resemble the Xt mouse than the previously defined features of Greig syndrome in humans. This suggests that a mutation in GLI3 may be responsible for FND in this family. We are currently using polymorphic dinucleotide repeat markers flanking GLI3 in a attempt to demonstrate linkage in this pedigree. Demonstration of a GLI3 mutation in this family would broaden our view of the spectrum of phenotypes possible in Greig syndrome and could provide insight into genotype/phenotype correlation in FND.

Cunningham, M.L.; Nunes, M.E. [Univ. of Washington, Seattle, WA (United States)

1994-09-01

208

Adult-onset autosomal dominant leukodystrophy without early autonomic dysfunctions linked to lamin B1 duplication: a phenotypic variant.  

PubMed

The early presentation of autonomic dysfunctions at the disease onset has been considered the mandatory clinical feature in adult-onset autosomal dominant leukodystrophy, which is a rarely recognised leukodystrophy caused by duplication of the lamin B1 gene. We report the first family with adult-onset autosomal dominant leukodystrophy and lamin B1 duplication, without the distinguishing early-appearing autonomic dysfunctions. Subjects from three consecutive generations of a multi-generational Serbian family affected by adult-onset autosomal dominant leukodystrophy underwent clinical, biochemical, neurophysiological, neuroradiological, and genetic studies. The patients atypically exhibited late autonomic dysfunctions commencing at the disease end-stages in some. Genetic findings of lamin B1 duplication verified adult-onset autosomal dominant leukodystrophy, which was supported also by neuroimaging studies. Exclusively, proton magnetic spectroscopy of the brain revealed a possibility of neuro-axonal damage in the white matter lesions, while magnetic resonance imaging of the spinal cord excluded spinal myelin affection as a required finding in this leukodystrophy. The detection of lamin B1 duplication, even when autonomic dysfunctions do not precede the other symptoms of the disease, proves for the first time that lamin B1-duplicated adult-onset autosomal dominant leukodystrophy may have a phenotypic variant with delayed autonomic dysfunctions. Prior to this report, such a phenotype had been speculated to represent an entity different from lamin B1-duplicated leukodystrophy. Hereby we confirm the underlying role of lamin B1 duplication, regardless of the autonomic malfunction onset in this disorder. It is the only report on adult-onset autosomal dominant leukodystrophy from Southeastern Europe. PMID:23681646

Potic, Ana; Pavlovic, Aleksandra M; Uziel, Graziella; Kozic, Dusko; Ostojic, Jelena; Rovelli, Attilio; Sternic, Nadezda; Bjelan, Mladen; Sarto, Elisa; Di Bella, Daniela; Taroni, Franco

2013-05-17

209

Preclinical trials in autosomal dominant AD: Implementation of the DIAN-TU trial.  

PubMed

The Dominantly Inherited Alzheimer's Network Trials Unit (DIAN-TU) was formed to direct the design and management of interventional therapeutic trials of international DIAN and autosomal dominant Alzheimer's disease (ADAD) participants. The goal of the DIAN-TU is to implement safe trials that have the highest likelihood of success while advancing scientific understanding of these diseases and clinical effects of proposed therapies. The DIAN-TU has launched a trial design that leverages the existing infrastructure of the ongoing DIAN observational study, takes advantage of a variety of drug targets, incorporates the latest results of biomarker and cognitive data collected during the observational study, and implements biomarkers measuring Alzheimer's disease (AD) biological processes to improve the efficiency of trial design. The DIAN-TU trial design is unique due to the sophisticated design of multiple drugs, multiple pharmaceutical partners, academics servings as sponsor, geographic distribution of a rare population and intensive safety and biomarker assessments. The implementation of the operational aspects such as home health research delivery, safety magnetic resonance imagings (MRIs) at remote locations, monitoring clinical and cognitive measures, and regulatory management involving multiple pharmaceutical sponsors of the complex DIAN-TU trial are described. PMID:24016464

Mills, S M; Mallmann, J; Santacruz, A M; Fuqua, A; Carril, M; Aisen, P S; Althage, M C; Belyew, S; Benzinger, T L; Brooks, W S; Buckles, V D; Cairns, N J; Clifford, D; Danek, A; Fagan, A M; Farlow, M; Fox, N; Ghetti, B; Goate, A M; Heinrichs, D; Hornbeck, R; Jack, C; Jucker, M; Klunk, W E; Marcus, D S; Martins, R N; Masters, C M; Mayeux, R; McDade, E; Morris, J C; Oliver, A; Ringman, J M; Rossor, M N; Salloway, S; Schofield, P R; Snider, J; Snyder, P; Sperling, R A; Stewart, C; Thomas, R G; Xiong, C; Bateman, R J

2013-09-06

210

Prevalence of Disease-Causing Mutations in Families with Autosomal Dominant Retinitis Pigmentosa  

PubMed Central

Purpose To survey families with clinical evidence of autosomal dominant retinitis pigmentosa (adRP) for mutations in genes known to cause adRP. Methods Two hundred adRP families, drawn from a cohort of more than 400 potential families, were selected by analysis of pedigrees. Minimum criteria for inclusion in the adRP cohort included either evidence of at least three generations of affected individuals or two generations with evidence of male-to-male transmission. Probands from each family were screened for mutations in 13 genes known to cause adRP: CA4, CRX, FSCN2, IMPDH1, NRL, PRPF3 (RP18), PRPF8 (RP13), PRPF31 (RP11), RDS, RHO, ROM1, RP1, and RP9. Families without mutations in autosomal genes and in which an X-linked mode of inheritance could not be excluded were tested for mutations in ORF 15 of X-linked RPGR. Potentially pathogenic variants were evaluated based on a variety of genetic and computational criteria, to confirm or exclude pathogenicity. Results A total of 82 distinct, rare (nonpolymorphic) variants were detected among the genes tested. Of these, 57 are clearly pathogenic based on multiple criteria, 10 are probably pathogenic, and 15 are probably benign. In the cohort of 200 families, 94 (47%) have one of the clearly pathogenic variants and 10 (5%) have one of the probably pathogenic variants. One family (0.5%) has digenic RDS-ROM1 mutations. Two families (1%) have a pathogenic RPGR mutation, indicating that families with apparent autosomal transmission of RP may actually have X-linked genetic disease. Thus, 107 families (53.5%) have mutations in known genes, leaving 93 whose underlying cause is still unknown. Conclusions Together, the known adRP genes account for retinal disease in approximately half of the families in this survey, mostly Americans of European origin. Among the adRP genes, IMPDH1, PRPF8, PRPF31, RDS, RHO, and RP1 each accounts for more than 2% of the total; CRX, PRPF3, and RPGR each accounts for roughly 1%. Disease-causing mutations were not found in CA4, FSCN2, NRL, or RP9. Because some mutations are frequent and some regions are more likely to harbor mutations than others, more than two thirds of the detected mutations can be found by screening less than 10% of the total gene sequences. Among the remaining families, mutations may lie in regions of known genes that were not tested, mutations may not be detectable by PCR-based sequencing, or other loci may be involved.

Sullivan, Lori S.; Bowne, Sara J.; Birch, David G.; Hughbanks-Wheaton, Dianna; Heckenlively, John R.; Lewis, Richard Alan; Garcia, Charles A.; Ruiz, Richard S.; Blanton, Susan H.; Northrup, Hope; Gire, Anisa I.; Seaman, Robyn; Duzkale, Hatice; Spellicy, Catherine J.; Zhu, Jingya; Shankar, Suma P.; Daiger, Stephen P.

2008-01-01

211

Herpes simplex encephalitis in children with autosomal recessive and dominant TRIF deficiency  

PubMed Central

Herpes simplex encephalitis (HSE) is the most common sporadic viral encephalitis of childhood. Autosomal recessive (AR) UNC-93B and TLR3 deficiencies and autosomal dominant (AD) TLR3 and TRAF3 deficiencies underlie HSE in some children. We report here unrelated HSE children with AR or AD TRIF deficiency. The AR form of the disease was found to be due to a homozygous nonsense mutation that resulted in a complete absence of the TRIF protein. Both the TLR3- and the TRIF-dependent TLR4 signaling pathways were abolished. The AD form of disease was found to be due to a heterozygous missense mutation, resulting in a dysfunctional protein. In this form of the disease, the TLR3 signaling pathway was impaired, whereas the TRIF-dependent TLR4 pathway was unaffected. Both patients, however, showed reduced capacity to respond to stimulation of the DExD/H-box helicases pathway. To date, the TRIF-deficient patients with HSE described herein have suffered from no other infections. Moreover, as observed in patients with other genetic etiologies of HSE, clinical penetrance was found to be incomplete, as some HSV-1–infected TRIF-deficient relatives have not developed HSE. Our results provide what we believe to be the first description of human TRIF deficiency and a new genetic etiology for HSE. They suggest that the TRIF-dependent TLR4 and DExD/H-box helicase pathways are largely redundant in host defense. They further demonstrate the importance of TRIF for the TLR3-dependent production of antiviral IFNs in the CNS during primary infection with HSV-1 in childhood.

Sancho-Shimizu, Vanessa; Perez de Diego, Rebeca; Lorenzo, Lazaro; Halwani, Rabih; Alangari, Abdullah; Israelsson, Elisabeth; Fabrega,, Sylvie; Cardon, Annabelle; Maluenda, Jerome; Tatematsu, Megumi; Mahvelati, Farhad; Herman, Melina; Ciancanelli, Michael; Guo, Yiqi; AlSum, Zobaida; Alkhamis, Nouf; Al-Makadma, Abdulkarim S.; Ghadiri, Ata; Boucherit, Soraya; Plancoulaine, Sabine; Picard, Capucine; Rozenberg, Flore; Tardieu, Marc; Lebon, Pierre; Jouanguy, Emmanuelle; Rezaei, Nima; Seya, Tsukasa; Matsumoto, Misako; Chaussabel, Damien; Puel, Anne; Zhang, Shen-Ying; Abel, Laurent; Al-Muhsen, Saleh; Casanova, Jean-Laurent

2011-01-01

212

Autosomal dominant cerebellar ataxia type I: a review of the phenotypic and genotypic characteristics.  

PubMed

Type I autosomal dominant cerebellar ataxia (ADCA) is a type of spinocerebellar ataxia (SCA) characterized by ataxia with other neurological signs, including oculomotor disturbances, cognitive deficits, pyramidal and extrapyramidal dysfunction, bulbar, spinal and peripheral nervous system involvement. The global prevalence of this disease is not known. The most common type I ADCA is SCA3 followed by SCA2, SCA1, and SCA8, in descending order. Founder effects no doubt contribute to the variable prevalence between populations. Onset is usually in adulthood but cases of presentation in childhood have been reported. Clinical features vary depending on the SCA subtype but by definition include ataxia associated with other neurological manifestations. The clinical spectrum ranges from pure cerebellar signs to constellations including spinal cord and peripheral nerve disease, cognitive impairment, cerebellar or supranuclear ophthalmologic signs, psychiatric problems, and seizures. Cerebellar ataxia can affect virtually any body part causing movement abnormalities. Gait, truncal, and limb ataxia are often the most obvious cerebellar findings though nystagmus, saccadic abnormalities, and dysarthria are usually associated. To date, 21 subtypes have been identified: SCA1-SCA4, SCA8, SCA10, SCA12-SCA14, SCA15/16, SCA17-SCA23, SCA25, SCA27, SCA28 and dentatorubral pallidoluysian atrophy (DRPLA). Type I ADCA can be further divided based on the proposed pathogenetic mechanism into 3 subclasses: subclass 1 includes type I ADCA caused by CAG repeat expansions such as SCA1-SCA3, SCA17, and DRPLA, subclass 2 includes trinucleotide repeat expansions that fall outside of the protein-coding regions of the disease gene including SCA8, SCA10 and SCA12. Subclass 3 contains disorders caused by specific gene deletions, missense mutation, and nonsense mutation and includes SCA13, SCA14, SCA15/16, SCA27 and SCA28. Diagnosis is based on clinical history, physical examination, genetic molecular testing, and exclusion of other diseases. Differential diagnosis is broad and includes secondary ataxias caused by drug or toxic effects, nutritional deficiencies, endocrinopathies, infections and post-infection states, structural abnormalities, paraneoplastic conditions and certain neurodegenerative disorders. Given the autosomal dominant pattern of inheritance, genetic counseling is essential and best performed in specialized genetic clinics. There are currently no known effective treatments to modify disease progression. Care is therefore supportive. Occupational and physical therapy for gait dysfunction and speech therapy for dysarthria is essential. Prognosis is variable depending on the type of ADCA and even among kindreds. PMID:21619691

Whaley, Nathaniel Robb; Fujioka, Shinsuke; Wszolek, Zbigniew K

2011-05-28

213

Autosomal dominant polycystic kidney disease: evidence for the existence of a third locus in a Portuguese family  

Microsoft Academic Search

Autosomal dominant polycystic kidney disease is characterized by clinical and genetic heterogeneity. Two loci implicated in the disease have previously been mapped (PKD1 on chromosome 16 and PKD2 on chromosome 4). By two point and multipoint linkage analysis, negative lod scores have been found for both chromosome 16 and chromosome 4 markers in a large Portuguese family, indicating that a

Salomé Almeida; Edgar Almeida; Dorien Peters; José Reimão Pinto; Isabel Távora; João Lavinha; Martjn Breuning; Mateus Martins Prata

1995-01-01

214

ROLE AND LONG-TERM RESULTS OF LAPAROSCOPIC DECORTICATION IN SOLITARY CYSTIC AND AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE  

Microsoft Academic Search

PurposeAccess to retroperitoneal structures via the laparoscope has become established for various conditions. This minimally invasive approach has distinct advantages over conventional open surgery. We document our experience with laparoscopic cyst decortication for diseases of the kidney, including simple and complex cysts, multiple cysts and autosomal dominant polycystic kidney disease.

BARRY J. LIFSON; JOEL M. H. TEICHMAN; JOHN C. HULBERT

1998-01-01

215

Relative Contribution of Mutations in Genes for Autosomal Dominant Distal Hereditary Motor Neuropathies: A Genotype-Phenotype Correlation Study  

ERIC Educational Resources Information Center

Distal hereditary motor neuropathy (HMN) is a clinically and genetically heterogeneous group of disorders affecting spinal alpha-motor neurons. Since 2001, mutations in six different genes have been identified for autosomal dominant distal HMN; "glycyl-tRNA synthetase (GARS)," "dynactin 1 (DCTN1)," "small heat shock 27 kDa protein 1 (HSPB1),"…

Dierick, Ines; Baets, Jonathan; Irobi, Joy; Jacobs, An; De Vriendt, Els; Deconinck, Tine; Merlini, Luciano; Van den Bergh, Peter; Rasic, Vedrana Milic; Robberecht, Wim; Fischer, Dirk; Morales, Raul Juntas; Mitrovic, Zoran; Seeman, Pavel; Mazanec, Radim; Kochanski, Andrzej; Jordanova, Albena; Auer-Grumbach, Michaela; Helderman-van den Enden, A. T. J. M.; Wokke, John H. J.; Nelis, Eva; De Jonghe, Peter; Timmerman, Vincent

2008-01-01

216

Study of candidate genes affecting the progression of renal disease in autosomal dominant polycystic kidney disease type 1  

Microsoft Academic Search

Background. Autosomal dominant polycystic kidney disease (ADPKD) is a systemic disorder with a wide spectrum of renal involvement. Differences in the age at onset of end-stage renal disease (ESRD) are partially explained by the genetic heterogeneity of the disease but intrafamilial variability remains to be explained. Modifier genes may play a role in disease severity. Methods. A total of 355

Barbara Tazon-Vega; Mireia Vilardell; Laureano Perez-Oller; Elisabet Ars; Patricia Ruiz; Olivier Devuyst; Xose Lens; Patricia Fernandez-Llama; Roser Torra

2007-01-01

217

Mutations in PDGFRB and NOTCH3 are the first genetic causes identified for autosomal dominant infantile myofibromatosis.  

PubMed

A recurrent PDGFRB mutation causes familial infantile myofibromatosis Cheung et al. (2013) The American Journal of Human Genetics 92: 996-1000. Mutations in PDGFRB cause autosomal-dominant infantile myofibromatosis Martignetti et al. (2013) The American Journal of Human Genetics 92: 1001-1007. PMID:23865785

Lee, Jw

2013-07-31

218

Exclusion of the familial Mediterranean fever locus as a susceptibility region for autosomal dominant familial Hibernian fever  

Microsoft Academic Search

Autosomal dominant periodic fevers constitute a range of syndromes characterised by recurrent attacks of fever and abdominal pain. Familial Hibernian fever (FHF) has been described in only one United Kingdom based family, but two other Irish families have been found with similar clinical features. FHF resembles familial Mediterranean fever (FMF) in several clinical features, but the mode of inheritance of

M F McDermott; E M McDermott; K A Quane; L C Jones; B W Ogunkolade; D Curtis; F Waldron-Lynch; M Phelan; G A Hitman; M G Molloy; R J Powell

1998-01-01

219

Is the neuropathological ‘gold standard’ diagnosis dead? Implications of clinicopathological findings in an autosomal dominant neurodegenerative disorder  

Microsoft Academic Search

Genetically-derived neurodegenerative disorders offer a rare opportunity to test validity of neuropathological criteria for diagnosis. Implications regarding an autosomal dominant neurodegenerative disorder (PARK 8) in which four different neuropathological diagnoses were found at autopsy are discussed. We suggest that just as there is currently no clinical ‘gold standard’ for Parkinson's disease, there is no pathological ‘gold standard.’ We conclude that

Ryan J. Uitti; Donald B. Calne; Dennis W. Dickson; Zbigniew K. Wszolek

2004-01-01

220

Relative Contribution of Mutations in Genes for Autosomal Dominant Distal Hereditary Motor Neuropathies: A Genotype-Phenotype Correlation Study  

ERIC Educational Resources Information Center

|Distal hereditary motor neuropathy (HMN) is a clinically and genetically heterogeneous group of disorders affecting spinal alpha-motor neurons. Since 2001, mutations in six different genes have been identified for autosomal dominant distal HMN; "glycyl-tRNA synthetase (GARS)," "dynactin 1 (DCTN1)," "small heat shock 27 kDa protein 1 (HSPB1),"…

Dierick, Ines; Baets, Jonathan; Irobi, Joy; Jacobs, An; De Vriendt, Els; Deconinck, Tine; Merlini, Luciano; Van den Bergh, Peter; Rasic, Vedrana Milic; Robberecht, Wim; Fischer, Dirk; Morales, Raul Juntas; Mitrovic, Zoran; Seeman, Pavel; Mazanec, Radim; Kochanski, Andrzej; Jordanova, Albena; Auer-Grumbach, Michaela; Helderman-van den Enden, A. T. J. M.; Wokke, John H. J.; Nelis, Eva; De Jonghe, Peter; Timmerman, Vincent

2008-01-01

221

Prenatal diagnosis of autosomal dominant polycystic kidney disease (PKD1) presenting in utero and prognosis for very early onset disease  

Microsoft Academic Search

We describe four prenatal diagnoses in a family with autosomal dominant polycystic kidney disease. Two pregnancies were terminated following the detection of enlarged echogenic fetal kidneys with cysts. Histopathological examination confirmed the diagnosis of polycystic kidney disease. Linkage to PKD1 was obtained by the analysis of DNA from relatives in three generations and from paraffin blocks and formalin fixed fetal

K D MacDermot; A K Saggar-Malik; D L Economides; S Jeffery

1998-01-01

222

Concurrent Renal Cell Carcinoma and Central Nervous System Lymphoma in a Patient with Autosomal Dominant Polycystic Kidney Disease  

Microsoft Academic Search

Objective: To report an unusual case of synchronous renal cell carcinoma and CNS lymphoma in a patient with autosomal dominant polycystic kidney disease (ADPKD). Case Presentation and Intervention: A 58-year-old woman presented with progressive right hemiparesis of 2 months’ duration. A brain CT scan revealed multiple enhanced lesions in the basal ganglia and the right occipital lobe. CNS lymphoma was

Ming-Yang Chang; Yu-Ming Chen; Yung-Cheng Chen; Ya-Chung Tian; Ji-Tseng Fang; Chih-Wei Yang

2009-01-01

223

A novel GJA8 mutation (p.I31T) causing autosomal dominant congenital cataract in a Chinese family  

Microsoft Academic Search

Purpose: To identify the genetic defect associated with autosomal dominant congenital nuclear cataract in a Chinese family. Methods: Family history and clinical data were recorded. The genomic DNA was extracted from peripheral blood leukocytes. All the members were genotyped with microsatellite markers at loci considered to be associated with cataracts. Two-point logarithm of odds (LOD) scores were calculated by using

Kaijie Wang; Binbin Wang; Jing Wang; Shiyi Zhou; Bo Yun; Peisu Suo; Jie Cheng; Xu Ma; Siquan Zhu

2009-01-01

224

Mitochondrial Oxidative Phosphorylation Compensation May Preserve Vision in Patients with OPA1Linked Autosomal Dominant Optic Atrophy  

Microsoft Academic Search

Autosomal Dominant Optic Atrophy (ADOA) is the most common inherited optic atrophy where vision impairment results from specific loss of retinal ganglion cells of the optic nerve. Around 60% of ADOA cases are linked to mutations in the OPA1 gene. OPA1 is a fission-fusion protein involved in mitochondrial inner membrane remodelling. ADOA presents with marked variation in clinical phenotype and

Nicole J. van Bergen; Jonathan G. Crowston; Lisa S. Kearns; Sandra E. Staffieri; Alex W. Hewitt; Amy C. Cohn; David A. Mackey; Ian A. Trounce; Janine Santos

2011-01-01

225

An autosomal dominant cataract locus mapped to 19q13-qter in a Chinese family  

PubMed Central

Purpose The aim of this study was to map the disease locus of autosomal dominant cataracts (ADC) in a Chinese family. Methods A four-generation family with multiple individuals affected by ADC was investigated. Genomic DNA was collected from 22 family members. A gene-scan at known candidate ADC loci was performed. To achieve fine-mapping we genotyped fourteen STR markers at the critical region of 19q. The two-point logarithm of odds (LOD) score was calculated using Linkage Software Package Version 5.1 for linkage analysis. The haplotype was constructed using Cyrillic software. Results Ten members of this Chinese family were affected by nuclear cataracts. Initially, linkage analysis revealed a significant LOD score of 3.82 at the STR marker D19S418. Subsequently, after refine-marker analysis, a maximum LOD score (Zmax=4.25) was obtained at the D19S877 (?=0). Haplotype analysis also confirmed the locus and further narrowed it down to a critical interval from the marker D19S924 to the 19qter. Conclusions We have successfully mapped an ADC locus to 19q13-qter. Previous studies have identified three cataract loci on 19q; however, we found no overlap between the locus of this study and any of the previously identified loci. We therefore suggest that the 19q13-qter locus in this family is a new locus for ADC.

Zhao, Rui; Yang, Yonjia; He, Xinyu; Liu, Zheng; Wang, Pin; Zhou, Lijun; Tang, Jinsong; Xu, Wei; Li, Liping

2011-01-01

226

From bone abnormalities to mineral metabolism dysregulation in autosomal dominant polycystic kidney disease.  

PubMed

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic cause of kidney failure. It is a systemic disorder, not only affecting the kidneys, but also associated with cyst formation in other organs such as the liver, spleen, pancreas, and seminal vesicles. Other extra-renal symptoms may consist of intracranial arterial aneurysms, cardiac valvular defects, abdominal and inguinal hernias and colonic diverticulosis. Very little is known regarding bone involvement in ADPKD; however, recent evidence has revealed the potential role of fibroblast growth factor 23 (FGF23). FGF23 is an endocrine fibroblast growth factor acting in the kidney as a phosphaturic hormone and a suppressor of active vitamin D with key effects on the bone/kidney/parathyroid axis, and has been shown to increase in patients with ADPKD, even with normal renal function. The aim of this review is to provide an overview of bone and mineral abnormalities found in experimental models and in patients with ADPKD, and to discuss the possible role of FGF23 in this disease. PMID:23340856

Mekahli, Djalila; Bacchetta, Justine

2013-01-24

227

A mutation in the dnmt1 gene causing autosomal dominant ataxia with deafness and cataplexy.  

PubMed

We describe the clinical features of the first UK family with the recently described autosomal dominant cerebellar ataxia, deafness and narcolepsy associated with mutations in exon 21 of the DNMT1 gene. Only four other families have been described Worldwide. The proband presented at the age of 53 years with a ten year history of unsteadiness and episodes of emotionally induced cataplexy. A cerebellar syndrome with accompanying ptosis, myoclonus and mild long-tract signs were notable on examination. The patient's father was said to have had epilepsy and deafness. Examination of two other of the patients siblings revealed two other affected individuals (aged 58 and 60 years) with similar clinical features but with varying degrees of additional cognitive disturbance and optic atrophy. In addition, investigation of two of the offspring of one of the affected siblings revealed problems with cataplexy from their 20s. MR Imaging of the proband revealed mild generalised involutional changes, EEG interictal epileptiform discharges, multiple sleep latency testing, neurophysiology and a muscle biopsy were within normal limits. Imaging of the more clinically affected siblings revealed more substantial cortical changes. Sequencing of exon 21 of the DNMT1 gene revealed the previously described Ala570Val mutation. PMID:24108910

David, Gosal; John, Ealing; Emmanuel, Mignot

2013-11-01

228

Molecular consequences of amyloid precursor protein and presenilin mutations causing autosomal-dominant Alzheimer's disease  

PubMed Central

Mutations in both the amyloid precursor protein (APP) and the presenilin (PSEN) genes cause familial Alzheimer's disease (FAD) with autosomal dominant inheritance and early onset of disease. The clinical course and neuropathology of FAD and sporadic Alzheimer's disease are highly similar, and patients with FAD constitute a unique population in which to conduct treatment and, in particular, prevention trials with novel pharmaceutical entities. It is critical, therefore, to exactly defi ne the molecular consequences of APP and PSEN FAD mutations. Both APP and PSEN mutations drive amyloidosis in FAD patients through changes in the brain metabolism of amyloid-? (A?) peptides that promote the formation of pathogenic aggregates. APP mutations do not seem to impair the physiological functions of APP. In contrast, it has been proposed that PSEN mutations compromise ?-secretase-dependent and -independent functions of PSEN. However, PSEN mutations have mostly been studied in model systems that do not accurately refl ect the genetic background in FAD patients. In this review, we discuss the reported cellular phenotypes of APP and PSEN mutations, the current understanding of their molecular mechanisms, the need to generate faithful models of PSEN mutations, and the potential bias of APP and PSEN mutations on therapeutic strategies that target A?.

2012-01-01

229

Linkage mapping and phenotypic analysis of autosomal dominant Pallister-Hall syndrome.  

PubMed Central

Pallister-Hall syndrome is a human developmental disorder that is inherited in an autosomal dominant pattern. The phenotypic features of the syndrome include hypothalamic hamartoma, polydactyly, imperforate anus, laryngeal clefting, and other anomalies. Here we describe the clinical characterisation of a family with 22 affected members and the genetic mapping of the corresponding locus. Clinical, radiographic, and endoscopic evaluations showed that this disorder is a fully penetrant trait with variable expressivity and low morbidity. By analysing 60 subjects in two families using anonymous STRP markers, we have established linkage to 7p13 by two point analysis with D7S691 resulting in a lod score of 7.0 at theta = 0, near the GLI3 locus. Deletions and translocations in GLI3 are associated with the Greig cephalopolysyndactyly syndrome. Although Greig cephalopolysyndactyly syndrome has some phenotypic overlap with Pallister-Hall syndrome, these two disorders are clinically distinct. The colocalisation of loci for these distinct phenotypes led us to analyse GLI3 for mutations in patients with Pallister-Hall syndrome. We have previously shown GLI3 mutations in two other small, moderately affected families with Pallister-Hall syndrome. The linkage data reported here suggest that these larger, mildly affected families may also have mutations in GLI3. Images

Kang, S; Allen, J; Graham, J M; Grebe, T; Clericuzio, C; Patronas, N; Ondrey, F; Green, E; Schaffer, A; Abbott, M; Biesecker, L G

1997-01-01

230

Identification of the autosomal dominant polycystic kidney disease gene, PKD1  

SciTech Connect

The PKDl gene was localized to an {approximately}480 kb interval of chromosome 16pl3. More than 20 independent transcripts were found in the interval. In view of the high new mutation rate in autosomal dominant polycystic kidney diseases (ADPKD), we anticipated the PKD1 gene would be large. The largest transcript in the region was represented by five cDNA clones located adjacent to the tuberin gene (TSC2). Two of these clones, KG8 and NKG9, contain {approximately}4.5 kb of contiguous sequence corresponding to the 3{prime} end of the 14 kb mRNA which is transcribed from telomeric to centromeric. They spans 11 exons, and to evaluate the reading frame of the cDNA, we have compared the human and monkey sequence using human primers, and found 90-94% identity at the DNA level, and by observing amino acid conservation, determined the reading frame. To date, our open-reading frame of {approximately}800 amino-acids contained only a potential threonine kinase site, but no other recognizable peptide motifs or repeats, and was not homologous to sequences in Swissprot and GenBank. No Southern blot abnormalities have been detected with the cDNA probes used. However, an exon-by-exon scan of 8 exons for mutations by SSCP and genomic sequencing (predicted missense changes) has identified 3 patients with mutations not found in normals, and identify the KG8 gene as the PKD1 gene.

Schneider, M.C.; Zhang, F.; Geng, L. [Harvard Medical School, Boston, MA (United States)] [and others

1994-09-01

231

Percutaneous Treatment of Pyocystis in Patients with Autosomal Dominant Polycystic Kidney Disease  

SciTech Connect

The course of autosomal dominant polycystic kidney disease (ADPKD) is frequently complicated by infection of a cyst within a polycystic kidney, which is a diagnostic and therapeutic dilemma damaging the clinical course of patients. The aim of this study was to demonstrate the safety and efficacy of percutaneous drainage in management of infected cysts in ADPKD patients. Between May 2003 and December 2006, percutaneous drainage was performed in 16 infected renal cysts of four kidneys in three patients (two females, one male), with a mean age of 57.3 years. Cyst dimensions, total amount of drained cyst fluid, catheterization duration, isolated microorganisms, and follow-up duration were recorded. Technical, clinical success rates were 100%; the complication rate was 0%. Diameters of cysts ranged between 3 and 8 cm. Average volume of drained fluid and average duration of catheterization for one cyst were 226 ml and 9.8 days. No recurrence was encountered but one patient (no. 3), who had pyocystis in the right kidney and was treated with catheterization, referred with left flank pain due to pyocystis in her left kidney 3 months later. Follow-up durations were 35, 47, and 11 months for patients 1, 2, and 3, respectively. For patient 3, follow-up duration for the second procedure was 7 months. We conclude that percutaneous drainage with antibiotic therapy should be the initial method in management of infected cysts in ADPKD patients, with high success and low complication rates.

Akinci, Devrim, E-mail: akincid@yahoo.com; Turkbey, Baris, E-mail: bturkbey@yahoo.co [Hacettepe University School of Medicine, Department of Radiology (Turkey); Yilmaz, Rahmi [Hacettepe University School of Medicine, Department of Nephrology (Turkey); Akpinar, Erhan; Ozmen, Mustafa N.; Akhan, Okan [Hacettepe University School of Medicine, Department of Radiology (Turkey)

2008-09-15

232

Liver cysts in autosomal-dominant polycystic kidney disease: clinical and computed tomographic study  

SciTech Connect

Hepatic CT findings were analyzed in 44 patients with autosomal-dominant polycystic kidney disease and were correlated with liver and renal function tests and liver, splenic, and renal CT volume measurements. CT showed many large liver cysts in 31.8% of patients, small liver cysts in 25%, and no liver cysts in 43.2%. Patients with many large cysts often showed increased liver volumes. There was no correlation between severity of liver involvement and extent of renal cystic disease as determined from urea nitrogen and creatinine levels and renal volumes. Liver function tests were normal except in two patients, one with a cholangiocarcinoma, which may have arisen from a cyst, and the other with an infected liver cyst and chronic active hepatitis. Accordingly, if liver function tests are abnormal, an attempt should be made to identify complications of polycystic liver disease such as tumor cyst infection, and biliary obstruction. CT is a useful method for detecting liver cysts and identifying patients at risk for these complications.

Levine, E.; Cook, L.T.; Grantham, J.J.

1985-08-01

233

A fourth locus for autosomal dominant hypercholesterolemia maps at 16q22.1  

PubMed Central

Autosomal dominant hypercholesterolemia (ADH) is characterized by isolated increase in plasmatic low-density lipoprotein (LDL) cholesterol levels associated with high risk of premature cardiovascular disease. Mutations in LDLR, APOB, and PCSK9 genes have been shown to cause ADH. We now report further genetic heterogeneity of ADH through the study of a large French family in which the involvement of these three genes was excluded. A genome-wide scan mapped the disease-causing gene, named HCHOLA4, at 16q22.1 in a 7.89-Mb interval containing 154 genes with a maximum LOD score of 3.9. To reduce the linked region, we genotyped 18 smaller non-LDLR/non-APOB/non-PCSK9-ADH families at the HCHOLA4 locus. Six families did not exclude linkage to the locus, but none allowed reduction of the disease interval. The 154 regional genes were sorted according to the function of the encoded protein and tissue expression profiles, and 57 genes were analyzed through sequencing of their coding region and close flanking intronic parts. No disease-causing mutation was identified in these families, particularly in the LCAT gene. Finally, our results also show the existence of other ADH genes as nine families were neither linked to LDLR, APOB, and PCSK9 genes nor to the new HCHOLA4 locus.

Marques-Pinheiro, Alice; Marduel, Marie; Rabes, Jean-Pierre; Devillers, Martine; Villeger, Ludovic; Allard, Delphine; Weissenbach, Jean; Guerin, Maryse; Zair, Yassine; Erlich, Daniele; Junien, Claudine; Munnich, Arnold; Krempf, Michel; Abifadel, Marianne; Jais, Jean-Philippe; Boileau, Catherine; Varret, Mathilde

2010-01-01

234

BEST1-related autosomal dominant vitreoretinochoroidopathy: a degenerative disease with a range of developmental ocular anomalies  

PubMed Central

Purpose To describe the spectrum of phenotypic characteristics of BEST1-related autosomal dominant vitreoretinochoroidopathy (ADVIRC) in a family with p.V86M mutation. Methods A retrospective review of the clinical, psychophysical, and electrophysiological phenotypes of six subjects with ADVIRC. Five family members were sequenced for mutations in the BEST1gene. Results A heterozygous change, p.V86M (c.256G>A), was identified in the BEST1gene in the three affected subjects tested, and was shown to segregate with the disease phenotype. The distance visual acuity ranged from ?20/25 to absent perception of light. Clinical features observed included angle closure glaucoma (n=2), microcornea with shallow anterior chamber (n=1), iris dysgenesis (n=2), cataracts (n=4), classical peripheral concentric band of retinal hyperpigmentation (n=5), and optic nerve dysplasia (n=1). Full-field electroretinogram response amplitudes ranged from low normal (two cases; 27 and 32 years) to non-recordable (two cases; 42 and 63 years). Goldmann fields were normal in two (27 and 28 years) but were abnormal in two older subjects. Optical coherence tomography showed macular thinning in the proband, whereas his affected daughter had normal macular thickness. Electro-oculography showed borderline Arden's ratio (1.50) in the lone case tested (27 years). Conclusion ADVIRC is a slowly progressive vitreoretinal degeneration that demonstrates marked intra-familial phenotypic variability. Optic nerve dysplasia and iris dysgenesis are novel observations that extend the ocular phenotype of ADVIRC.

Vincent, A; McAlister, C; VandenHoven, C; Heon, E

2011-01-01

235

WHIM syndrome, an autosomal dominant disorder: clinical, hematological, and molecular studies.  

PubMed

The acronym WHIM refers to Warts, Hypogammaglobulinemia, Infections, and Myelokathexis. The latter refers to the retention of white cells in the marrow, which becomes hypercellular. We have found approximately 20 examples of WHIM syndrome in the literature under various designations; the first examples are Zuelzer [1964] and Krill et al. [1964]. Chronic noncyclic neutropenia and hypercellular bone marrow represent defective release of marrow cells into the peripheral stream (myelokathexis). The hypermature neutrophils are bizarre in form. Condensed nuclei connected by long, stringy filaments and vacuolated cytoplasm suggest apoptosis. Fever or other stress increases the release of neutrophils. Hypogammaglobulinemia is marked and associated with recurrent upper respiratory infections (sinusitis, tonsillitis, otitis media, pneumonia). Patients have numerous warts, some venereal, with resultant cervical and vulval premalignant dysplasia. We report on a kindred of 6 affected individuals in 3 generations with autosomal dominant WHIM syndrome. The sex ratio among reported patients and in our kindred is 17 female to 8 male. Because there had been no male-to-male transmssion, search of the entire X-chromosome including the pseudoautosomal area was carried out and no linkage was found. Recently, the propositus has had an unaffected daughter, confirming our finding that the gene is not X-linked. A genome-wide search is being carried out. PMID:10767001

Gorlin, R J; Gelb, B; Diaz, G A; Lofsness, K G; Pittelkow, M R; Fenyk, J R

2000-04-24

236

A Novel Missense SNRNP200 Mutation Associated with Autosomal Dominant Retinitis Pigmentosa in a Chinese Family  

PubMed Central

The SNRNP200 gene encodes hBrr2, a helicase essential for pre-mRNA splicing. Six mutations in SNRNP200 have recently been discovered to be associated with autosomal dominant retinitis pigmentosa (adRP). In this work, we analyzed a Chinese family with adRP and identified a novel missense mutation in SNRNP200. To identify the genetic defect in this family, exome of the proband was captured and sequencing analysis was performed to exclude known genetic defects and find possible pathogenic mutations. Subsequently, candidate mutations were validated in affected family members using Sanger sequencing. A novel missense mutation, c.2653C>G transition (p.Q885E), in exon 20 of SNRNP200 was identified. The mutation co-segregated with the disease phenotype over four generations and was absent in 100 normal unaffected individuals. This mutation occurs at highly conserved position in hBrr2 and is predicted to have a functional impact, suggesting that hBrr2-dependent small nuclear riboproteins (snRNPs) unwinding and spliceosome activation is important in the pathogenesis of some variants of RP.

Yuan, Huijun; Cheng, Jing; Lee, Janet; Zhang, Baoquan; Zhang, Maonian; Wu, Jing; Wang, Lijuan; Tian, Geng; Wang, Weifeng

2012-01-01

237

Multiple liver cyst infection caused by Salmonella ajiobo in autosomal dominant polycystic kidney disease.  

PubMed

Most Salmonella infections are usually self-limited; however, some cases of enteritis result in bacteremia, and there have been reports of extra-intestinal manifestations. Cyst infections are rare, and few cases have been reported. We report a 77-year-old woman with autosomal dominant polycystic kidney disease (ADPKD) complicated with a multiple liver cyst infection caused by Salmonella ajiobo. The patient was hospitalized for fever, abdominal pain, and diarrhea. The blood culture identified Salmonella sp., but the source of infection was not detected by computed tomography or echography. The patient was initially treated with meropenem followed by fluoroquinolones for 3 weeks; however, her C-reactive protein level was high (10-20 mg/dL) even after the antimicrobial therapy. The patient had a fever again on day 51, and Salmonella sp. was detected again from 2 sets of blood cultures. Despite the antimicrobial treatment, her general condition gradually deteriorated, and she died on day 66. The autopsy revealed that most of the liver had been replaced by cysts. Several cysts filled with pus were detected and Salmonella ajiobo was identified in the pus of the infected cysts. PMID:23053500

Himeno, Akihiro; Suzuki, Hiromichi; Suzuki, Yumiko; Kawaguchi, Hiroshi; Isozaki, Taisuke

2012-10-06

238

Differential Expression of PKD2-Associated Genes in Autosomal Dominant Polycystic Kidney Disease.  

PubMed

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by formation of multiple fluid-filled cysts that expand over time and destroy renal architecture. The proteins encoded by the PKD1 and PKD2 genes, mutations in which account for nearly all cases of ADPKD, may help guard against cystogenesis. Previously developed mouse models of PKD1 and PKD2 demonstrated an embryonic lethal phenotype and massive cyst formation in the kidney, indicating that PKD1 and PKD2 probably play important roles during normal renal tubular development. However, their precise role in development and the cellular mechanisms of cyst formation induced by PKD1 and PKD2 mutations are not fully understood. To address this question, we presently created Pkd2 knockout and PKD2 transgenic mouse embryo fibroblasts. We used a mouse oligonucleotide microarray to identify messenger RNAs whose expression was altered by the overexpression of the PKD2 or knockout of the Pkd2. The majority of identified mutations was involved in critical biological processes, such as metabolism, transcription, cell adhesion, cell cycle, and signal transduction. Herein, we confirmed differential expressions of several genes including aquaporin-1, according to different PKD2 expression levels in ADPKD mouse models, through microarray analysis. These data may be helpful in PKD2-related mechanisms of ADPKD pathogenesis. PMID:23105924

Yook, Yeon Joo; Woo, Yu Mi; Yang, Moon Hee; Ko, Je Yeong; Kim, Bo Hye; Lee, Eun Ji; Chang, Eun Sun; Lee, Min Joo; Lee, Sunyoung; Park, Jong Hoon

2012-03-31

239

Familial paroxysmal exercise-induced dystonia: atypical presentation of autosomal dominant GTP-cyclohydrolase 1 deficiency.  

PubMed

Paroxysmal exercise-induced dystonia (PED) is one of the rarer forms of paroxysmal dyskinesia, and can occur in sporadic or familial forms. We report a family (male index case, mother and maternal grandfather) with autosomal dominant inheritance of paroxysmal exercise-induced dystonia. The dystonia began in childhood and was only ever induced after many minutes of exercise, and was never present at rest, or on initiation of movements. In addition, family members suffered restless legs syndrome (RLS), depression, and adult-onset Parkinsonism. The index case had low cerebrospinal fluid neurotransmitters and pterins. The PED and RLS stopped on initiation of L-Dopa therapy. Both live family members were found to have a nonsense mutation (p.E84X) in exon 1 of the GTP-cyclohydrolase 1 (GCH-1) gene. We propose that GCH-1 mutations should be considered a genetic cause of familial PED, especially if additional clinical features of monoaminergic deficiency are present in affected individuals. PMID:20187889

Dale, Russell C; Melchers, Anna; Fung, Victor S C; Grattan-Smith, Padraic; Houlden, Henry; Earl, John

2010-02-19

240

Mechanism-based therapeutics for autosomal dominant polycystic kidney disease: recent progress and future prospects.  

PubMed

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease, accounting for up to 10% of patients on renal replacement therapy. There are presently no proven treatments for ADPKD and an effective disease-modifying drug would have significant implications for patients and their families. Since the identification of PKD1 and PKD2, there has been an explosion in knowledge identifying new disease mechanisms and testing new drugs. Currently, the three major treatment strategies are to: (1) reduce cAMP levels; (2) inhibit cell proliferation, and (3) reduce fluid secretion. Several compounds shown to be effective in preclinical models have already undergone clinical trials and more are planned. In addition, a whole raft of other compounds have been developed from preclinical studies. The purpose of this paper is to evaluate the results of recent published trials, review current trials and highlight the most promising compounds in the pipeline. There appears to be no shortage of potential candidates, but several key issues need to be addressed to facilitate clinical translation. PMID:22205396

Chang, Ming-Yang; Ong, Albert C M

2011-12-23

241

A case report of a family with overlapping features of autosomal dominant febrile seizures and GEFS+.  

PubMed

Familial febrile seizures occur in both generalized epilepsy with febrile seizures plus (GEFS+) and autosomal dominant febrile seizures (ADFS). The literature largely separates families with GEFS+ from those with ADFS. However, there is clinical overlap, and families with ADFS also include individuals with afebrile seizures. The phenotypic spectrum of GEFS+ is broader now than when first described, resulting in unclear boundaries between these two familial syndromes. The purpose of this report is to highlight the phenotypic similarities of GEFS+ and ADFS. A multigenerational family with febrile and afebrile seizures is described and the clinical features are compared to those of previously reported GEFS+ and ADFS families. This family meets the requirements for both ADFS and the broader definition of GEFS+. Linkage analysis has shown no clear linkage to known febrile seizure or GEFS+ loci. Despite locus heterogeneity, identified mutations in reported GEFS+ have so far all been in sodium channel or gamma-aminobutyric acid (GABA)-receptor genes, with other modifier genes postulated to affect individual phenotypes. The two mutations identified in families with ADFS are in genes implicated in GEFS+, SCN1A, and GABRG2. We conclude that it is inappropriate to separate GEFS+ and ADFS at present given the clinical and genotypic overlap. PMID:19054398

Hindocha, Neeti; Nabbout, Rima; Elmslie, Frances; Makoff, Andrew; Al-Chalabi, Ammar; Nashef, Lina

2008-11-19

242

Autosomal dominant C1149R von Willebrand disease: phenotypic findings and their implications  

PubMed Central

Background Mutation C1149R in the von Willebrand factor (VWF) gene has been thought to cause autosomal dominant severe type 1 von Willebrand disease (VWD). Design and Methods Eight patients from three unrelated families with this mutation were included in the present study who had distinct VWF abnormalities, not described in earlier studies. Results The patients showed notably low levels of VWF antigen (VWF:Ag), VWF ristocetin cofactor activity (VWF:RCo), VWF collagen binding (VWF:CB), and a reduced ristocetin-induced platelet aggregation (RIPA). VWF:RCo/VWF:Ag and VWF:CB/VWF:Ag ratios were lower than 0.7. At basal conditions, all the VWF multimers were decreased in plasma, with a clearly lower relative proportion of the high molecular weight VWF multimers (HMWM). In high-resolution agarose gels, a large decrease in the relative proportions of the satellite bands was seen. The patients had a brief good response to desmopressin (DDAVP) administration, but the released VWF half-life was shorter than normal, indicating an accelerated clearance of their VWF. Platelet VWF was abnormal. Conclusions We conclude from the results obtained in these patients for plasma phenotypic data that this mutation should be classified as a VWD type 2A (IIE). DDAVP therapy may be somewhat helpful for this mutation, at least for mild to moderate bleeding. These data provide evidence that for VWD classification factors other than basal VWF, such as DDAVP response and platelet VWF, should be considered.

Perez-Rodriguez, Almudena; Garcia-Rivero, Aranzazu; Loures, Esther; Lopez-Fernandez, Maria Fernanda; Rodriguez-Trillo, Angela; Batlle, Javier

2009-01-01

243

Neuronal nicotinic acetylcholine receptors: their properties and alterations in autosomal dominant nocturnal frontal lobe epilepsy.  

PubMed

Identification of genes coding for the neuronal nicotinic acetylcholine receptors (nAChRs) has allowed rapid progress in the field of neuroscience. Determination of a high-affinity binding site for nicotine that correlates with the expression of mRNAs coding for nAChRs as well as protein expression is the best demonstration for localization of these receptors. Reconstitution of functional nAChRs in cells following cDNAs injection opened new ways to study these receptors in isolation. Furthermore, the recent linkage analysis between a form of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) with a mutation in the gene coding for the alpha 4 subunit of the neuronal nAChRs constituted the first demonstration that alteration of these receptors may be at the origin of epileptic discharges. Physiological and pharmacological studies of these mutated receptors revealed that the two mutations so far identified in ADNFLE patient cause a loss of function. In this work we shall review, in the light of the latest findings, properties of control and mutated receptors and evaluate how their alteration can be at the origin of nocturnal seizures. PMID:10472659

Bertrand, D

1999-07-01

244

Evidence for a fourth locus for autosomal dominant nocturnal frontal lobe epilepsy.  

PubMed

Mutations responsible for autosomal dominant nocturnal frontal lobe epilepsy have been identified in two members of the neuronal nicotinic acetylcholine receptor gene family: CHRNA4(ENFL1 locus) and CHRNB2 (ENFL3 locus) coding for alpha4 and beta2 subunit, respectively. However, mutations in these genes account for only a minority (less than 10%) of cases. For a third ADNFLE locus (ENFL2) on chromosome 15q24 the gene was not identified. The involvement of the three loci in the pathogenesis of ADNFLE was investigated in 12 unrelated Italian families, selected on the basis of anamnestic and video-polysomnographic data. Compliant family members were typed for polymorphic markers spanning the analyzed chromosome regions. Linkage analyses excluded association of all chromosome regions with ADNFLE in 72% of cases. In two, four and one families it was impossible to ascertain or exclude association with ENFL1, ENFL2, or ENFL3, respectively, however, no mutations have been detected in the nicotinic receptor genes located in these regions. These data strongly suggest that ENFL1, ENFL2 and ENFL3 are minor loci for the disease and point to the existence of at least a fourth locus for ADNFLE. PMID:15245761

Combi, Romina; Dalprà, Leda; Malcovati, Massimo; Oldani, Alessandro; Tenchini, Maria Luisa; Ferini-Strambi, Luigi

2004-06-30

245

Autosomal dominant nocturnal frontal lobe epilepsy with a mutation in the CHRNB2 gene.  

PubMed

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE; MIM 600513) has been associated with mutations in the genes coding for the alfa-4 (CHRNA4), beta-2 (CHRNB2), and alpha-2 (CHRNA2) subunits of the neuronal nicotinic acetylcholine receptor (nAChR) and for the corticotropin-releasing hormone (CRH). A four-generation ADNFLE family with six affected members was identified. All affected members presented the clinical characteristics of ADNFLE. Interictal awake and sleep EEG recordings showed no epileptiform abnormalities. Ictal video-EEG recordings showed focal seizures with frontal lobe semiology. Mutation analysis of the CHRNB2 gene revealed a c.859G>A transition (Val287Met) within the second transmembrane domain, identical to that previously described in a Scottish ADNFLE family. To our knowledge, this is the third family reported presenting a mutation in CHRNB2. The clinical phenotype appears similar to that described with mutations in CHRNA4, suggesting that mutations in these two subunits lead to similar functional alterations of the nAChR. PMID:17900292

Díaz-Otero, Fernando; Quesada, Mar; Morales-Corraliza, José; Martínez-Parra, Carlos; Gómez-Garre, Pilar; Serratosa, José M

2007-09-26

246

Neuronal nicotinic acetylcholine receptors and autosomal dominant nocturnal frontal lobe epilepsy: a critical review.  

PubMed

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a distinct human epileptic syndrome. In some families, it is associated with mutations of the alpha4 or the beta2 subunit of the neuronal nicotinic acetylcholine receptor (nAChR). It has been suggested that these mutations are the causative factors responsible for the induction and expression of this syndrome. However, the pathogenic mechanisms leading to ADNFLE are unknown and, in this review, we discuss the following yet unresolved questions concerning the involvement of mutated nAChRs in the phenotypic development of the disorder: (1) why do seizures associated with ADNFLE arise explicitly from the frontal lobe of the neocortex? (2) why do the seizures arise mainly from sleep? (3) why does ADNFLE starts predominantly during childhood? A survey of our current knowledge on neocortical and thalamic cholinergic systems, including their ontogenetic development, leads us to the conclusion that there are, at least at the moment, no convincing answers to these questions. Furthermore, we believe that, even in those cases where mutations of the alpha4 or the beta2 subunit of the nAChR cosegregate with ADNFLE, there must be some crucial additional factors contributing to the development of the specific symptoms of ADNFLE. PMID:11512019

Sutor, B; Zolles, G

2001-08-01

247

Pathogenesis of Autosomal Dominant Hereditary Spastic Paraplegia (SPG6) Revealed by a Rat Model.  

PubMed

Hereditary spastic paraplegias (HSPs) are characterized by progressive spasticity and weakness in the lower extremities that result from length-dependent central to peripheral axonal degeneration. Mutations in the non-imprinted Prader-Willi/Angelman syndrome locus 1 (NIPA1) transmembrane protein cause an autosomal dominant form of HSP (SPG6). Here, we report that transgenic (Tg) rats expressing a human NIPA1/SPG6 mutation in neurons (Thy1.2-hNIPA1) show marked early onset behavioral and electrophysiologic abnormalities. Detailed morphologic analyses reveal unique histopathologic findings, including the accumulation of tubulovesicular organelles with endosomal features that start at axonal and dendritic terminals, followed by multifocal vacuolar degeneration in both the CNS and peripheral nerves. In addition, the NIPA1 mutation in the spinal cord from older Tg rats results in an increase in bone morphogenetic protein type II receptor expression, suggesting that its degradation is impaired. This Thy1.2-hNIPA1 Tg rat model may serve as a valuable tool for understanding endosomal trafficking in the pathogenesis of a subgroup of HSP with an abnormal interaction with bone morphogenetic protein type II receptor, as well as for developing potential therapeutic strategies for diseases with axonal degeneration and similar pathogenetic mechanisms. PMID:24128679

Watanabe, Fumihiro; Arnold, William D; Hammer, Robert E; Ghodsizadeh, Odelia; Moti, Harmeet; Schumer, Mackenzie; Hashmi, Ahmed; Hernandez, Anthony; Sneh, Amita; Sahenk, Zarife; Kisanuki, Yaz Y

2013-11-01

248

Short wavelength-automated perimetry compared with standard achromatic perimetry in autosomal dominant optic atrophy  

PubMed Central

Background Autosomal dominant optic atrophy (ADOA, Kjer?type) is a heterogeneous, non?inflammatory degeneration of retinal ganglion cells. The diagnosis of ADOA can be challenging owing to its insidious onset and large variability in phenotypic expression, both within and between individual pedigrees. The earliest literature reports relatively mild centrocaecal scatomas to white targets in ADOA, but extensive and dense peripheral field loss to coloured targets, especially blue, with Bjerrum perimetry. The phrase “inverted peripheral visual fields to coloured targets” has been used to describe this phenomenon. Methods Humphrey standard achromatic perimetry (SAP) and short wavelength?automated perimetry (SWAP) were carried out on five patients with ADOA. Results Regardless of wide variations in patient age, visual acuity, disc appearance and colour vision, the SWAP mean deviation (MD) was between 10 and 20?times more depressed than the SAP MD. The actual differences ranged from 9.38 to 13.78?dB. Conclusions These data are consistent with the original reports suggesting that, early in this disease process, the blue?target deficits are typically peripheral and that this difference between SAP and SWAP perimetry may be a robust indicator of ADOA in both early and late stages of this disease.

Walters, J W; Gaume, A; Pate, L

2006-01-01

249

Antibody deficiency associated with an inherited autosomal dominant mutation in TWEAK  

PubMed Central

Mutations in the TNF family of proteins have been associated with inherited forms of immune deficiency. Using an array-based sequencing assay, we identified an autosomal-dominant deficiency in TNF-like weak inducer of apoptosis (TWEAK; TNFSF12) in a kindred with recurrent infection and impaired antibody responses to protein and polysaccharide vaccines. This mutation occurs in the sixth exon of TWEAK and results in the amino acid substitution R145C within the conserved TNF-homology domain of the full-length protein. TWEAK mutant protein formed high molecular weight aggregates under nonreducing conditions, suggesting an increased propensity for intermolecular interactions. As a result, mutant TWEAK associated with B-cell–activating factor (BAFF) protein and down-regulated the BAFF-mediated activation of the noncanonical NF-?B pathway through inhibition of p100 processing to p52, resulting in inhibition of BAFF-dependent B-cell survival and proliferation. As BAFF mediates T-cell–independent isotype switching and B-cell survival, our data implicate TWEAK as a disease-susceptibility gene for a humoral immunodeficiency.

Wang, Hong-Ying; Ma, Chi A.; Zhao, Yongge; Fan, Xiying; Zhou, Qing; Edmonds, Pamela; Uzel, Gulbu; Oliveira, Joao Bosco; Orange, Jordan; Jain, Ashish

2013-01-01

250

A Novel Autosomal Dominant Inclusion Body Myopathy Linked to 7q22.1-31.1  

PubMed Central

We describe a novel autosomal dominant hereditary inclusion body myopathy (HIBM) that clinically mimics limb girdle muscular dystrophy in a Chinese family. We performed a detailed clinical assessment of 36 individuals spanning four generations. The age of onset ranged from the 30s to the 50s. Hip girdle, neck flexion and axial muscle weakness were involved at an early stage. This disease progressed slowly, and a shoulder girdle weakness appeared later in the disease course. Muscle biopsies showed necrotic, regenerating, and rimmed vacuolated fibers as well as congophilic inclusions in some of the fibers. Electron micrograph revealed cytoplasmic inclusions of 15–21 nm filaments. A genomewide scan and haplotype analyses were performed using an Illumina Linkage-12 DNA Analysis Kit (average spacing 0.58 cM), which traced the disease to a new locus on chromosome 7q22.1–31.1 with a maximum multi-point LOD score of 3.65. The critical locus for this unique disorder, which is currently referred to as hereditary inclusion body myopathy 4 (HIBM4), spans 8.78 Mb and contains 65 genes. This localization raises the possibility that one of the genes clustered within this region may be involved in this disorder.

Wang, Min; Li, Xin; Zhang, Feng; Li, Yun; Zhang, Meng; Da, Yuwei; Yu, Jun; Jia, Jianping

2012-01-01

251

High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease.  

PubMed

Performing exome sequencing in 14 autosomal dominant early-onset Alzheimer disease (ADEOAD) index cases without mutation on known genes (amyloid precursor protein (APP), presenilin1 (PSEN1) and presenilin2 (PSEN2)), we found that in five patients, the SORL1 gene harbored unknown nonsense (n=1) or missense (n=4) mutations. These mutations were not retrieved in 1500 controls of same ethnic origin. In a replication sample, including 15 ADEOAD cases, 2 unknown non-synonymous mutations (1 missense, 1 nonsense) were retrieved, thus yielding to a total of 7/29 unknown mutations in the combined sample. Using in silico predictions, we conclude that these seven private mutations are likely to have a pathogenic effect. SORL1 encodes the Sortilin-related receptor LR11/SorLA, a protein involved in the control of amyloid beta peptide production. Our results suggest that besides the involvement of the APP and PSEN genes, further genetic heterogeneity, involving another gene of the same pathway is present in ADEOAD. PMID:22472873

Pottier, C; Hannequin, D; Coutant, S; Rovelet-Lecrux, A; Wallon, D; Rousseau, S; Legallic, S; Paquet, C; Bombois, S; Pariente, J; Thomas-Anterion, C; Michon, A; Croisile, B; Etcharry-Bouyx, F; Berr, C; Dartigues, J-F; Amouyel, P; Dauchel, H; Boutoleau-Bretonnière, C; Thauvin, C; Frebourg, T; Lambert, J-C; Campion, D

2012-04-03

252

Expanded motor and psychiatric phenotype in autosomal dominant Segawa syndrome due to GTP cyclohydrolase deficiency  

PubMed Central

Background Segawa syndrome due to GTP cyclohydrolase deficiency is an autosomal dominant disorder with variable expression, that is clinically characterised by l?dopa responsive, diurnally fluctuating dystonia and parkinsonian symptoms. Objective To delineate the neurological and psychiatric phenotype in all affected individuals of three extended families. Methods GTP cyclohydrolase deficiency was documented by biochemical analyses, enzymatic measurements in fibroblasts, and molecular investigations. All affected individuals were examined neurologically, and psychiatric data were systematically reviewed. Results Eighteen affected patients from three families with proven GTP cyclohydrolase deficiency were identified. Eight patients presenting at less than 20?years of age had typical motor symptoms of dystonia with diurnal variation. Five family members had late?presenting mild dopa?responsive symptoms of rigidity, frequent falls, and tendonitis. Among mutation carriers older than 20?years of age, major depressive disorder, often recurrent, and obsessive?compulsive disorder were strikingly more frequent than observed in the general population. Patients responded well to medication increasing serotonergic neurotransmission and to l?dopa substitution. Sleep disorders including difficulty in sleep onset and maintenance, excessive sleepiness, and frequent disturbing nightmares were present in 55% of patients. Conclusion Physicians should be aware of this expanded phenotype in affected members of families with GTP cyclohydrolase deficiency.

Van Hove, J L K; Steyaert, J; Matthijs, G; Legius, E; Theys, P; Wevers, R; Romstad, A; M?ller, L B; Hedrich, K; Goriounov, D; Blau, N; Klein, C; Casaer, P

2006-01-01

253

A gene for autosomal dominant hearing loss on the short arm of chromosome 1  

SciTech Connect

Hearing loss is the most common form of sensory impairment and many cases are attributable to genetic causes. The genetic defects underlying several syndromic forms of deafness have been identified, but little is known about the causes of non-syndromic hereditary deafness which accounts for the majority of inherited hearing loss. We report here a large Indonesian family with non-syndromal postlingual hearing loss starting in the high frequencies and showing autosomal dominant inheritance. To locate the gene responsible for the hearing loss in this family, we performed a genome search by genetic linkage analysis with microsatellite markers distributed over the whole genome. We have mapped the gene causing deafness in an extended Indonesian family to chromosome 1p with a multipoint lod score higher than 7. Two other smaller families, showing a similar hereditary hearing loss, were also tested for linkage with chromosome 1p. One family originating from the U.S. was linked to this new locus with a multipoint lod score exceeding 5. In another family from the Netherlands this locus was excluded. The flanking markers D1S255 and D1S211 define a region of 6 cM on chromosome 1p which is likely to contain the deafness gene present in the Indonesian and American family.

Van Camp, G.; Coucke, P.; Willems, P.J. [and others

1994-09-01

254

Mapping of locus for autosomal dominant retinitis pigmentosa on chromosome 6q23.  

PubMed

Retinitis pigmentosa (RP) is a genetically heterogeneous group of retinal degenerative disorders resulting in severe visual loss and blindness that have remained incurable till date. We report the mapping of the disease locus in a 3-generation family of Indian origin with autosomal dominant RP (ADRP). Diagnosis of RP and recruitment was made after a complete clinical evaluation of all members. Manifestations of the disease included night blindness with blurred central vision in some cases, loss of peripheral vision, and diffuse degeneration of the retinal pigment epithelium. Linkage analysis using microsatellite markers was carried out on 34 members (14 affected). After testing for linkage to known retinal dystrophy loci as well as a subsequent genome-wide analysis, we detected linkage to markers on chromosome 6q23: D6S262 at 130 cM, D6S457 (130 cM) and D6S1656 (131 cM) gave significant 2-point LOD scores of 3.0-3.8. Multipoint LOD scores of ?3.0 were obtained for markers between 121 and 130 cM. Haplotype analysis with several markers in the same region on chromosome 6 shows a disease-cosegregating region of about 25 Mb between 109 and 135 Mb. There are no known RP genes in this interval, which contains >100 genes. This study provides evidence for a novel ADRP locus on chromosome 6q23. PMID:22083234

Kannabiran, Chitra; Singh, Hardeep Pal; Jalali, Subhadra

2011-11-15

255

Identification of gene mutations in autosomal dominant polycystic kidney disease through targeted resequencing.  

PubMed

Mutations in two large multi-exon genes, PKD1 and PKD2, cause autosomal dominant polycystic kidney disease (ADPKD). The duplication of PKD1 exons 1-32 as six pseudogenes on chromosome 16, the high level of allelic heterogeneity, and the cost of Sanger sequencing complicate mutation analysis, which can aid diagnostics of ADPKD. We developed and validated a strategy to analyze both the PKD1 and PKD2 genes using next-generation sequencing by pooling long-range PCR amplicons and multiplexing bar-coded libraries. We used this approach to characterize a cohort of 230 patients with ADPKD. This process detected definitely and likely pathogenic variants in 115 (63%) of 183 patients with typical ADPKD. In addition, we identified atypical mutations, a gene conversion, and one missed mutation resulting from allele dropout, and we characterized the pattern of deep intronic variation for both genes. In summary, this strategy involving next-generation sequencing is a model for future genetic characterization of large ADPKD populations. PMID:22383692

Rossetti, Sandro; Hopp, Katharina; Sikkink, Robert A; Sundsbak, Jamie L; Lee, Yean Kit; Kubly, Vickie; Eckloff, Bruce W; Ward, Christopher J; Winearls, Christopher G; Torres, Vicente E; Harris, Peter C

2012-03-01

256

New insights into the pathogenesis of autosomal dominant cutis laxa with report of five ELN mutations  

PubMed Central

Autosomal dominant cutis laxa (ADCL) is characterized by a typical facial appearance and generalized loose skin folds, occasionally associated with aortic root dilatation and emphysema. We sequenced exons 28–34 of the ELN gene in 5 probands with ADCL features and found 5 de novo heterozygous mutations: c.2296_2299dupGCAG (CL-1), c.2333delC (CL-2), c.2137delG (CL-3), c.2262delA (monozygotic twin CL-4 and CL-5) and c.2124del25 (CL-6). Four probands (CL-1, -2, -3, -6) presented with progressive aortic root dilatation. CL-2 and CL-3 also had bicuspid aortic valves. CL-2 presented with severe emphysema. Electron microscopy revealed elastic fiber fragmentation and diminished dermal elastin deposition. RT-PCR studies showed stable mutant mRNA in all patients. Exon 32 skipping explains a milder phenotype in patients with exon 32 mutations. Mutant protein expression in fibroblast cultures impaired deposition of tropoelastin onto microfibril-containing fibers, and enhanced tropoelastin coacervation and globule formation leading to lower amounts of mature, insoluble elastin. Mutation-specific effects also included endoplasmic reticulum stress and increased apoptosis. Increased pSMAD2 staining in ADCL fibroblasts indicated enhanced transforming growth factor beta (TGF?) signaling. We conclude that ADCL is a systemic disease with cardiovascular and pulmonary complications, associated with increased TGF? signaling and mutation-specific differences in endoplasmic reticulum stress and apoptosis.

Callewaert, Bert; Renard, Marjolijn; Hucthagowder, Vishwanathan; Albrecht, Beate; Hausser, Ingrid; Blair, Edward; Dias, Cristina; Albino, Alice; Wachi, Hiroshi; Sato, Fumiaki; Mecham, Robert P.; Loeys, Bart; Coucke, Paul J.; De Paepe, Anne; Urban, Zsolt

2011-01-01

257

Assignment of a gene (NEM1) for autosomal dominant nemaline myopathy to chromosome 1  

PubMed Central

Nemaline myopathy (NEM) is a neuromuscular disorder characterized by the presence, in skeletal muscle, of nemaline rods composed at least in part of ?-actinin. A candidate gene and linkage approach was used to localize the gene (NEM1) for an autosomal dominant form (MIM 161800) in one large kindred with 10 living affected family members. Markers on chromosome 19 that were linked to the central core disease gene, a marker at the complement 3 locus, and a marker on chromosome 1 at the ?-actinin locus exclude these three candidate genes. The family was fully informative for APOA2, which is localized to 1q21-q23. NEM1 was assigned to chromosome 1 by close linkage for APOA2, which is localized to 1q21-q23. NEM1 was assigned to chromosome 1 by close linkage to APOA2, with a lod score of 3.8 at a recombination fraction of 0. Recombinants with NGFB (1p13) and AT3 (1q23-25.1) indicate that NEM1 lies between 1p13 and 1q25.1. In total, 47 loci were investigated on chromosomes 1, 2, 4, 5, 7–11, 14, 16, 17, and 19, with no indications of significant linkage other than to markers on chromosome 1. ImagesFigure 2

Laing, N. G.; Majda, B. T.; Akkari, P. A.; Layton, M. G.; Mulley, J. C.; Phillips, H.; Haan, E. A.; White, S. J.; Beggs, A. H.; Kunkel, L. M.; Groth, D. M.; Boundy, K. L.; Kneebone, C. S.; Blumberg, P. C.; Wilton, S. D.; Speer, M. C.; Kakulas, B. A.

1992-01-01

258

A genome-wide search for genes predisposing to manic-depression, assuming autosomal dominant inheritance  

SciTech Connect

Manic-depressive illness (MDI), also known as [open quotes]bipolar affective disorder[close quotes], is a common and devastating neuropsychiatric illness. Although pivotal biochemical alterations underlying the disease are unknown, results of family, twin, and adoption studies consistently implicate genetic transmission in the pathogenesis of MDI. In order to carry out linkage analysis, the authors ascertained eight moderately sized pedigrees containing multiple cases of the disease. For a four-allele marker mapping at 5 cM from the disease gene, the pedigree sample has >97% power to detect a dominant allele under genetic homogeneity and has >73% power under 20% heterogeneity. To date, the eight pedigrees have been genotyped with 328 polymorphic DNA loci throughout the genome. When autosomal dominant inheritance was assumed, 273 DNA markers gave lod scores <[minus]2.0 at [theta] = .05, and 4 DNA marker loci yielded lod scores >1 (chromosome 5 -- D5S39, D5S43, and D5S62; chromosome 11 -- D11S85). Of the markers giving lod scores >1, only D5S62 continued to show evidence for linkage when the affected-pedigree-member method was used. The D5S62 locus maps to distal 5q, a region containing neurotransmitter-receptor genes for dopamine, norepinephrine, glutamate, and gamma-aminobutyric acid. Although additional work in this region may be warranted, the linkage results should be interpreted as preliminary data, as 68 unaffected individuals are not past the age of risk. 72 refs., 2 tabs.

Coon, H.; Jensen, S.; Hoff, M.; Holik, J.; Plaetke, R.; Reimherr, F.; Wender, P.; Leppert, M.; Byerley, W. (Univ. of Utah, Salt Lake City (United States))

1993-06-01

259

Linkage of autosomal-dominant common variable immunodeficiency to chromosome 4q.  

PubMed

The phenotype of common variable immunodeficiency (CVID) is characterized by recurrent infections owing to hypogammaglobulinemia, with deficiency in immunoglobulin (Ig)G and at least one of IgA or IgM. Family studies have shown a genetic association between CVID and selective IgA deficiency (IgAD), the latter being a milder disorder compatible with normal health. Approximately 20-25% of CVID cases are familial, if one includes families with at least one case of CVID and one of IgAD. Nijenhuis et al described a five-generation family with six cases of CVID, five cases of IgAD, and three cases of dysgammaglobulinemia. We conducted a genome-wide scan on this family seeking genetic linkage. One interval on chromosome 4q gives a peak multipoint LOD score of 2.70 using a strict model that treats only the CVID patients and one obligate carrier with dysgammaglobulinemia as affected. Extending the definition of likely affected to include IgAD boosts the peak multipoint LOD score to 3.38. The linkage interval spans at least from D4S2361 to D4S1572. We extended our study to a collection of 32 families with at least one CVID case and a second case of either CVID or IgAD. We used the same dominant penetrance model and genotyped and analyzed nine markers on 4q. The 32 families have a peak multipoint LOD score under heterogeneity of 0.96 between markers D4S423 and D4S1572 within the suggested linkage interval of the first family, and an estimated proportion of linked families (alpha) of 0.32, supporting the existence of a disease-causing gene for autosomal-dominant CVID/IgAD on chromosome 4q. PMID:16639407

Finck, Anemone; Van der Meer, Jos W M; Schäffer, Alejandro A; Pfannstiel, Jessica; Fieschi, Claire; Plebani, Alessandro; Webster, A David B; Hammarström, Lennart; Grimbacher, Bodo

2006-04-26

260

A genome-wide search for genes predisposing to manic-depression, assuming autosomal dominant inheritance.  

PubMed Central

Manic-depressive illness (MDI), also known as "bipolar affective disorder," is a common and devastating neuropsychiatric illness. Although pivotal biochemical alterations underlying the disease are unknown, results of family, twin, and adoption studies consistently implicate genetic transmission in the pathogenesis of MDI. In order to carry out linkage analysis, we ascertained eight moderately sized pedigrees containing multiple cases of the disease. For a four-allele marker mapping 5 cM from the disease gene, the pedigree sample has > 97% power to detect a dominant allele under genetic homogeneity and has > 73% power under 20% heterogeneity. To date, the eight pedigrees have been genotyped with 328 polymorphic DNA loci throughout the genome. When autosomal dominant inheritance was assumed, 273 DNA markers gave lod scores < -2.0 at recombination fraction (theta) = .0, 174 DNA loci produced lod scores < -2.0 at theta = .05, and 4 DNA marker loci yielded lod scores > 1 (chromosome 5--D5S39, D5S43, and D5S62; chromosome 11--D11S85). Of the markers giving lod scores > 1, only D5S62 continued to show evidence for linkage when the affected-pedigree-member method was used. The D5S62 locus maps to distal 5q, a region containing neurotransmitter-receptor genes for dopamine, norepinephrine, glutamate, and gamma-aminobutyric acid. Although additional work in this region may be warranted, our linkage results should be interpreted as preliminary data, as 68 unaffected individuals are not past the age of risk.

Coon, H; Jensen, S; Hoff, M; Holik, J; Plaetke, R; Reimherr, F; Wender, P; Leppert, M; Byerley, W

1993-01-01

261

Further evidence for a locus for autosomal dominant juvenile glaucoma on chromosome 1q and evidence for genetic heterogeneity  

SciTech Connect

Glaucoma is a term used to describe a group of disorders which have in common a characteristic degeneration of the optic nerve associated with typical visual field defects and usually associated with elevated intraocular pressure. Two percent of white Americans and 6-10% of black Americans are affected by the disease. Compelling data indicate that susceptibility to many types of glaucoma is inherited. Hereditary juvenile glaucoma is one form of glaucoma that develops in children and is inherited as an autosomal dominant trait with high penetrance. Using a single large Caucasian pedigree affected with autosomal dominant juvenile glaucoma, Sheffield discovered positive linkage to a group of markers that map to a 30 cM region on the long arm of chromosome 1 (1q21-q31). We have subsequently identified three unrelated Caucasian pedigrees affected with autosomal dominant juvenile glaucoma that also demonstrate linkage to this region on chromosome 1, with the highest combined lod score of 5.12 at theta = .05 for marker D1S218. The identification of critical recombinant individuals in our three pedigrees has allowed us to further localize the disease gene to a 12 cM region between markers D1S242 and D1S431. In addition, we have identified several pedigrees which do not demonstrate linkage to chromosome 1q, including a black family affected with autosomal dominant juvenile glaucoma that is indistinguishable clinically from the disorder affecting the caucasian pedigrees and three pedigrees affected with pigmentary dispersion syndrome, a form of glaucoma that also affects the juvenile population and is also inherited as an autosomal dominant trait. These findings provide evidence for genetic heterogeneity in juvenile glaucoma.

Wiggs, J.; Paglinauan, C.; Stawski, S. [New England Medical Center, Boston, MA (United States)] [and others

1994-09-01

262

A novel locus for autosomal dominant “uncomplicated” hereditary spastic paraplegia maps to chromosome 8p21.1-q13.3  

Microsoft Academic Search

Hereditary spastic paraplegias (HSPs) are genetically and phenotypically heterogeneous. Both “uncomplicated” and “complicated”\\u000a forms have been described, with autosomal dominant, autosomal recessive, and X-linked inheritance. Hitherto, ten autosomal\\u000a dominant “uncomplicated” HSP (ADHSP) loci have been mapped. Here, we report linkage of ADHSP with markers of the 8p21.1-q13.3\\u000a chromosomal region in a large French family, including 29 examined at-risk individuals. The

Sylvain Hanein; Alexandra Dürr; Pascale Ribai; Sylvie Forlani; Anne-Louise Leutenegger; Isabelle Nelson; Marie-Claude Babron; Nizar Elleuch; Christel Depienne; Céline Charon; Alexis Brice; Giovanni Stevanin

2007-01-01

263

Prevalence and novelty of PRPF31 mutations in French autosomal dominant rod-cone dystrophy patients and a review of published reports  

Microsoft Academic Search

BACKGROUND: Rod-cone dystrophies are heterogeneous group of inherited retinal disorders both clinically and genetically characterized by photoreceptor degeneration. The mode of inheritance can be autosomal dominant, autosomal recessive or X-linked. The purpose of this study was to identify mutations in one of the genes, PRPF31, in French patients with autosomal dominant RP, to perform genotype-phenotype correlations of those patients, to

Isabelle Audo; Kinga Bujakowska; Saddek Mohand-Saïd; Marie-Elise Lancelot; Veselina Moskova-Doumanova; Naushin H Waseem; Aline Antonio; José-Alain Sahel; Shomi S Bhattacharya; Christina Zeitz

2010-01-01

264

Mutation analysis of CRYAA, CRYGC, and CRYGD associated with autosomal dominant congenital cataract in Brazilian families  

PubMed Central

Purpose Congenital cataracts are one of the most treatable causes of visual impairment and blindness during infancy. Approximately 50% of all congenital cataract cases may have a genetic cause. Once there is an intimate relationship between crystallin genes and lens transparency, they are excellent candidate genes for inherited cataract. The purpose of this study was to investigate mutations in ?A-crystallin (CRYAA), ?C-crystallin (CRYGC), and ?D-crystallin (CRYGD) in Brazilian families with nuclear and lamellar autosomal dominant congenital cataract. Methods Eleven Brazilian families were referred to the Santa Casa de São Paulo Ophthalmology Department. The coding regions and intron/exon boundaries of CRYAA, CRYGC, and CRYGD were amplified by polymerase chain reaction (PCR) and directly sequenced. Mutation screening was performed in the control group by restriction digestion. Results Two mutations were observed in different families (Family 4 and Family 10), one is a new mutation (Y56X) in CRYGD and the other a previously reported mutation (R12C) in CRYAA that is correlated with a different phenotype. Genetic analysis revealed previously described polymorphisms in CRYAA (D2D) and CRYGD (Y17Y and R95R). A new polymorphism in CRYGC (S119S) was identified only in Family 1. The mutations as well as the new polymorphism were not observed in the control group. Conclusions In conclusion, we report a novel nonsense mutation (Y56X) in CRYGD and a previously reported missense mutation (R12C) in CRYAA associated with nuclear cataract in Brazilian families. Both tyrosine in amino acid 56 in CRYGD and arginine in amino acid 12 in CRYAA have been highly conserved throughout evolution in different species. A new polymorphism (S119S) in CRYGC was also observed in one family. The analysis of nine families excluded possible mutations in the crystallin genes, suggesting that other genes could be involved with congenital cataract.

Santana, Alessandro; Waiswol, Mauro; Arcieri, Enyr Saran; Cabral de Vasconcellos, Jose Paulo

2009-01-01

265

Autosomal dominant gnathodiaphyseal dysplasia maps to chromosome 11p14.3-15.1.  

PubMed

Gnathodiaphyseal dysplasia (GDD) is a syndrome characterized by bone fragility, sclerosis of tubular bones, and cemento-osseous lesions of jawbones. Although some cases of this syndrome exist in families with autosomal dominant inheritance, the underlying gene has never been identified. We analyzed a large four-generation family with GDD by linkage analysis using genomic DNA from nine affected and six nonaffected family members. A genome-wide search using a set of highly polymorphic microsatellite markers showed evidence for linkage to chromosome 11p14.3-15.1. Two-point linkage analysis of microsatellite markers spanning this locus resulted in a maximum logarithm of odds (LOD) score of 2.70 with a recombination fraction (theta) of 0 at D11S1755, D11S1759, and D11S915, and a maximum LOD score of 3.01 at D11S4114 was obtained in multipoint linkage analysis. Haplotype analysis detected no recombination between GDD and six closely linked markers (D11S928, D11S1755, D11S4114, D11S1759, D11S915, and D11S929) and established the candidate interval of 8.7 cM on chromosome 11p for GDD. Although GDD has been considered to be a variation of osteogenesis imperfecta (MIM 166260), our results indicate that this syndrome is a new and distinct disease entity from other systemic bone diseases. Furthermore, these genetic markers are useful for presymptomatic diagnosis of GDD in some families and for identification of the GDD gene. PMID:12619924

Tsutsumi, Satoshi; Kamata, Nobuyuki; Maruoka, Yutaka; Ando, Miki; Tezuka, Osamu; Enomoto, Shoji; Omura, Ken; Nagayama, Masaru; Kudo, Eiji; Moritani, Maki; Yamaoka, Takashi; Itakura, Mitsuo

2003-03-01

266

Autosomal dominant cerebellar ataxia type III: a review of the phenotypic and genotypic characteristics.  

PubMed

Autosomal Dominant Cerebellar Ataxia (ADCA) Type III is a type of spinocerebellar ataxia (SCA) classically characterized by pure cerebellar ataxia and occasionally by non-cerebellar signs such as pyramidal signs, ophthalmoplegia, and tremor. The onset of symptoms typically occurs in adulthood; however, a minority of patients develop clinical features in adolescence. The incidence of ADCA Type III is unknown. ADCA Type III consists of six subtypes, SCA5, SCA6, SCA11, SCA26, SCA30, and SCA31. The subtype SCA6 is the most common. These subtypes are associated with four causative genes and two loci. The severity of symptoms and age of onset can vary between each SCA subtype and even between families with the same subtype. SCA5 and SCA11 are caused by specific gene mutations such as missense, inframe deletions, and frameshift insertions or deletions. SCA6 is caused by trinucleotide CAG repeat expansions encoding large uninterrupted glutamine tracts. SCA31 is caused by repeat expansions that fall outside of the protein-coding region of the disease gene. Currently, there are no specific gene mutations associated with SCA26 or SCA30, though there is a confirmed locus for each subtype. This disease is mainly diagnosed via genetic testing; however, differential diagnoses include pure cerebellar ataxia and non-cerebellar features in addition to ataxia. Although not fatal, ADCA Type III may cause dysphagia and falls, which reduce the quality of life of the patients and may in turn shorten the lifespan. The therapy for ADCA Type III is supportive and includes occupational and speech modalities. There is no cure for ADCA Type III, but a number of recent studies have highlighted novel therapies, which bring hope for future curative treatments. PMID:23331413

Fujioka, Shinsuke; Sundal, Christina; Wszolek, Zbigniew K

2013-01-18

267

Distinct patterns of APP processing in the CNS in autosomal-dominant and sporadic Alzheimer disease.  

PubMed

Autosomal-dominant Alzheimer disease (ADAD) is a genetic disorder caused by mutations in Amyloid Precursor Protein (APP) or Presenilin (PSEN) genes. Studies from families with ADAD have been critical to support the amyloid cascade hypothesis of Alzheimer disease (AD), the basis for the current development of amyloid-based disease-modifying therapies in sporadic AD (SAD). However, whether the pathological changes in APP processing in the CNS in ADAD are similar to those observed in SAD remains unclear. In this study, we measured ?-site APP-cleaving enzyme (BACE) protein levels and activity, APP and APP C-terminal fragments in brain samples from subjects with ADAD carrying APP or PSEN1 mutations (n = 18), patients with SAD (n = 27) and age-matched controls (n = 22). We also measured sAPP? and BACE protein levels, as well as BACE activity, in CSF from individuals carrying PSEN1 mutations (10 mutation carriers and 7 non-carrier controls), patients with SAD (n = 32) and age-matched controls (n = 11). We found that in the brain, the pattern in ADAD was characterized by an increase in APP ?-C-terminal fragment (?-CTF) levels despite no changes in BACE protein levels or activity. In contrast, the pattern in SAD in the brain was mainly characterized by an increase in BACE levels and activity, with less APP ?-CTF accumulation than ADAD. In the CSF, no differences were found between groups in BACE activity or expression or sAPP? levels. Taken together, these data suggest that the physiopathological events underlying the chronic A? production/clearance imbalance in SAD and ADAD are different. These differences should be considered in the design of intervention trials in AD. PMID:23224319

Pera, Marta; Alcolea, Daniel; Sánchez-Valle, Raquel; Guardia-Laguarta, Cristina; Colom-Cadena, Martí; Badiola, Nahuai; Suárez-Calvet, Marc; Lladó, Albert; Barrera-Ocampo, Alvaro A; Sepulveda-Falla, Diego; Blesa, Rafael; Molinuevo, José L; Clarimón, Jordi; Ferrer, Isidre; Gelpi, Ellen; Lleó, Alberto

2012-12-06

268

Autocrine, endocrine and paracrine regulation of growth abnormalities in autosomal dominant polycystic kidney disease.  

PubMed

Genetic polycystic kidney disease (ADPKD) is an autosomal dominant trait in man, the phenotypic expression of which is characterized by enormous cystic enlargement of renal tubules. Since this is, in part, a result of aberrant epithelial cell proliferation, the nature of this defect has been characterized by comparison of growth factor action on defined epithelial primary monolayer cultures derived from individually microdissected normal human renal proximal and distal tubules and ADPKD cyst-lining epithelia. Mitogenic assays showed an increased sensitivity of ADPKD epithelia to stimulation by the combination of the endocrine factors hydrocortisone (dexamethasone) and insulin, and Northern analysis suggested increased levels of insulin receptor steady state mRNA. The most potent, single mitogen was epidermal growth factor (EGF), and hypersensitivity to EGF in ADPKD epithelia was correlated with increased mRNA levels for EGF receptor in ADPKD kidneys. The localization in vivo of EGF immunoreactivity in ADPKD cyst-lining epithelia and in (apical) cyst fluids and the demonstration of EGF-receptor immunostaining and specific [125I]EGF binding to apical cell surfaces suggested an autocrine mechanism of growth stimulation by EGF in ADPKD epithelia. Transforming growth factor beta was an inhibitor of normal renal tubule proliferation but was unable to completely inhibit EGF stimulation in ADPKD cultures. Platelet-derived growth factor (PDGF) immunoreactivity which was also seen in ADPKD cyst epithelia, was not mitogenic to ADPKD epithelia but did stimulate division in ADPKD fibroblasts in vitro. This suggested a paracrine regulation of the observed fibrosis in ADPKD. PMID:8223698

Wilson, P D; Du, J; Norman, J T

1993-06-01

269

Allele-Specific Gene Silencing in Two Mouse Models of Autosomal Dominant Skeletal Myopathy  

PubMed Central

We explored the potential of mutant allele-specific gene silencing (ASGS) in providing therapeutic benefit in two established mouse models of the autosomal dominantly-inherited muscle disorders, Malignant Hyperthermia (MH) and Central Core Disease (CCD). Candidate ASGS siRNAs were designed and validated for efficacy and specificity on ryanodine receptor (RyR1) cDNA mini-constructs expressed in HEK293 cells using RT-PCR- and confocal microscopy-based assays. In vivo delivery of the most efficacious identified siRNAs into flexor digitorum brevis (FDB) muscles was achieved by injection/electroporation of footpads of 4–6 month old heterozygous Ryr1Y524S/+ (YS/+) and Ryr1I4895T/+ (IT/+) knock-in mice, established mouse models of MH with cores and CCD, respectively. Treatment of IT/+ mice resulted in a modest rescue of deficits in the maximum rate (?38% rescue) and magnitude (?78%) of ligand-induced Ca2+ release that occurred in the absence of a change in the magnitude of electrically-evoked Ca2+ release. Compared to the difference between the caffeine sensitivity of Ca2+ release in FDB fibers from YS/+ and WT mice treated with SCR siRNA (EC50: 1.1 mM versus 4.4 mM, respectively), caffeine sensitivity was normalized in FDB fibers from YS/+ mice following 2 (EC50: 2.8 mM) and 4 week (EC50: 6.6 mM) treatment with YS allele-specific siRNA. Moreover, the temperature-dependent increase in resting Ca2+ observed in FDB fibers from YS/+ mice was normalized to WT levels after 2 weeks of treatment with YS allele-specific siRNA. As determined by quantitative real time PCR, the degree of functional rescue in YS/+ and IT/+ mice correlated well with the relative increase in fractional WT allele expression.

Loy, Ryan E.; Lueck, John D.; Mostajo-Radji, Mohammed A.; Carrell, Ellie M.; Dirksen, Robert T.

2012-01-01

270

Glomerular Hyperfiltration and Renal Progression in Children with Autosomal Dominant Polycystic Kidney Disease  

PubMed Central

Summary Background and objectives The purpose of this study was to determine whether glomerular hyperfiltration (GH) occurring early in autosomal dominant polycystic kidney disease (ADPKD) is indicative of more rapid disease progression in children. Design, setting, participants, & measurements One hundred eighty children with ADPKD (ages 4 to 18 years) with normal renal function were examined by renal ultrasound. Renal volume was calculated using a standard formula for a modified ellipsoid. Creatinine clearance was calculated from serum creatinine and 24-hour urine creatinine. GH was defined as creatinine clearance ?140 ml/min per 1.73 m2. Results Thirty-two children had GH (mean age 11.4 ± 3.6 years) and 148 had normal renal function (mean age 10.8 ± 3.9 years). Patients with GH at baseline demonstrated an increased rate of total renal volume growth (?: rate of change = +19.3 ± 10.8 cm3/year) over 5 years compared with those without GH at baseline (? = ?4.3 ± 7.7 cm3/year), P = 0.008. Those with GH at baseline experienced a faster decline in creatinine clearance in subsequent years (? = ?5.0 ± 0.8 ml/min per 1.73 m2 per year) compared with those without GH at baseline (? = +1.0 ± 0.4 ml/min per 1.73 m2 per year), P < 0.0001. Conclusions This study revealed that occurrence of GH in ADPKD children is associated with a significantly faster decline in renal function and higher rate of kidney enlargement over time. GH combined with the increased renal volume may therefore be used as an early marker for a more severe progression of ADPKD in children.

Helal, Imed; Reed, Berenice; McFann, Kim; Yan, Xiang-Dong; Fick-Brosnahan, Godela M.; Cadnapaphornchai, Melissa

2011-01-01

271

The impact of type II diabetes mellitus in patients with autosomal dominant polycystic kidney disease  

PubMed Central

Background The epidemic of obesity and diabetes is increasing within the USA and worldwide. We have previously shown that body mass index has increased significantly in autosomal dominant polycystic kidney disease (ADPKD) subjects seen at our center in more recent years. However, the impact of Type II diabetes in ADPKD patients has not been well studied. Methods This retrospective cohort study compared clinical characteristics in 44 pre-renal transplant patients with ADPKD and diabetes and 88 age- and sex-matched non-diabetic patients with ADPKD who were seen at the University of Colorado between 1977 and 2008. The primary outcomes in this study were renal volume determined by renal ultrasonography, renal function assessed by estimated glomerular filtration rate and time to onset of end-stage renal disease or death by Kaplan–Meier analyses. Results Diabetic patients had significantly larger kidney volumes than those with ADPKD alone [geometric mean (95% confidence interval (CI)]: 2456 (1510–3992) versus 1358 (1186–1556) cm3, P = 0.02. Among those whose age at hypertension diagnosis was known, the diabetic ADPKD patients had earlier median (95% CI) age at onset of hypertension compared to those with ADPKD alone: 32.5 (28–40) versus 38 (35–42) years, P = 0.04. Diabetic ADPKD patients tended to have an earlier median age of death than those with ADPKD alone. Conclusions Patients with ADPKD and type II diabetes have larger renal volumes, earlier age at diagnosis of hypertension and may die at a younger age compared to those patients with ADPKD alone. This study emphasizes the importance of diabetes risk management in ADPKD.

Reed, Berenice; Helal, Imed; McFann, Kim; Wang, Wei; Yan, Xiang-Dong; Schrier, Robert W.

2012-01-01

272

A YAC contig encompassing the chromosome 7p locus for autosomal dominant retinitis pigmentosa  

SciTech Connect

Retinitis pigmentosa is an inherited retinal degeneration characterized by night blindness and loss of peripheral vision, often leading to complete blindness. The autosomal dominant form (adRP) maps to at least six different loci, including the rhodopsin and peripherin/Rds genes and four loci identified only by linkage analysis on chromosomes 7p, 7q, 8cen and 19q. The 7p locus was reported by this laboratory in a large English family, with a lod score of 16.5. Several new genetic markers have been tested in the family and this locus has now been refined to an interval of approximately 1 cM between markers D7S795 and D7S484 in the 7p13-15 region. In order to clone the gene for adRP, we have used microsatellites and STSs from the region to identify over 80 YACs, from four different libraries, which map to this interval. End clones from key YACs were isolated for the generation of additional STSs. Eleven microsatellite markers between D7S435 (distal) and D7S484 (proximal) have been ordered by a combination of both physical and genetic mapping. In this way we have now obtained a YAC contig spanning approximately 3 megabases of chromosome 7p within which the adRP gene must lie. One gene (aquaporin) and one chromosome 7 brain EST have been placed on the contig but both map distal to the region of interest. Sixteen other ESTs and three further known 7p genes mapping in the region have been excluded. We are now attempting to build a cosmid contig in the defined interval and identify further expressed sequences from both YACs and cosmids to test as candidates for the adRP gene.

Inglehearn, C.F.; Keen, T.J.; Ratel, R. [Institute of Ophthalmology, London (United Kingdom)] [and others

1994-09-01

273

Mutation G61C in the CRYGD gene causing autosomal dominant congenital coralliform cataracts  

PubMed Central

Purpose We sought to identify the genetic defect in a four-generation Chinese family with autosomal dominant congenital coralliform cataracts and demonstrate the functional analysis of a candidate gene in the family. Methods Family history data were recorded. Clinical and ophthalmologic examinations were performed on affected and unaffected family members. All the members were genotyped with microsatellite markers at loci considered to be associated with cataracts. Two-point LOD scores were calculated using the Linkage software after genotyping. A mutation was detected by direct sequencing, using gene-specific primers. Wild-type and mutant proteins were analyzed with online software. Results Affected members of this family had coralliform cataracts. Linkage analysis was obtained at markers, D2S72 (LOD score [Z]=3.31, recombination fraction [?]=0.0) and D2S1782 (Z=3.01, ?=0.0). Haplotype analysis indicated that the cataract gene was closely linked to these two markers. Sequencing the ?D-crystallin gene (CRYGD) revealed a G>T transversion in exon 2, which caused a conservative substitution of Gly to Cys at codon 61 (P.G61C). This mutation co-segregated with the disease phenotype in all affected individuals and was not observed in any of the unaffected or 100 normal, unrelated individuals. Bioinformatic analyses showed that a highly conserved region was located around Gly61. Data generated with online software revealed that the mutation altered the protein’s stability, solvent-accessibility, and interactions with other proteins. Conclusions This is the first reported case of a congenital coralliform cataract phenotype associated with the mutation of Gly61Cys (P.G61C) in the CRYGD gene; it demonstrates a possible mechanism of action for the mutant gene.

Li, Feifeng; Wang, Shuzhen; Gao, Chang; Liu, Shiguo; Zhao, Baojian; Zhang, Meng; Huang, Shangzhi; Zhu, Siquan

2008-01-01

274

The Genetics of Vascular Complications in Autosomal Dominant Polycystic Kidney Disease (ADPKD).  

PubMed

The most important extra-renal manifestation of autosomal dominant polycystic kidney disease (ADPKD) in terms of debilitating injury and premature death is the development of intracranial aneurysms (IAs) and other vascular complications, resulting in subarachnoid hemorrhage (SAH). IAs are found at a rate approximately five times higher in ADPKD patients than in the general population and in patients with a family history of SAH/IAs the frequency is elevated further three to five times, indicating the importance of genetic factors in its etiology. Expression of the ADPKD gene products, polycystin-1 (PKD1) and polycystin-2 (PKD2), in vascular smooth muscle and the endothelium, and evidence that reduced levels of these proteins leads to IA development in mouse models, suggests a direct role of these proteins in the vascular disease. PKD1 and PKD2 patients seem equally likely to develop IAs, while patients with mutations to the 5' half of PKD1 may more likely have vascular complications. Genome wide association and candidate studies of multiplex families with IAs without ADPKD have identified a number of genes/proteins that may be risk factors for the development of IAs. These candidate proteins largely have roles in the maintenance and remodeling of the arterial wall of small brain arteries. The development of the genetic methodologies of massively parallel sequencing mean it is now possible to test these and other candidates in ADPKD families with multiplex and singleton IA cases. Identifying strong modifiers of this phenotype will be important for prioritizing patients for presymptomatic screening and interventions. PMID:23971643

Rossetti, Sandro; Harris, Peter C

2013-02-01

275

Impaired TH17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome  

PubMed Central

The autosomal dominant hyper-IgE syndrome (HIES, ‘Job's syndrome’) is characterized by recurrent and often severe pulmonary infections, pneumatoceles, eczema, staphylococcal abscesses, mucocutaneous candidiasis, and abnormalities of bone and connective tissue1,2. Mutations presumed to underlie HIES have recently been identified in stat3, the gene encoding STAT3 (signal transducer and activator of transcription 3) (refs 3, 4). Although impaired production of interferon-? and tumour-necrosis factor by T cells5, diminished memory T-cell populations, decreased delayed-type-hypersensitivity responses and decreased in vitro lymphoproliferation in response to specific antigens6 have variably been described, specific immunological abnormalities that can explain the unique susceptibility to particular infections seen in HIES have not yet been defined. Here we show that interleukin (IL)-17 production by T cells is absent in HIES individuals. We observed that ex vivo T cells from subjects with HIES failed to produce IL-17, but not IL-2, tumour-necrosis factor or interferon-?, on mitogenic stimulation with staphylococcal enterotoxin B or on antigenic stimulation with Candida albicans or streptokinase. Purified naive T cells were unable to differentiate into IL-17-producing (TH17) T helper cells in vitro and had lower expression of retinoid-related orphan receptor (ROR)-?t, which is consistent with a crucial role for STAT3 signalling in the generation of TH17 cells7–14. TH17 cells have emerged as an important subset of helper T cells15 that are believed to be critical in the clearance of fungal16 and extracellular bacterial17 infections. Thus, our data suggest that the inability to produce TH17 cells is a mechanism underlying the susceptibility to the recurrent infections commonly seen in HIES.

Milner, Joshua D.; Brenchley, Jason M.; Laurence, Arian; Freeman, Alexandra F.; Hill, Brenna J.; Elias, Kevin M.; Kanno, Yuka; Spalding, Christine; Elloumi, Houda Z.; Paulson, Michelle L.; Davis, Joie; Hsu, Amy; Asher, Ava I.; O'Shea, John; Holland, Steven M.; Paul, William E.; Douek, Daniel C.

2010-01-01

276

Differences in allele frequencies of autosomal dominant hypercholesterolemia SNPs in the Malaysian population.  

PubMed

Hypercholesterolemia is caused by different interactions of lifestyle and genetic determinants. At the genetic level, it can be attributed to the interactions of multiple polymorphisms, or as in the example of familial hypercholesterolemia (FH), it can be the result of a single mutation. A large number of genetic markers, mostly single nucleotide polymorphisms (SNP) or mutations in three genes, implicated in autosomal dominant hypercholesterolemia (ADH), viz APOB (apolipoprotein B), LDLR (low density lipoprotein receptor) and PCSK9 (proprotein convertase subtilisin/kexin type-9), have been identified and characterized. However, such studies have been insufficiently undertaken specifically in Malaysia and Southeast Asia in general. The main objective of this study was to identify ADH variants, specifically ADH-causing mutations and hypercholesterolemia-associated polymorphisms in multiethnic Malaysian population. We aimed to evaluate published SNPs in ADH causing genes, in this population and to report any unusual trends. We examined a large number of selected SNPs from previous studies of APOB, LDLR, PCSK9 and other genes, in clinically diagnosed ADH patients (n=141) and healthy control subjects (n=111). Selection of SNPs was initiated by searching within genes reported to be associated with ADH from known databases. The important finding was 137 mono-allelic markers (44.1%) and 173 polymorphic markers (55.8%) in both subject groups. By comparing to publicly available data, out of the 137 mono-allelic markers, 23 markers showed significant differences in allele frequency among Malaysians, European Whites, Han Chinese, Yoruba and Gujarati Indians. Our data can serve as reference for others in related fields of study during the planning of their experiments. PMID:22534770

Alex, Livy; Chahil, Jagdish Kaur; Lye, Say Hean; Bagali, Pramod; Ler, Lian Wee

2012-04-26

277

Kelch-like homologue 9 mutation is associated with an early onset autosomal dominant distal myopathy.  

PubMed

Distal myopathies are a heterogeneous group of disorders characterized by progressive weakness and muscular atrophy, beginning in distal limb muscles and affecting proximal limb muscles at a later stage. We studied a large German kindred with 10 affected members. Weakness and atrophy of the anterior tibial muscles started between the ages of 8 and 16 years, followed by atrophy of intrinsic hand muscles. Progression was slow, and patients retained the ability to walk until the seventh decade. Serum creatinine kinase levels were increased in the range of 150-1400 U/l. Muscle biopsies showed myopathic changes, whereas immunohistochemistry showed normal expression of marker proteins for muscular dystrophies. Patients had reduced sensation with stocking-glove distribution in the distal limbs in later life. Nerve conduction studies revealed no evidence of neuropathy. Genome-wide linkage analysis in this family revealed a new locus for distal myopathy at 9p21.2-p22.3 (multipoint logarithm of the odds ratio=4.21). By positional cloning we found a heterozygous mutation L95F in the Kelch-like homologue 9 gene, encoding a bric-a-brac Kelch protein. Molecular modelling indicated that the mutation may interfere with the interaction of the bric-a-brac domain with Cullin 3. Coimmunoprecipitation experiments confirmed that the mutation reduces association with Cullin 3 in the Kelch-like homologue 9-Cullin 3-E3 ubiquitin ligase complex, which is involved in ubiquitin-dependent protein degradation. We identified a unique form of early onset autosomal dominant distal myopathy which is associated with a Kelch-like homologue 9 mutation and interferes with normal skeletal muscle through a novel pathogenetic mechanism. PMID:20554658

Cirak, Sebahattin; von Deimling, Florian; Sachdev, Shrikesh; Errington, Wesley J; Herrmann, Ralf; Bönnemann, Carsten; Brockmann, Knut; Hinderlich, Stephan; Lindner, Tom H; Steinbrecher, Alice; Hoffmann, Katrin; Privé, Gilbert G; Hannink, Mark; Nürnberg, Peter; Voit, Thomas

2010-06-16

278

Autosomal dominant cerebellar ataxia type III: a review of the phenotypic and genotypic characteristics  

PubMed Central

Autosomal Dominant Cerebellar Ataxia (ADCA) Type III is a type of spinocerebellar ataxia (SCA) classically characterized by pure cerebellar ataxia and occasionally by non-cerebellar signs such as pyramidal signs, ophthalmoplegia, and tremor. The onset of symptoms typically occurs in adulthood; however, a minority of patients develop clinical features in adolescence. The incidence of ADCA Type III is unknown. ADCA Type III consists of six subtypes, SCA5, SCA6, SCA11, SCA26, SCA30, and SCA31. The subtype SCA6 is the most common. These subtypes are associated with four causative genes and two loci. The severity of symptoms and age of onset can vary between each SCA subtype and even between families with the same subtype. SCA5 and SCA11 are caused by specific gene mutations such as missense, inframe deletions, and frameshift insertions or deletions. SCA6 is caused by trinucleotide CAG repeat expansions encoding large uninterrupted glutamine tracts. SCA31 is caused by repeat expansions that fall outside of the protein-coding region of the disease gene. Currently, there are no specific gene mutations associated with SCA26 or SCA30, though there is a confirmed locus for each subtype. This disease is mainly diagnosed via genetic testing; however, differential diagnoses include pure cerebellar ataxia and non-cerebellar features in addition to ataxia. Although not fatal, ADCA Type III may cause dysphagia and falls, which reduce the quality of life of the patients and may in turn shorten the lifespan. The therapy for ADCA Type III is supportive and includes occupational and speech modalities. There is no cure for ADCA Type III, but a number of recent studies have highlighted novel therapies, which bring hope for future curative treatments.

2013-01-01

279

Ocular manifestations in autosomal dominant retinitis pigmentosa with a Lys-296-Glu rhodopsin mutation at the retinal binding site.  

PubMed Central

A lysine to glutamic acid substitution at codon 296 in the rhodopsin gene has been reported in a family with autosomal dominant retinitis pigmentosa. This mutation is of particular functional interest as this lysine molecule is the binding site of 11-cis-retinal. The clinical features of a family with this mutation have not been reported previously. We examined 14 patients with autosomal dominant retinitis pigmentosa and a lysine-296-glutamic acid rhodopsin mutation. Four had detailed psychophysical and electrophysiological testing. Most affected subjects had severe disease with poor night vision from early life, and marked reduction of visual acuity and visual field by their early forties. Psychophysical testing showed no demonstrable rod function and severely reduced cone function in all patients tested. Images

Owens, S L; Fitzke, F W; Inglehearn, C F; Jay, M; Keen, T J; Arden, G B; Bhattacharya, S S; Bird, A C

1994-01-01

280

Molecular characterization of GDD1\\/TMEM16E, the gene product responsible for autosomal dominant gnathodiaphyseal dysplasia  

Microsoft Academic Search

The human GDD1\\/TMEM16E gene has been found to be mutated in gnathodiaphyseal dysplasia, an unusual skeletal syndrome with autosomal dominant inheritance. The molecular and biochemical function(s) of GDD1 protein has not yet been elucidated. In this study, we examined the murine GDD1 gene expression pattern during embryonic development, and characterized the cellular and tissue localizations of its gene product using

Kuniko Mizuta; Satoshi Tsutsumi; Hiroshi Inoue; Yukiko Sakamoto; Katsutoshi Miyatake; Katsuyuki Miyawaki; Sumihare Noji; Nobuyuki Kamata; Mitsuo Itakura

2007-01-01

281

Genomic organisation of the spinocerebellar ataxia type 7 ( SCA7 ) gene responsible for autosomal dominant cerebellar ataxia with retinal degeneration  

Microsoft Academic Search

Autosomal dominant cerebellar ataxia with retinal degeneration (ADCA type II) is a progressive neurodegenerative disorder caused by a CAG expansion in the spinocerebellar ataxia 7 (SCA7) gene. Here, we describe the genomic organisation of the human SCA7 gene. The exon-intron boundaries were identified by sequencing plasmid subclones of a P1 artificial chromosome (PAC) clone containing the entire SCA7 gene. We

Andrej Michalík; Jurgen Del-Favero; Claire Mauger; Ann Löfgren; Christine Van Broeckhoven

1999-01-01

282

Clinical and genetic characterization of 16q-linked autosomal dominant spinocerebellar ataxia in South Kyushu, Japan  

Microsoft Academic Search

16q-ADCA (OMIM no. 117210) is an autosomal dominant spinocerebellar ataxia (AD-SCA) characterized by late-onset pure cerebellar ataxia and ?16C>T substitution of the puratrophin-1 gene. Recently, a series of single-nucleotide polymorphisms (haplotype block) were found to be specific to 16q-ADCA. We screened patients with ataxia and found 62 patients, including four homozygotes who carry the C–T substitution of the puratrophin-1 gene.

Ryuki Hirano; Hiroshi Takashima; Ryuichi Okubo; Yuji Okamoto; Yoshimitsu Maki; Shimon Ishida; Masahito Suehara; Youichi Hokezu; Kimiyoshi Arimura

2009-01-01

283

DFNA8\\/12 caused by TECTA mutations is the most identified subtype of nonsyndromic autosomal dominant hearing loss  

Microsoft Academic Search

The prevalence of DFNA8\\/DFNA12 (DFNA8\\/12), a type of autosomal dominant nonsyndromic hearing loss (ADNSHL), is unknown as comprehensive population-based genetic screening has not been conducted. We therefore completed unbiased screening for TECTA mutations in a Spanish cohort of 372 probands from ADNSHL families. Three additional families (Spanish, Belgian, and English) known to be linked to DFNA8\\/12 were also included in

M. S. Hildebrand; M. Morin; N. C. Meyer; F. Mayo; S. Modamio-Hoybjor; A. Mencia; L. Olavarrieta; C. Morales-Angulo; C. J. Nishimura; H. Workman; A. P. DeLuca; I. del Castillo; K. R. Taylor; B. Tompkins; C. W. Goodman; I. Schrauwen; M. V. Wesemael; K. Lachlan; A. E. Shearer; T. A. Braun; P. L. M. Huygen; J. M. J. Kremer; G. van Camp; F. Moreno; T. L. Casavant; R. J. Smith; M. A. Moreno-Pelayo

2011-01-01

284

The Caenorhabditis elegans autosomal dominant polycystic kidney disease gene homologs lov-1 and pkd-2 act in the same pathway  

Microsoft Academic Search

Autosomal dominant polycystic kidney disease (ADPKD) strikes 1 in 1000 individuals and often results in end-stage renal failure. Mutations in either PKD1 or PKD2 account for 95% of all cases [1–3]. It has recently been demonstrated that polycystin-1 and polycystin-2 (encoded by PKD1 and PKD2, respectively) assemble to form a cation channel in vitro [4]. Here we determine that the

Maureen M. Barr; John DeModena; Douglas Braun; Can Q. Nguyen; David H. Hall; Paul W. Sternberg

2001-01-01

285

Mutations in autosomal dominant polycystic kidney disease 2 gene: Reduced expression of PKD2 protein in lymphoblastoid cells  

Microsoft Academic Search

The polycystic kidney disease 2 (PKD2) gene, encoding a 968-amino acid integral membrane protein with six predicted membrane-spanning domains and intracellular NH2 and COOH termini, is mutated in approximately 15% of the cases of autosomal dominant polycystic kidney disease (ADPKD), a common genetic disease frequently resulting in renal failure. For a better understanding of the cause of this disorder, we

Gianluca Aguiari; Elisa Manzati; Letizia Penolazzi; Fabiola Micheletti; Giuseppina Augello; Ermanno De Vitali; Gianni Cappelli; Yiqiang Cai; David Reynolds; Stefan Somlo; Roberta Piva; Laura del Senno

1999-01-01

286

Hemoperfusion Treatment in a Septic Shock Patient with Autosomal Dominant Polycystic Kidney Disease and Increased HMGB1 Protein Levels  

Microsoft Academic Search

This case report describes polymyxin B-immobilized fiber (PMX-F) treatment of septic shock caused by pyelonephritis in a 68-year-old woman with autosomal dominant polycystic kidney disease. She was admitted for severe lower left abdominal pain, high fever (40°C) and gross hematuria. Her endotoxin and high-mobility group box-1 protein (HMGB1) levels were extremely elevated. Her blood pressure was 68\\/36 mm Hg. Urinalysis

Tsukasa Nakamura; Yasuhiro Kawagoe; Yoshihiko Ueda; Shingo Yamada; Hikaru Koide

2011-01-01

287

Clinical and genetic features of nonsyndromic autosomal dominant sensorineural hearing loss: KCNQ4 is a gene responsible in Japanese  

Microsoft Academic Search

Sixteen Japanese nonsyndromic autosomal dominant sensorineural hearing loss (ADSNHL) families were investigated clinically\\u000a as well as genetically. Most families showed postlingual hearing loss. Although the severity of their hearing loss varied,\\u000a most patients showed mild-moderate sensorineural hearing loss of a progressive nature. Mutation analysis was performed for\\u000a the MYO7A, KCNQ4, and GJB3 genes, which are known to be responsible for

Jiro Akita; Satoko Abe; Hideichi Shinkawa; William J. Kimberling; Shin-ichi Usami

2001-01-01

288

Autosomal dominant acute necrotising encephalopathy: A case report with possible disease-expression modification by coincidental homocysteinuria  

Microsoft Academic Search

We report the case of a 5-year old girl with autosomal dominant acute necrotising encephalopathy (ADANE), who presented with encephalopathy, seizures and coma following a short febrile illness. MR imaging demonstrated characteristic symmetrical, T2 hyper-intense changes involving the external capsule, thalami, brainstem and cerebellum. Unique to this case was co-existing previously unrecognized homocysteinuria due to cystathionine-?-synthase (CBS) deficiency. We discuss

Clare Gilson; Robert McFarland; Rob Forsyth

2011-01-01

289

The prevalence of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) in the west of Scotland  

Microsoft Academic Search

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is caused by mutations of the Notch3 gene on 19p13. Varying phenotypic expression leads to under recognition and misdiagnosis. Prevalence therefore remains uncertain. We sought to estimate the prevalence of CADASIL in the west of Scotland.Methods: A register for CADASIL was established at a regional neurosciences centre in 2002.

S S M Razvi; R Davidson; I Bone; K W Muir

2005-01-01

290

Refinement of the locus for autosomal dominant cerebellar ataxia type II to chromosome 3p21.1–14.1  

Microsoft Academic Search

We have previously mapped the gene for autosomal dominant cerebellar ataxia type II (ADCAII) to chromosome 3p12-p21.1 in\\u000a a region of 33 cM by using four families of different geographic origin. In this study, we analysed the families with nine\\u000a additional simple tandem repeat markers located in the ADCAII candidate region. An extensive clinical evaluation was also\\u000a performed in the

Luc Krols; Jean-Jacques Martin; Gilles David; Nicole Van Regemorter; Ali Benomar; Ann Löfgren; Giovanni Stevanin; Alexandra Dürr; Alexis Brice; Christine Van Broeckhoven

1997-01-01

291

Urodynamic evaluation of patients with autosomal dominant pure spastic paraplegia linked to chromosome 2p21-p24  

Microsoft Academic Search

OBJECTIVESThere are at least three clinically indistinguishable but genetically different types of autosomal dominant pure spastic paraplegia (ADPSP). Lower urinary tract symptoms are often present but have not been described in a homogeneous patient population. In this study lower urinary tract symptoms, cystometrical, and neurophysiological characteristics are described in patients with ADPSP linked to chromosome 2p21-p24.METHODSLower urinary tract symptoms were

L Neerup Jensen; T Gerstenberg; E B Kallestrup; P Koefoed; J Nordling; J E Nielsen

1998-01-01

292

Autosomal dominant aplasia cutis congenita: report of a large Italian family and no hint for candidate chromosomal regions  

Microsoft Academic Search

\\u000a Abstract We studied a three-generation pedigree in which seven individuals were affected by aplasia cutis congenita, a rare disorder\\u000a characterized by the congenital absence of the epidermis, dermis and subcutaneous tissue of the vertex or occipital region.\\u000a Accurate clinical and formal genetic analysis suggested that this family was affected by the autosomal dominant form of the\\u000a disease, a hereditary condition

Michele Fimiani; Marco Seri; Pietro Rubegni; Roberto Cusano; Giovambattista De Aloe; Paola Forabosco; Marcella Devoto; Lucio Andreassi; Alessandra Renieri

1999-01-01

293

A Novel Activating Mutation in Calcium-Sensing Receptor Gene Associated with a Family of Autosomal Dominant Hypocalcemia  

Microsoft Academic Search

Autosomal dominant hypocalcemia (ADH), caused by activating mutations of the calcium-sensing receptor (CaSR), is characterized by hypocalcemia with an inappropriately low concentration of PTH. Among 11 missense mutations of CaSR reported to date in patients with ADH or sporadic hypocalcemia, functional properties of 8 mutant CaSRs were characterized. Here, we describe a novel mutation of CaSR and its functional property

RYO OKAZAKI; NORIKO CHIKATSU; MASAMI NAKATSU; YASUHIRO TAKEUCHI; MIHO AJIMA; JUNKO MIKI; TOSHIRO FUJITA; MASANOBU ARAI; YASUO TOTSUKA; KOSHI TANAKA; SEIJI FUKUMOTO

294

Characterization of large rearrangements in autosomal dominant polycystic kidney disease and the PKD1\\/TSC2 contiguous gene syndrome  

Microsoft Academic Search

Large DNA rearrangements account for about 8% of disease mutations and are more common in duplicated genomic regions, where they are difficult to detect. Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in either PKD1 or PKD2. PKD1 is located in an intrachromosomally duplicated region. A tuberous sclerosis gene, TSC2, lies immediately adjacent to PKD1 and large deletions

Mark B Consugar; Wai C Wong; Patrick A Lundquist; Sandro Rossetti; Vickie J Kubly; Denise L Walker; Laureano J Rangel; Richard Aspinwall; W Patrick Niaudet; Seza Özen; Albert David; Milen Velinov; Eric J Bergstralh; Kyongtae T Bae; Arlene B Chapman; Lisa M Guay-Woodford; Jared J Grantham; Vicente E Torres; Julian R Sampson; Brian D Dawson; Peter C Harris

2008-01-01

295

Glomerular pathology in autosomal dominant MYH9 spectrum disorders: what are the clues telling us about disease mechanism?  

Microsoft Academic Search

Genetic variation in MYH9, encoding non-muscle heavy chain IIA, has been recognized for over a decade as the cause of an autosomal dominant syndrome characterized by macrothrombocytopenia, neutrophil inclusions, and glomerular pathology. More recently, genetic variation in the MYH9 region on chromosome 22 has been associated with chronic kidney disease in African-descent individuals. A better understanding of the disease mechanisms

Jeffrey B Kopp

2010-01-01

296

Genetic linkage of autosomal dominant primary open angle glaucoma to chromosome 3q in a Greek pedigree  

Microsoft Academic Search

A locus for juvenile onset open angle glaucoma (OAG) has been assigned to chromosome 1q in families with autosomal dominant inheritance (GLC1A), due to mutations in the TIGR\\/MYOC gene. For adult onset OAG, called primary open angle glaucoma or POAG, five loci have so far been mapped to different chromosomes (GLC1B-GLC1F). Except for the GLC1B locus, the other POAG loci

George Kitsos; Hans Eiberg; Effrosini Economou-Petersen; Mary K Wirtz; Patricia L Kramer; Miltiadis Aspiotis; Niels Tommerup; Michael B Petersen; Konstantinos Psilas

2001-01-01

297

Molecular genetic diagnosis of autosomal dominant polycystic kidney disease in a newborn with bilateral cystic kidneys detected prenatally and multiple skeletal malformations  

Microsoft Academic Search

We report a case of an unusual prenatal presentation of polycystic kidneys associated with multiple skeletal limb defects, including polydactyly, syndactyly, bilateral agenesis of the tibia, and club foot. The ultrasonographic picture was consistent with a diagnosis of polycystic kidney disease, either the adult onset autosomal dominant type (ADPKD) or the early onset autosomal recessive form (ARPKD). However, there was

A E Turco; E M Padovani; G P Chiaffoni; B Peissel; S Rossetti; A Marcolongo; L Gammaro; G Maschio; P F Pignatti

1993-01-01

298

Peculiar facial appearance and generalized brachydactyly in a patient with congenital onychodysplasia of the index fingers (Iso-Kikuchi syndrome).  

PubMed

We report on a patient with clinical manifestations consistent with a diagnosis of congenital onychodysplasia of the index fingers (COIF). This syndrome has been found mainly in Japan, and as far as we know, this is the first case reported in Italy. In addition to the typical bilateral split nail of the second finger, the patient showed bilateral inguinal hernia, a peculiar face, and short hands. The metacarpophalangeal profile showed a generalized brachydactyly with all the hand long bones below x3 SD. The patient's father showed a peculiar kind of micronychia on both the fifth toes, suggesting a possible autosomal dominant transmission of the syndrome. In utero ischemia of the palmar digital artery and a dysplastic change in the crescent-shaped cap of the distal phalanx are the two main candidate pathogenetic mechanisms that have been proposed. In our opinion, the gradual broadening of the spectrum of this syndrome brings support to the hypothesis of a basal dysplastic pathogenetic mechanism involving not only the index fingers but also perhaps other tissues outside. We think that for the moment the definition of COIF for this syndrome should be maintained, the alternative proposed term "congenital onychodysplasia" being too indefinite. PMID:11170077

Franceschini, P; Licata, D; Guala, A; Di Cara, G; Franceschini, D

2001-02-01

299

Achalasia familiar: report of a family with an autosomal dominant pattern of inherence.  

PubMed

Esophageal achalasia is a well-known pathology with an autosomal recessive pattern of inherence described in the familiar cases. Its principal symptom is dysphagia, secondary to the poor relaxation of the lower esophageal sphincter. Chagas disease is one of the many causes involved in the development of this disease, being of great importance in our country because of the high prevalence of the vector. Various syndromes include achalasia in their symptomatology, such as the triple A syndrome or Allgrove syndrome (Addisonianism, achalasia, and alacrimia). We reported a family with a classical autosomal pattern of inherence with six affected members, four men and two women, with achalasia diagnosis as well as esophagus cancer in two of them, secondary to the disease, and no other findings. PMID:21073617

Gordillo-González, G; Guatibonza, Y P; Zarante, I; Roa, P; Jacome, L A; Hani, A

2010-11-12

300

Mutations in the human homologue of mouse dl cause autosomal recessive and dominant hypohidrotic ectodermal dysplasia  

Microsoft Academic Search

X-linked hypohidrotic ectodermal dysplasia results in abnormal morphogenesis of teeth, hair and eccrine sweat glands. The gene (ED1) responsible for the disorder has been identified, as well as the analogous X-linked gene (Ta) in the mouse. Autosomal recessive disorders, phenotypically indistinguishable from the X-linked forms, exist in humans and at two separate loci (crinkled, cr, and downless, dl) in mice.

Alex W. Monreal; Denis J. Headon; Paul A. Overbeek; Jonathan Zonana; Betsy M. Ferguson

1999-01-01

301

Linkage to chromosome 2q36.1 in autosomal dominant Dandy-Walker malformation with occipital cephalocele and evidence for genetic heterogeneity  

Microsoft Academic Search

We previously reported a Vietnamese-American family with isolated autosomal dominant occipital cephalocele. Upon further neuroimaging\\u000a studies, we have recharacterized this condition as autosomal dominant Dandy-Walker with occipital cephalocele (ADDWOC). A\\u000a similar ADDWOC family from Brazil was also recently described. To determine the genetic etiology of ADDWOC, we performed genome-wide\\u000a linkage analysis on members of the Vietnamese-American and Brazilian pedigrees. Linkage

Ali Jalali; Kimberly A. Aldinger; Ajit Chary; David G. Mclone; Robin M. Bowman; Luan Cong Le; Phillip Jardine; Ruth Newbury-Ecob; Andrew Mallick; Nadereh Jafari; Eric J. Russell; John Curran; Pam Nguyen; Karim Ouahchi; Charles Lee; William B. Dobyns; Kathleen J. Millen; Joao M. Pina-Neto; John A. Kessler; Alexander G. Bassuk

2008-01-01

302

Renal structure in early autosomal-dominant polycystic kidney disease (ADPKD): The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) cohort1  

Microsoft Academic Search

Renal structure in early autosomal-dominant polycystic kidney disease (ADPKD): The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) cohortBackgroundAutosomal-dominant polycystic kidney disease (ADPKD) is characterized by gradual renal enlargement and cyst growth prior to loss of renal function. Standard radiographic imaging has not provided the resolution and accuracy necessary to detect small changes in renal volume or to

Arlene B. Chapman; Lisa M. Guay-Woodford; Jared J. Grantham; Vicente E. Torres; Kyongtae T. Bae; Deborah A. Baumgarten; Philip J. Kenney; Bernard F. King; James F. Glockner; Louis H. Wetzel; Marijn E. Brummer; W. Charles O'Neill; Michelle L. Robbin; William M. Bennett; Saulo Klahr; Gladys H. Hirschman; Paul L. Kimmel; Paul A. Thompson; J. Philip Miller

2003-01-01

303

Experimental transmission of an autosomal dominant spongiform encephalopathy: does the infectious agent originate in the human genome?  

PubMed Central

Marmosets inoculated intracerebrally with brain tissue from a woman with Gerstmann-Straussler syndrome (an autosomal dominant dementia associated with spongiform change and amyloid deposition) developed an encephalopathy indistinguishable from that seen in marmosets inoculated with brain tissue from a typical case of Creutzfeldt-Jakob disease. As in Huntington's disease, in the pedigree of the patient with Gerstmann-Straussler syndrome women who subsequently developed the illness had increased fecundity. The pathogen in human transmissible dementia may arise from a sequence (which itself sometimes confers a selective advantage) located within the human genome.

Baker, H F; Ridley, R M; Crow, T J

1985-01-01

304

Nicotine Normalizes Intracellular Subunit Stoichiometry of Nicotinic Receptors Carrying Mutations Linked to Autosomal Dominant Nocturnal Frontal Lobe Epilepsy  

Microsoft Academic Search

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is linked with high penetrance to several distinct nicotinic re- ceptor (nAChR) mutations. We studied (4)3(2)2 versus (4)2(2)3 subunit stoichiometry for five channel-lining M2 do- main mutations: S247F, S252L, 776ins3 in 4, V287L, and V287M in 2. 4 and 2 subunits were constructed with all possible combinations of mutant and wild-type (WT) M2

Cagdas D. Son; Fraser J. Moss; Bruce N. Cohen; Henry A. Lester

2009-01-01

305

Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy.  

PubMed

We performed genomic mapping of a family with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) and intellectual and psychiatric problems, identifying a disease-associated region on chromosome 9q34.3. Whole-exome sequencing identified a mutation in KCNT1, encoding a sodium-gated potassium channel subunit. KCNT1 mutations were identified in two additional families and a sporadic case with severe ADNFLE and psychiatric features. These findings implicate the sodium-gated potassium channel complex in ADNFLE and, more broadly, in the pathogenesis of focal epilepsies. PMID:23086396

Heron, Sarah E; Smith, Katherine R; Bahlo, Melanie; Nobili, Lino; Kahana, Esther; Licchetta, Laura; Oliver, Karen L; Mazarib, Aziz; Afawi, Zaid; Korczyn, Amos; Plazzi, Giuseppe; Petrou, Steven; Berkovic, Samuel F; Scheffer, Ingrid E; Dibbens, Leanne M

2012-10-21

306

Exclusion of autosomal dominant polycystic kidney disease type II (ADPKD2) from 160 cM of chromosome 1.  

PubMed Central

Autosomal dominant polycystic kidney disease is a heritable disorder and recent studies have shown genetic heterogeneity, with some, but not all, families showing linkage with markers on chromosome 16p. Members of a large ADPKD family, unlinked to chromosome 16, have been typed for 12 marker loci located on both arms of chromosome 1. Multipoint analysis excluded ADPKD2 from the region between D1S81 (pTHH33) and D1S67 (pHHH106) on the long arm and between Rh and PGM1 on the short arm. This excludes the disease locus from about 61% of chromosome 1.

Kumar, S; Kimberling, W J; Gabow, P A; Shugart, Y Y; Pieke-Dahl, S

1990-01-01

307

Identification of six novel MYH9 mutations and genotype–phenotype relationships in autosomal dominant macrothrombocytopenia with leukocyte inclusions  

Microsoft Academic Search

The autosomal dominant macrothrombocytopenia with leukocyte inclusions, May-Hegglin anomaly (MHA), Sebastian syndrome (SBS),\\u000a and Fechtner syndrome (FTNS), are rare platelet disorders characterized by a triad of giant platelets, thrombocytopenia, and\\u000a characteristic D?hle body-like leukocyte inclusions. The locus for these disorders was previously mapped on chromosome 22q12.3–q13.2\\u000a and the disease gene was recently identified as MYH9, the gene encoding the nonmuscle

Shinji Kunishima; Tadashi Matsushita; Tetsuhito Kojima; Norihiko Amemiya; Yong Mook Choi; Naoki Hosaka; Masakazu Inoue; Youngzoon Jung; Shigeo Mamiya; Kimikazu Matsumoto; Yuji Miyajima; Guangsen Zhang; Changgeng Ruan; Koki Saito; Kyung Soon Song; Hwi-Joong Yoon; Tadashi Kamiya; Hidehiko Saito

2001-01-01

308

Autosomal dominant retinitis pigmentosa: Absence of the rhodopsin proline->histidine substitution (codon 23) in pedigrees from Europe  

PubMed Central

In exon 1 at codon 23 of the rhodopsin gene, a mutation resulting in a proline-to-histidine substitution has previously been observed in approximately 12% of American autosomal dominant retinitis pigmentosa (ADRP) patients. The region around the site of this mutation in the rhodopsin gene has been amplified and analyzed in affected individuals from 91 European ADRP pedigrees. The codon 23 mutation has been found to be absent in all cases, including a large Irish pedigree in which the disease gene has previously been shown to be closely linked to the rhodopsin locus. This indicates the presence of either allelic or nonallelic heterogeneity in ADRP. ImagesFigure 1

Farrar, G. J.; Kenna, P.; Redmond, R.; McWilliam, P.; Bradley, D. G.; Humphries, M. M.; Sharp, E. M.; Inglehearn, C. F.; Bashir, R.; Jay, M.; Watty, A.; Ludwig, M.; Schinzel, A.; Samanns, C.; Gal, A.; Bhattacharya, S.; Humphries, P.

1990-01-01

309

Autosomal dominant juvenile amyotrophic lateral sclerosis and distal hereditary motor neuronopathy with pyramidal tract signs: synonyms for the same disorder?  

PubMed

Autosomal dominant juvenile amyotrophic lateral sclerosis (ALS) is a rare disorder and so far only one family has been reported. Genetic linkage studies mapped the disease locus to chromosome 9q34 (ALS4). The diagnosis of ALS in this family is based on the clinical signs with almost exclusively lower motor neurone pathology in combination with less prominent pyramidal tract signs. Atypical features include normal life expectancy, the absence of bulbar involvement and the symmetrical distal distribution of atrophy and weakness. We performed a molecular genetic study in three families that we had diagnosed as having distal hereditary motor neuronopathy, i.e. distal spinal muscular atrophy or spinal Charcot-Marie-Tooth syndrome, and found linkage to the ALS4 locus. The clinical phenotype in these three families, of different geographic origin (Austria, Belgium and England), is strikingly similar to the autosomal dominant juvenile ALS family except for a younger onset age in two of the distal hereditary motor neuronopathy families. These data suggest that ALS4 and distal hereditary motor neuronopathy with pyramidal tract signs may be one and the same disorder. PMID:12023320

De Jonghe, P; Auer-Grumbach, M; Irobi, J; Wagner, K; Plecko, B; Kennerson, M; Zhu, D; De Vriendt, E; Van Gerwen, V; Nicholson, G; Hartung, H-P; Timmerman, V

2002-06-01

310

[Autosomal dominant nocturnal frontal lobe epilepsy. An electroclinical and genetic description of a Norwegian family with ten affected members].  

PubMed

We describe a Norwegian family with clusters of brief nocturnal motor seizures with hyperkinetic or tonic manifestations. Seizures started in childhood. Neurological examination and neuroimaging were normal. Interictal EEG registrations were mostly normal, ictal EEG registrations disclosed left frontal epileptiform discharges in two of three patients examined and just shallow arousal preceding the attack in one of the three patients. Segregation analysis indicated an autosomal dominant inheritance pattern, and the patients were subsequently diagnosed as having autosomal dominant nocturnal frontal lobe epilepsy, a disorder first described in 1995. A missense mutation in the gene for the alpha-4 subunit of the neuronal nicotinergic acetylcholine receptor was recently described in an Australian family with this disorder. Our Norwegian family proved to have a novel insertion mutation (776ins3) in the same gene. This mutation affects the second transmembrane domain (M2) which forms the critical section of the ion channel. This is the first case of idiopathic partial epilepsy where the underlying molecular defect has been found. The fact that a dysfunction of the nicotinergic acetylcholine receptor may give rise to frontal epileptic seizures was surprising and may shed new light on the basic mechanisms of epileptogenesis. Manipulations of the cholinergic system may open up a new therapeutic approach. PMID:9528368

Nakken, K O; Magnusson, A; Steinlein, O K

1998-02-20

311

Autosomal Dominant Retinal Degeneration and Bone Loss in Patients with a 12-bp Deletion in the CRX Gene  

PubMed Central

Purpose To define the phenotypic expression of a deletion in the gene encoding the transcription factor CRX in a large, seven-generation, white family. Methods Fourteen affected individuals, all heterozygous for the Leu146del12 mutation in the cone-rod homeobox gene (CRX), and four nonaffected relatives from the same family were examined with visual function tests, and 10 underwent bone mineral density (BMD) measurement. Results The ability of the mutated CRX protein to transactivate rhodopsin promoter was decreased by approximately 25%, and its ability to react synergistically with neural retinal leucine zipper (NRL) was reduced by more than 30%. The affected members of the family had an autosomal dominant ocular condition most closely resembling Leber congenital amaurosis (LCA) with severe visual impairment at an early age. Depending on age, affected members showed varying degrees of significant visual acuity loss, elevated dark-adaptation thresholds, significantly reduced cone and rod electroretinogram (ERG) amplitudes, and progressive constriction of the visual fields, in most cases leading to complete blindness. Six affected members had reduced levels of BMD in the spine and the hip (osteopenia). Four affected female members who were receiving long-term hormonal replacement therapy (HRT) demonstrated normal values of BMD. Conclusions This large deletion of the CRX gene is associated with a severe form of autosomal dominant retinal degeneration. Affected members not receiving HRT showed reduced BMD (osteopenia). This phenotype may reflect the abnormal influence of mutant CRX on both retinal and pineal development.

Tzekov, Radouil T.; Liu, Yuhui; Sohocki, Melanie M.; Zack, Donald J.; Daiger, Stephen P.; Heckenlively, John R.; Birch, David G.

2008-01-01

312

Beta spectrin kissimmee: a spectrin variant associated with autosomal dominant hereditary spherocytosis and defective binding to protein 4.1.  

PubMed Central

We analyzed the DNA sequence of the cDNA encoding the NH2 terminal region of beta spectrin from members of a kindred with autosomal dominant hereditary spherocytosis associated with defective protein 4.1 binding. We found a point mutation at codon 202 within the 272 amino acid NH2-terminal region of beta spectrin. TGG was changed to CGG, resulting in the replacement of tryptophan by arginine. The base change eliminates a normally occurring PvuII restriction site and creates a new MspI site. This finding enabled rapid detection or exclusion of the mutation at the DNA level among the family members, including one member for whom this analysis was performed prenatally. The mutation was found only in the affected family members and occurred as a de novo mutation in the proband. It has not been found in 20 other kindreds. The recombinant peptide derived from the normal cDNA retains the capacity to sediment with protein 4.1 and F-actin. The mutant peptide spontaneously degrades. This variant represents both the first point mutation and the first beta spectrin mutation demonstrated in autosomal dominant hereditary spherocytosis. Furthermore, the mutation is located within a conserved sequence among spectrinlike proteins and may define an amino acid critical for protein 4.1 binding activity. Images

Becker, P S; Tse, W T; Lux, S E; Forget, B G

1993-01-01

313

Clinical and molecular analysis of three families with autosomal dominant neurohypophyseal diabetes insipidus associated with a novel and recurrent mutations in the vasopressin-neurophysin II gene  

Microsoft Academic Search

Objective: To test further the hypothesis that autosomal dominant neurohypophyseal diabetes insipi- dus (adFNDI) is caused by heterozygous mutations in the vasopressin - neurophysin II (AVP-NPII ) gene that exert a dominant negative effect by producing a precursor that misfolds, accumulates and eventually destroys the neurosecretory neurons. Methods: Antidiuretic function, magnetic resonance imaging (MRI) of the posterior pituitary and AVP-NPII

Jonas Rutishauser; Peter Kopp; Mary Beth Gaskill; Thomas J Kotlar; Gary L Robertson

2002-01-01

314

Clinical and molecular analysis of the enamelin gene ENAM in Colombian families with autosomal dominant amelogenesis imperfecta  

PubMed Central

In this study, we analyzed the phenotype, clinical characteristics and presence of mutations in the enamelin gene ENAM in five Colombian families with autosomal dominant amelogenesis imperfecta (ADAI). 22 individuals (15 affected and seven unaffected) belonging to five Colombian families with ADAI and eight individuals (three affected and five unaffected) belonging to three Colombian families with autosomal recessive amelogenesis imperfecta (ARAI) that served as controls for molecular alterations and inheritance patterns were studied. Clinical, radiographic and genetic evaluations were done in all individuals. Eight exons and three intron-exon boundaries were sequenced for mutation analysis. Two of the five families with ADAI had the hypoplasic phenotype, two had the hypocalcified phenotype and one had the hypomaturative phenotype. Anterior open bite and mandibular retrognathism were the most frequent skeletal abnormalities in the families with ADAI. No mutations were found. These findings suggest that ADAI in these Colombian families was unrelated to previously described mutations in the ENAM gene. These results also indicate that other regions not included in this investigation, such as the promoter region, introns and other genes should be considered as potential ADAI candidates.

Gutierrez, Sandra; Torres, Diana; Briceno, Ignacio; Gomez, Ana Maria; Baquero, Eliana

2012-01-01

315

Clinical and molecular analysis of the enamelin gene ENAM in Colombian families with autosomal dominant amelogenesis imperfecta.  

PubMed

In this study, we analyzed the phenotype, clinical characteristics and presence of mutations in the enamelin gene ENAM in five Colombian families with autosomal dominant amelogenesis imperfecta (ADAI). 22 individuals (15 affected and seven unaffected) belonging to five Colombian families with ADAI and eight individuals (three affected and five unaffected) belonging to three Colombian families with autosomal recessive amelogenesis imperfecta (ARAI) that served as controls for molecular alterations and inheritance patterns were studied. Clinical, radiographic and genetic evaluations were done in all individuals. Eight exons and three intron-exon boundaries were sequenced for mutation analysis. Two of the five families with ADAI had the hypoplasic phenotype, two had the hypocalcified phenotype and one had the hypomaturative phenotype. Anterior open bite and mandibular retrognathism were the most frequent skeletal abnormalities in the families with ADAI. No mutations were found. These findings suggest that ADAI in these Colombian families was unrelated to previously described mutations in the ENAM gene. These results also indicate that other regions not included in this investigation, such as the promoter region, introns and other genes should be considered as potential ADAI candidates. PMID:23055792

Gutiérrez, Sandra; Torres, Diana; Briceño, Ignacio; Gómez, Ana Maria; Baquero, Eliana

2012-08-17

316

A new form of autosomal dominant limb-girdle muscular dystrophy (LGMD1G) with progressive fingers and toes flexion limitation maps to chromosome 4p21  

Microsoft Academic Search

Limb-girdle muscular dystrophy (LGMD) is a genetic disorder characterized by progressive weakness of pelvic and scapular girdles and great clinical variability. It is a highly heterogeneous disease with 16 identified loci: six of them autosomal dominant (AD) (LGMD1) and 10 autosomal recessive (AR) (LGMD2). The responsible genes are known for three of the AD-LGMD and for all 10 AR-LGMD. Linkage

Alessandra Starling; Fernando Kok; Maria Rita Passos-Bueno; Mariz Vainzof; Mayana Zatz

2004-01-01

317

Atypical presentation of perforated sigmoid diverticulitis in a kidney transplant recipient with autosomal dominant polycystic kidney disease.  

PubMed

Perforated sigmoid diverticulitis, a complication of colonic diverticulosis commonly associated with autosomal dominant polycystic kidney disease (ADPKD), can be life-threatening in allogeneic kidney transplant recipients in the postoperative period. Immunosuppressive medications not only place the patient at risk for intestinal perforation, but also mask classic clinical symptoms and signs of acute abdomen, and subsequently lead to delayed diagnosis and treatment. We report a case of an ADPKD patient post kidney transplantation presenting with nausea, vomiting, and abdominal pain without signs of peritonitis. Chest x-ray revealed free air under the diaphragm consistent with intestinal perforation. Post kidney transplant recipients with ADPKD presenting with abdominal pain should prompt a search for possible perforated colonic diverticulitis in order to diagnose and treat this life-threatening condition early. PMID:23901392

Tantisattamo, Ekamol; Guasch, Antonio

2013-07-01

318

Malignant autosomal dominant frontal lobe epilepsy with repeated episodes of status epilepticus: successful treatment with vagal nerve stimulation.  

PubMed

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a familial partial epilepsy syndrome characterized by seizures suggesting a frontal lobe origin occurring predominantly during sleep. Up to a third of patients may have refractory seizures, with repeated episodes of status epilepticus, intellectual disability of variable degree and psychiatric disturbances. We report a patient with ADNFLE, refractory seizures and repeated episodes of life-threatening convulsive status epilepticus who underwent prolonged video-EEG monitoring and was implanted with a vagal nerve stimulator. At 3.5 years of follow-up, a decrease of more than 80% in seizure frequency was achieved, episodes of status were completely controlled and he displayed improved mood and alertness. Vagal nerve stimulation may be considered as therapy for patients with refractory epilepsies of genetic cause, as well as repeated status epilepticus. PMID:20478764

Carreño, Mar; Garcia-Alvarez, Dionisio; Maestro, Iratxe; Fernández, Santiago; Donaire, Antonio; Boget, Teresa; Rumià, Jordi; Pintor, Luis; Setoain, Xavier

2010-05-18

319

Recent advances on autosomal dominant nocturnal frontal lobe epilepsy: "understanding the nicotinic acetylcholine receptor (nAChR)".  

PubMed

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is characterized by clusters of nocturnal motor seizures, which are often stereotyped and brief. They vary from simple arousals during sleep to dramatic, bizarre, hyperkinetic events with tonic or dystonic features. A minority of patients may experience aura. This disease is caused by various mutations of genes coding for subunits of neuronal acetylcholine receptor comprising the sodium/potassium ion channel. Recent advances in molecular genetics have provided the means for a better understanding of human epileptogenesis at a molecular level, which can facilitate clinical diagnosis and provides a more rational basis of therapy of this form of epilepsy. In this review, we report the recent data in the genetics of ADNFLE. PMID:15843070

di Corcia, G; Blasetti, A; De Simone, M; Verrotti, A; Chiarelli, F

2005-01-01

320

The French series of autosomal dominant early onset Alzheimer's disease cases: mutation spectrum and cerebrospinal fluid biomarkers.  

PubMed

We describe 56 novel autosomal dominant early-onset Alzheimer disease (ADEOAD) families with PSEN1, PSEN2, and A?PP mutations or duplications, raising the total of families with mutations on known genes to 111 (74 PSEN1, 8 PSEN2, 16 A?PP, and 13 A?PP duplications) in the French series. In 33 additional families (23% of the series), the genetic determinism remained uncharacterized after this screening. Cerebrospinal fluid (CSF) biomarker levels were obtained for patients of 58 families (42 with known mutations and 16 without genetic characterization). CSF biomarkers profile was consistent with an AD diagnosis in 90% of families carrying mutations on known genes. In families without mutation, CSF biomarkers were consistent with AD diagnosis in 14/16 cases. Overall, these results support further genetic heterogeneity in the determinism of ADEOAD and suggest that other major genes remain to be characterized. PMID:22475797

Wallon, David; Rousseau, Stéphane; Rovelet-Lecrux, Anne; Quillard-Muraine, Muriel; Guyant-Maréchal, Lucie; Martinaud, Olivier; Pariente, Jérémie; Puel, Michèle; Rollin-Sillaire, Adeline; Pasquier, Florence; Le Ber, Isabelle; Sarazin, Marie; Croisile, Bernard; Boutoleau-Bretonnière, Claire; Thomas-Antérion, Catherine; Paquet, Claire; Moreaud, Olivier; Gabelle, Audrey; Sellal, François; Sauvée, Mathilde; Laquerrière, Annie; Duyckaerts, Charles; Delisle, Marie-Bernadette; Streichenberger, Nathalie; Lannes, Béatrice; Frebourg, Thierry; Hannequin, Didier; Campion, Dominique

2012-01-01

321

A novel mutation of the glomulin gene in an Italian family with autosomal dominant cutaneous glomuvenous malformations.  

PubMed

Glomuvenous malformations (GVM) are hamartomas characterized histologically by glomus cells, which should be distinguished from glomus tumors. Familial GVM are rare, often present as multiple lesions, and exhibit familial aggregation, with autosomal dominant transmission. GVM are caused by mutations of the glomulin (GLMN) gene on chromosome 1p21-p22. Their development is thought to follow the 'two-hit' hypothesis, with a somatic mutation required in addition to the inherited germline mutation. We describe a novel GLMN mutation in an Italian family with GVM in which some members present with the less commonly observed phenotype of solitary lesions. A second somatic 'hit' mutation in GLMN was not discovered in our family. We further provide histological, immunohistochemical and electron microscopic data exhibiting the classic features of GVM. The diagnosis of GVM is critical because of distinction from venous malformations and blue rubber bleb nevus syndrome, which may demonstrate clinical similarities but require different treatment. PMID:22092580

Borroni, Riccardo G; Narula, Nupoor; Diegoli, Marta; Grasso, Maurizia; Concardi, Monica; Rosso, Renato; Cerica, Alessandra; Brazzelli, Valeria; Arbustini, Eloisa

2011-12-01

322

Emergent early markers of renal progression in autosomal-dominant polycystic kidney disease patients: implications for prevention and treatment.  

PubMed

Autosomal-dominant polycystic kidney disease (ADPKD) is the most common single cause of end-stage renal disease after diabetes, hypertension and glomerulonephritis. The clinical course of ADPKD is highly variable. Even with optimal care and therapy monitoring, currently the progression of ADPKD is slowed but not stopped. Newer treatments will no doubt become available in the future, but their side effect profiles will always need to be considered. Therefore, markers to distinguish ADPKD patients with a poor versus a good prognosis will be helpful. Several risk factors influencing kidney disease progression in ADPKD have been identified in the current era. The present review will discuss the spectrum of early markers of ADPKD renal disease progression. Specifically, the volume of total kidney, hypertension, glomerular hyperfiltration, renal blood flow, microalbuminuria, uric acid, and urinary molecular markers will be discussed. On this background, implications for the prevention and treatment of kidney disease progression in ADPKD are also discussed. PMID:22846584

Helal, Imed; Reed, Berenice; Schrier, Robert W

2012-07-26

323

Identification of a known GJB6 mutation in an autosomal dominant inherited Chinese family with hidrotic ectodermal dysplasia.  

PubMed

Objective: Mutation in the gap junction beta 6 (GJB6) gene has been reported to be associated with an autosomal dominant disorder hidrotic ectodermal dysplasia (HED), characterized by congenital nail clubbing, alopecia and palmoplantar keratoderma. The aim of this study is to investigate relationship between genetic mutation in GJB6 and HED in an affected Chinese family. Methods: We selected a Chinese HED family consisting of a total of 17 individuals including 8 HED patients (5 males and 3 females). The whole coding region of GJB6 was amplified by polymerase chain reaction and sequenced. Results: Sequence analysis identified a heterozygous missense mutation c.31G>A (p.G11R) in GJB6 gene of affected individuals, but not in healthy individuals. Conclusion: A c.31G>A (p.G11R) missense mutation in GJB6 gene is the genotypic characteristic for HED in Chinese population. PMID:23981984

Mousumi, Tania; Xiong, Zhimin; Lu, Lina; Liu, Shuanglin; Xia, Kun; Hu, Zhengmao

2013-08-01

324

Identification of Disease-Causing Mutations in Autosomal Dominant Retinitis Pigmentosa (adRP) Using Next-Generation DNA Sequencing  

PubMed Central

Purpose. To determine whether massively parallel next-generation DNA sequencing offers rapid and efficient detection of disease-causing mutations in patients with monogenic inherited diseases. Retinitis pigmentosa (RP) is a challenging application for this technology because it is a monogenic disease in individuals and families but is highly heterogeneous in patient populations. RP has multiple patterns of inheritance, with mutations in many genes for each inheritance pattern and numerous, distinct, disease-causing mutations at each locus; further, many RP genes have not been identified yet. Methods. Next-generation sequencing was used to identify mutations in pairs of affected individuals from 21 families with autosomal dominant RP, selected from a cohort of families without mutations in “common” RP genes. One thousand amplicons targeting 249,267 unique bases of 46 candidate genes were sequenced with the 454GS FLX Titanium (Roche Diagnostics, Indianapolis, IN) and GAIIx (Illumina/Solexa, San Diego, CA) platforms. Results. An average sequence depth of 70× and 125× was obtained for the 454GS FLX and GAIIx platforms, respectively. More than 9000 sequence variants were identified and analyzed, to assess the likelihood of pathogenicity. One hundred twelve of these were selected as likely candidates and tested for segregation with traditional di-deoxy capillary electrophoresis sequencing of additional family members and control subjects. Five disease-causing mutations (24%) were identified in the 21 families. Conclusion. This project demonstrates that next-generation sequencing is an effective approach for detecting novel, rare mutations causing heterogeneous monogenic disorders such as RP. With the addition of this technology, disease-causing mutations can now be identified in 65% of autosomal dominant RP cases.

Bowne, Sara J.; Sullivan, Lori S.; Koboldt, Daniel C.; Ding, Li; Fulton, Robert; Abbott, Rachel M.; Sodergren, Erica J.; Birch, David G.; Wheaton, Dianna H.; Heckenlively, John R.; Liu, Qin; Pierce, Eric A.; Weinstock, George M.

2011-01-01

325

Autosomal Dominant Familial Dyskinesia and Facial Myokymia: Single Exome Sequencing Identifies a Mutation in Adenylate Cyclase 5  

PubMed Central

Background Familial dyskinesia with facial myokymia (FDFM) is an autosomal dominant disorder that is exacerbated by anxiety. In a five-generation family of German ancestry we previously mapped FDFM to chromosome 3p21-3q21. The 72.5 Mbp linkage region was too large for traditional positional mutation identification. Objective To identify the gene responsible for FDFM by exome resequencing of a single affected individual. Design, Setting and Participants We performed whole exome sequencing in one affected individual and used a series of bioinformatic filters, including functional significance and presence in dbSNP or 1000 Genomes project, to reduce the number of candidate variants. Co-segregation analysis was performed in 15 additional individuals in three generations. Results The exome contained 23428 single nucleotide variants, of which 9391 were missense, nonsense or splice site alterations. The critical region contained 323 variants, five of which were not present in one of the sequence-databases. Adenylate cyclase 5 (ADCY5) was the only gene in which the variant (c.2176G>A) was co-transmitted perfectly with disease status and was not present in 3510 control Caucasian exomes. This residue is highly conserved and the change is nonconservative and predicted to be damaging. Conclusions ADCY5 is highly expressed in striatum. Mice deficient in Adcy5 develop a movement disorder that is worsened by stress. We conclude that FDFM likely results from a missense mutation in ADCY5. This study demonstrates the power of a single exome sequence in combination with linkage information to identify causative genes for rare autosomal dominant Mendelian diseases.

Chen, Ying-Zhang; Matsushita, Mark M.; Robertson, Peggy; Rieder, Mark; Girirajan, Santhosh; Antonacci, Francesca; Lipe, Hillary; Eichler, Evan E.; Nickerson, Deborah A.; Bird, Thomas D.; Raskind, Wendy H.

2012-01-01

326

Evaluation of autosomal dominant retinal dystrophy genes in an unaffected cohort suggests rare or private missense variants may often be benign  

PubMed Central

Background Many genes have been reported as harboring autosomal dominant mutations causing retinal dystrophy. As newly available gene panel sequencing and whole exome sequencing will open these genes up to greater scrutiny, we assess the rate of rare coding variation in these genes among unaffected individuals to provide context for variants that will be discovered when clinical subjects are sequenced. Methods Publicly available data from the Exome Variant Project were analyzed, focusing on 36 genes known to harbor mutations causing autosomal dominant macular dystrophy. Results Rates of rare (minor allele frequency ?0.1%) and private missense variants within autosomal dominant retinal dystrophy genes were found to occur at a high frequency in unaffected individuals, while nonsense variants were not. Conclusions We conclude that rare missense variations in most of these genes identified in individuals with retinal dystrophy cannot be confidently classified as disease-causing in the absence of additional information such as linkage or functional validation.

Strom, Samuel P.

2013-01-01

327

Renal failure in a patient with autosomal dominant polycystic kidney disease and coexisting dermato-polymyositis: first report in the literature.  

PubMed Central

Autosomal dominant polycystic kidney disease is a multisystem disorder characterized by multiple, bilateral renal cysts and is also associated with cysts in other organs, such as the liver, pancreas, and arachnoid membranes. Dermatomyositis is a disease which mainly involves the skin and muscles, although occasionally other organs are affected. In this report, a 56-year-old male patient with a four-year history of autosomal dominant polycystic kidney disease was presented. Renal failure was exacerbated by a coexisting dermato-polymyositis. Prednisone treatment with hemodialysis improved the situation. This is the first report renal failure in a patient with autosomal dominant polycystic kidney disease and dermato-polymyositis. Images Figure 1 Figure 2 Figure 3

Bahceci, Funda; Sari, Ramazan; Sarikaya, Metin; Atik, Esin; Karincaoglu, Yelda; Sevinc, Alper

2004-01-01

328

A pregnancy following PGD for X-linked dominant [correction of X-linked autosomal dominant] incontinentia pigmenti (Bloch-Sulzberger syndrome): case report.  

PubMed

Incontinentia Pigmenti (Bloch-Sulzberger syndrome) is a rare multisystem, ectodermal disorder associated with dermatological, dental and ocular features, and in <10% of cases, severe neurological deficit. Pedigree review suggests X-linked dominance with lethality in affected males. Presentation in female carriers is variable. Following genetic counselling, a mildly affected female carrier diagnosed in infancy with a de novo mutation was referred for preimplantation sexing, unusually selecting for male gender, with an acceptance of either normality or early miscarriage in an affected male. Following standard in-vitro fertilization and embryo biopsy, fluorescence in situ hybridization (FISH) unambiguously identified two male and two female embryos. A single 8-cell, grade 4 male embryo was replaced. A positive pregnancy test was reported 2 weeks after embryo transfer, although ultrasonography failed to demonstrate a viable pregnancy. Post abortive fetal tissue karyotyping diagnosed a male fetus with trisomy 16. This is an unusual report of preimplantation genetic diagnosis (PGD) being used for selection of males in an X-linked autosomal dominant disorder and demonstrates the value of PGD where amniocentesis or chorion villus sampling followed by abortion is not acceptable to the patient. This case also demonstrates the importance of follow-up prenatal diagnosis. PMID:11098039

Pettigrew, R; Kuo, H C; Scriven, P; Rowell, P; Pal, K; Handyside, A; Braude, P; Ogilvie, C M

2000-12-01

329

In cis autosomal dominant mutation of Senataxin associated with tremor/ataxia syndrome.  

PubMed

Senataxin mutations are the molecular basis of two distinct syndromes: (1) ataxia oculomotor apraxia type 2 (AOA2) and (2) juvenile amyotrophic lateral sclerosis 4 (ALS4). The authors describe clinical and molecular genetic studies of mother and daughter who display symptoms of cerebellar ataxia/atrophy, oculomotor defects, and tremor. Both patients share Senataxin mutations N603D and Q653K in cis (N603D-Q653K), adjacent to an N-terminal domain thought to function in protein-protein interaction. The N-terminal and helicase domains appear to harbor missense mutation clusters associated with AOA2 and ALS4. Working synergistically, the N603D-Q653K mutations may confer a partial dominant negative effect, acting on the senataxin N-terminal, further expanding the phenotypic spectrum associated with Senataxin mutations. PMID:17096168

Bassuk, A G; Chen, Y Z; Batish, S D; Nagan, N; Opal, P; Chance, P F; Bennett, C L

2006-11-10

330

Autosomal dominant inheritance of Williams-Beuren syndrome in a father and son with haploinsufficiency for FKBP6.  

PubMed

Williams-Beuren syndrome (WBS) is a neurodevelopmental microdeletion disorder that usually occurs sporadically due to its location within a highly repetitive genomic region that is unstable and prone to unequal cross-over during meiosis. The consequential loss of chromosomal material includes approximately 1.5 Mb of DNA at 7q11.23. Whilst cases of dominant inheritance have been described in the literature, there have been few reports of molecular confirmation and none have carried out detailed genotyping. We describe a Bulgarian father and son with WBS detected by fluorescent in situ hybridisation (with an elastin gene probe) and loss of heterozygosity mapping using microsatellite markers located in the critical region. These individuals appear to have a common WBS heterozygous deletion, confirming the expected dominant transmission and adding to the few familial cases reported. The deletion includes the gene FKBP6 which has recently been shown to play a role in homologous chromosome pairing in meiosis and male fertility in mouse models. Homozygous Fkbp6 -/- male mice are infertile and our data suggests that haploinsufficiency for FKBP6 does not appear to preclude male fertility in WBS, although male infertility involving this gene has the potential to follow the mouse model as a human autosomal recessive condition. PMID:15770126

Metcalfe, Kay; Simeonov, Emil; Beckett, William; Donnai, Dian; Tassabehji, May

2005-04-01

331

Mutation detection in autosomal dominant Hirschsprung disease: SSCP analysis of the RET proto-oncogene  

SciTech Connect

Hirschsprung disease (HSCR), or congenital aganglionic megacolon, is the most common cause of congenital bowel obstruction, with an incidence of 1 in 5000. Recently, linkage of an incompletely penetrant, dominant form of HSCR to the pericentromeric region of chromosome 10 was reported, followed by identification of mutations in the RET proto-oncogene in HSCR patients. RET mutations have also been reported in both sporadic and familial forms of three neuroendrocrine tumor syndromes. Unlike the clustered RET mutations observed in these syndromes, the 18 reported HSCR mutations are distributed throughout the extracellular and tryosine kinase domains of RET. In an effort to determine the frequency of RET mutations in HSCR and correlate genotype with phenotype, we have begun to screen for mutations among 80 HSCR probands representing a wide range of phenotypes and pedigree structures. Non-isotopic single strand conformation of polymorphism (SSCP) analysis was carried out using the Pharmacia PhastSystem{trademark}. Initial screening of exons 2 through 6 detected variants in 11 patients not seen in 24 controls. One additional band shift in exon 6 has been observed in both patients and controls. Preliminary sequence analysis has revealed two putative familial mutations in exon 2: a single base pair deletion (49Pro del C 296) and a point mutation that leads to a conservative amino acid substitution (93Gly{r_arrow}Ser). These results suggest that HSCR may be associated with a range of alterations in the coding sequence of the RET extracellular domain. Additional mutations will be described.

Angrist, M.; Bolk, S.; Chakravarti, A. [Case Western Reserve Univ., Cleveland, OH (United States)

1994-09-01

332

Autosomal-dominant woolly hair resulting from disruption of keratin 74 (KRT74), a potential determinant of human hair texture.  

PubMed

Autosomal-dominant woolly hair (ADWH) is a rare disorder characterized by tightly curled hair. The molecular basis of ADWH has not previously been reported. In this study, we identified a Pakistani family with ADWH. The family showed linkage to chromosome 12q12-q14.1, containing the type II keratin gene cluster. We discovered a heterozygous mutation, p.Asn148Lys, within the helix initiation motif of the keratin 74 (KRT74) gene in all affected family members. KRT74 encodes the inner root sheath (IRS)-specific epithelial (soft) keratin 74. We demonstrate that the mutant K74 protein results in disruption of keratin intermediate filament formation in cultured cells, most likely in a dominant-negative manner. Furthermore, we sequenced the mouse Krt71-74 genes in the dominant Caracul-like 4 (Cal4) allele, which is characterized by a wavy-coat phenotype and maps to the same region of mouse chromosome 15 as the Caracul (Ca) and Reduced coat (Rco) alleles. We identified a heterozygous mutation, p.Glu440Lys, not in Krt74 but in the neighboring gene, Krt71. Krt71 was previously reported to harbor Ca and Rco mutations, as well as a coding SNP that is associated with curly-coated dogs. In this study, we define the ADWH phenotype resulting from a mutation in a hair-follicle-specific epithelial keratin in humans. Our findings not only further underscore the crucial roles of the IRS-specific epithelial keratin genes Krt71-74 in hair disorders but also open the possibility that these genes might function as genetic determinants of normal variation in hair texture across mammalian species. PMID:20346438

Shimomura, Yutaka; Wajid, Muhammad; Petukhova, Lynn; Kurban, Mazen; Christiano, Angela M

2010-03-25

333

Autosomal-Dominant Woolly Hair Resulting from Disruption of Keratin 74 (KRT74), a Potential Determinant of Human Hair Texture  

PubMed Central

Autosomal-dominant woolly hair (ADWH) is a rare disorder characterized by tightly curled hair. The molecular basis of ADWH has not previously been reported. In this study, we identified a Pakistani family with ADWH. The family showed linkage to chromosome 12q12-q14.1, containing the type II keratin gene cluster. We discovered a heterozygous mutation, p.Asn148Lys, within the helix initiation motif of the keratin 74 (KRT74) gene in all affected family members. KRT74 encodes the inner root sheath (IRS)-specific epithelial (soft) keratin 74. We demonstrate that the mutant K74 protein results in disruption of keratin intermediate filament formation in cultured cells, most likely in a dominant-negative manner. Furthermore, we sequenced the mouse Krt71-74 genes in the dominant Caracul-like 4 (Cal4) allele, which is characterized by a wavy-coat phenotype and maps to the same region of mouse chromosome 15 as the Caracul (Ca) and Reduced coat (Rco) alleles. We identified a heterozygous mutation, p.Glu440Lys, not in Krt74 but in the neighboring gene, Krt71. Krt71 was previously reported to harbor Ca and Rco mutations, as well as a coding SNP that is associated with curly-coated dogs. In this study, we define the ADWH phenotype resulting from a mutation in a hair-follicle-specific epithelial keratin in humans. Our findings not only further underscore the crucial roles of the IRS-specific epithelial keratin genes Krt71-74 in hair disorders but also open the possibility that these genes might function as genetic determinants of normal variation in hair texture across mammalian species.

Shimomura, Yutaka; Wajid, Muhammad; Petukhova, Lynn; Kurban, Mazen; Christiano, Angela M.

2010-01-01

334

No evidence of linkage between the transforming growth factor-alpha gene in families with apparently autosomal dominant inheritance of cleft lip and palate.  

PubMed Central

Eight families have been identified with cleft lip, with or without cleft palate (CL/P), inherited in an apparently autosomal dominant manner. Transforming growth factor-alpha (TGFA) has been tested as a candidate gene for clefting in these families. Negative lod scores were generated in an autosomal dominant model with 80% penetrance (Z = -3.152 at theta = 0.05 and Z = -2.49 at theta = 0.05 with only affected subjects scored). After testing with a reduced penetrance of 28%, less negative lod scores were generated (Z = -0.157 at theta = 0.00), but there was still no evidence of linkage. An autosomal recessive model with a penetrance of 35% was also tested. Regardless of the model used there was little evidence of linkage between TGFA and the CL/P phenotype, which is in contrast to the previously published findings of an association between TGFA and CL/P in unrelated subjects.

Vintiner, G M; Holder, S E; Winter, R M; Malcolm, S

1992-01-01

335

The role of the SCA2 trinucleotide repeat expansion in 89 autosomal dominant cerebellar ataxia families. Frequency, clinical and genetic correlates  

Microsoft Academic Search

Summary The spinocerebellar ataxia type 2 (SCA2) is caused by a trinucleotide (CAG) expansion in the coding region of the ataxin 2 gene on chromosome 12q. 89 families with autosomal dominant cerebellar ataxia (ADCA) types I, II and III, and 47 isolated cases with idiopathic late onset cerebellar ataxia (ILOCA), were analysed for this mutation. The identification of the SCA2

P. Giunti; G. Sabbadini; M. G. Sweeney; M. B. Davis; L. Veneziano; E. Mantuano; A. Federico; R. Plasmati; M. Frontali; N. W. Wood

1998-01-01

336

Search for the Chromosomal Location of Autosomal Dominant Cerebellar Ataxia from Holguin, Cuba: Exclusion from Candidate Regions on Chromosome 4 and 11q  

Microsoft Academic Search

A gene locus for autosomal dominant cerebellar ataxia (ADCA) has been found on chromosome 6p and named spinocerebellar ataxia 1. However, linkage exclusion from chromosome 6p and thus locus heterogeneity has been proven in Cuban ADCA, the largest known collective of ADCA patients, probably due to a founder effect. Two chromosomal regions were analyzed for linkage to Cuban ADCA: chromosome

Suzana Gispert; Christian Nothers; Guillermo Orozco; Georg Auburger

1993-01-01

337

Overexpression of semicarbazide sensitive amine oxidase in the cerebral blood vessels in patients with Alzheimer’s disease and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy  

Microsoft Academic Search

Semicarbazide sensitive amine oxidase (SSAO) metabolizes oxidative deamination of primary aromatic and aliphatic amines, and, in the brain, it is selectively expressed in blood vessels. SSAO expression is examined, by immunohistochemistry with a purified polyclonal antibody to SSAO from bovine lung, in the brains of subjects with Alzheimer disease (AD; n=10), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

I. Ferrer; J. M. Lizcano; M. Hernández; M. Unzeta

2002-01-01

338

Autosomal dominant polycystic kidney disease (ADPKD, MIM 173900, PKD1 and PKD2 genes, protein products known as polycystin-1 and polycystin-2)  

Microsoft Academic Search

Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited nephropathy affecting over 1:1000 of the worldwide population. It is a systemic condition with frequent hepatic and cardiovascular manifestations in addition to the progressive development of renal cysts that eventually result in loss of renal function in the majority of affected individuals. The diagnosis of ADPKD is typically made using

Catherine Boucher; Richard Sandford

2004-01-01

339

A gene for autosomal dominant juvenile amyotrophic lateral sclerosis ( ALS4? ) localizes to a 500-kb interval on chromosome 9q34  

Microsoft Academic Search

Amyotrophic lateral sclerosis (ALS) denotes a heterogeneous group of neurodegenerative disorders affecting upper and lower motor neurons. ALS4 is a juvenile-onset, autosomal dominant form of ALS that is characterized by slow progression, distal limb weakness and amyotrophy, and pyramidal signs associated with severe loss of motor neurons in the brain and spinal cord. The ALS4 locus was recently mapped by

Ian P. Blair; Craig L. Bennett; Annette Abel; Bruce A. Rabin; John W. Griffin; Kenneth H. Fischbeck; David R. Cornblath; Phillip F. Chance

2000-01-01

340

Expression and localization of nuclear proteins in autosomal-dominant Emery-Dreifuss muscular dystrophy with LMNA R377H mutation  

Microsoft Academic Search

BACKGROUND: The autosomal dominant form of Emery-Dreifuss muscular dystrophy (AD-EDMD) is caused by mutations in the gene encoding for the lamins A and C (LMNA). Lamins are intermediate filament proteins which form the nuclear lamina underlying the inner nuclear membrane. We have studied the expression and the localization of nuclear envelope proteins in three different cell types and muscle tissue

Beate Reichart; Ruth Klafke; Christine Dreger; Eleonora Krüger; Isabell Motsch; Andrea Ewald; Jochen Schäfer; Heinz Reichmann; Clemens R Müller; Marie-Christine Dabauvalle

2004-01-01

341

Proximal myotonic dystrophy—a family with autosomal dominant muscular dystrophy, cataracts, hearing loss and hypogonadism: heterogeneity of proximal myotonic syndromes?  

Microsoft Academic Search

We describe a family with an autosomal dominant, multisystem disorder, consisting of late-onset proximal muscular dystrophy, electrophysiological myotonia, cataracts, late-onset deafness and male hypogonadism. Four patients were available for clinical examinations. Examination of asymptomatic family members revealed another patient with bilateral cataracts but without definite muscle disorder. Five deceased members of the family had proximal muscle weakness, reportedly or confirmed

Bjarne Udd; Ralf Krahe; Carina Wallgren-Pettersson; Björn Falck; Hannu Kalimo

1997-01-01

342

EXTENSIVE CLINICAL EXPERIENCE Autosomal Dominant Osteopetrosis: Clinical Severity and Natural History of 94 Subjects with a Chloride Channel 7 Gene Mutation  

Microsoft Academic Search

Context: Autosomal dominant osteopetrosis (ADO) is a sclerosing bone disorder caused by heterozygous mutations in the chloride chan- nel 7 (ClCN7) gene. The clinical manifestations of this disease have not been well characterized since the discovery of the genetic basis of ADO. Objectives: The primary objectives were to improve our understand- ing of ADO clinical characteristics and to study the

Steven G. Waguespack; Siu L. Hui; Linda A. DiMeglio; Michael J. Econs

2010-01-01

343

Exclusion of the chromosomal 1p21 region in a large pedigree with a phenotypic variant of type II autosomal dominant osteopetrosis  

Microsoft Academic Search

Purpose. To describe a large family including nine subjects with a mild phenotypic variant of type II autosomal dominant osteopetrosis (ADO II). Methods. Clinical and radiological description. Results are compared to those previously obtained in 42 patients (23 families) with classical ADO II. The present family was haplotyped with five markers from the chromosomal 1p21 region, which was previously shown

Olivier David Bénichou; Els Van Hul; Wim Van Hul; Marie-Christine de Vernejoul

2001-01-01

344

The Spatial Distribution of MR Imaging Abnormalities in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy and Their Relationship to Age and Clinical Features  

Microsoft Academic Search

BACKGROUND AND PURPOSE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a condition causing recurrent subcortical strokes. MR imaging, which shows focal lacunar infarcts and leukoaraiosis, plays a central role in the diagnosis and evaluation. We studied MR imaging abnormalities in a large prospectively recruited cohort of CADASIL patients to describe the spatial distribution of abnormalities, determine

Sumeet Singhal; Philip Rich; Hugh S. Markus

345

Uncommon cause of chest pain in a renal transplantation patient with autosomal dominant polycystic kidney disease: a case report.  

PubMed

Autosomal dominant polycystic kidney disease (ADPKD) is a common cause of end-stage renal disease (ESRD) and, because of its intrinsic systemic involvement, its treatment can be a medical and surgical challenge. This condition is often associated with the presence of hepatic cysts and their prevalence generally increases with age. Most patients remain asymptomatic, but some of these will develop complications associated with enlargement and infection of their cysts. Chest pain is a rare manifestation of these complications and, after exclusion of more common cardiovascular and pulmonary causes, should raise the suspicion of an infected hepatic cyst in these patients. We report the case of a 62-year-old male who underwent a kidney transplantation from a cadaveric donor in 1997 (etiology of the ESRD was ADPKD), and was admitted to the emergency department with complaints of chest pain radiating to both shoulders and the interscapular region. An echocardiogram was showed compression of the right atrium by a large liver cyst without associated ventricular dysfunction. Computer tomography-guided drainage of the cyst was performed and an Enterobacter aerogenes sensitive to carbamapenemes was isolated from respective cultures. The patient presented a favorable clinical outcome with prolonged administration of antibiotic therapy according to the antibiotic susceptibility testing. There was no need for surgical intervention. PMID:23026633

Rodrigues, L; Neves, M; Machado, S; Sá, H; Macário, F; Alves, R; Mota, A; Campos, M

2012-10-01

346

Four New Families with Autosomal Dominant Partial Epilepsy with Auditory Features: Clinical Description and Linkage to Chromosome 10q24  

PubMed Central

Summary Purpose Autosomal dominant partial epilepsy with auditory features (ADPEAF) is a rare form of nonprogressive lateral temporal lobe epilepsy characterized by partial seizures with auditory disturbances. The gene predisposing to this syndrome was localized to a 10-cM region on chromosome 10q24. We assessed clinical features and linkage evidence in four newly ascertained families with ADPEAF, to refine the clinical phenotype and confirm the genetic localization. Methods We genotyped 41 individuals at seven microsatellite markers spanning the previously defined 10-cM minimal genetic region. We conducted two-point linkage analysis with the ANALYZE computer package, and multipoint parametric and nonparametric linkage analyses as implemented in GENEHUNTER2. Results In the four families, the number of individuals with idiopathic epilepsy ranged from three to nine. Epilepsy was focal in all of those with idiopathic epilepsy who could be classified. The proportion with auditory symptoms ranged from 67 to 100%. Other ictal symptoms also were reported; of these, sensory symptoms were most common. Linkage analysis showed a maximum 2-point LOD score of 1.86 at (? = 0.0 for marker D10S603, and a maximum multipoint LOD score of 2.93. Conclusions These findings provide strong confirmation of linkage of a gene causing ADPEAF to chromosome 10q24. The results suggest that the susceptibility gene has a differential effect on the lateral temporal lobe, thereby producing the characteristic clinical features described here. Molecular studies aimed at the identification of the causative gene are underway.

Winawer, Melodie R.; Boneschi, Filippo Martinelli; Barker-Cummings, Christie; Lee, Joseph H.; Liu, Jianjun; Mekios, Constantine; Gilliam, T. Conrad; Pedley, Timothy A.; Hauser, W. Allen; Ottman, Ruth

2009-01-01

347

Molecular characterization of GDD1/TMEM16E, the gene product responsible for autosomal dominant gnathodiaphyseal dysplasia.  

PubMed

The human GDD1/TMEM16E gene has been found to be mutated in gnathodiaphyseal dysplasia, an unusual skeletal syndrome with autosomal dominant inheritance. The molecular and biochemical function(s) of GDD1 protein has not yet been elucidated. In this study, we examined the murine GDD1 gene expression pattern during embryonic development, and characterized the cellular and tissue localizations of its gene product using a GDD1-specific antibody. In the developing embryos, GDD1 mRNA expression was principally associated with differentiating and developing somites, with a highly complex spatiotemporal pattern that involved the myotomal and sclerotomal lineages of somites. Biochemical studies indicated that GDD1 protein is an integral membrane glycoprotein that resides predominantly in intracellular vesicles. Immunohistochemical analysis showed a high level of murine GDD1 protein expression in cardiac and skeletal muscle tissues, and in growth-plate chondrocytes and osteoblasts in bone. These observations suggest diverse cellular role(s) of GDD1 in the development of musculoskeletal system. PMID:17418107

Mizuta, Kuniko; Tsutsumi, Satoshi; Inoue, Hiroshi; Sakamoto, Yukiko; Miyatake, Katsutoshi; Miyawaki, Katsuyuki; Noji, Sumihare; Kamata, Nobuyuki; Itakura, Mitsuo

2007-03-28

348

A nonsense mutation of CRYGC associated with autosomal dominant congenital nuclear cataracts and microcornea in a Chinese pedigree  

PubMed Central

Purpose To report the identification of a nonsense mutation in ?C-crystallin (CRYGC) associated with autosomal dominant congenital nuclear cataracts and microcornea in a Chinese family. Methods We investigated four generations of a Chinese family six of whose members were affected by nuclear cataracts and microcornea. The genomic DNA was extracted from peripheral blood leukocytes. All reported nuclear cataract-related candidate genes were screened for causative mutations by direct DNA sequencing. The effects of amino acid changes on the structure and function of proteins were predicted by bioinformatics analysis. Results All affected individuals in this family exhibited nuclear cataracts and microcornea. Direct sequencing of the candidate gene cluster showed a c.471G>A transition in exon 3 of CRYGC, which co-segregated according to family members with cataracts, and was not observed in 100 normal controls. This single nucleotide change was predicted to introduce a translation stop codon at tryptophan 157 (W157X). Bioinformatics analysis showed that the mutation was predicted to affect the function and secondary structure of the CRYGC protein. Conclusions This study identified a disease-causing mutation c.471G>A in CRYGC in a Chinese family with cataracts, expanding the mutation spectrum of CRYGC causing congenital cataracts.

Guo, Yuanyuan; Su, Dongmei; Li, Qian; Yang, Zhenfei; Ma, Zicheng; Ma, Xu

2012-01-01

349

Mutation Spectrum in the Large GTPase Dynamin 2, and Genotype-Phenotype Correlation in Autosomal Dominant Centronuclear Myopathy  

PubMed Central

Centronuclear myopathy (CNM) is a genetically heterogeneous disorder associated with general skeletal muscle weakness, type I fiber predominance and atrophy, and abnormally centralized nuclei. Autosomal dominant CNM is due to mutations in the large GTPase dynamin 2 (DNM2), a mechanochemical enzyme regulating cytoskeleton and membrane trafficking in cells. To date, 40 families with CNM-related DNM2 mutations have been described, and here we report 60 additional families encompassing a broad genotypic and phenotypic spectrum. In total, 18 different mutations are reported in 100 families and our cohort harbors nine known and four new mutations, including the first splice-site mutation. Genotype–phenotype correlation hypotheses are drawn from the published and new data, and allow an efficient screening strategy for molecular diagnosis. In addition to CNM, dissimilar DNM2 mutations are associated with Charcot–Marie–Tooth (CMT) peripheral neuropathy (CMTD1B and CMT2M), suggesting a tissue-specific impact of the mutations. In this study, we discuss the possible clinical overlap of CNM and CMT, and the biological significance of the respective mutations based on the known functions of dynamin 2 and its protein structure. Defects in membrane trafficking due to DNM2 mutations potentially represent a common pathological mechanism in CNM and CMT.

Bohm, Johann; Biancalana, Valerie; DeChene, Elizabeth T.; Bitoun, Marc; Pierson, Christopher R.; Schaefer, Elise; Karasoy, Hatice; Dempsey, Melissa A.; Klein, Fabrice; Dondaine, Nicolas; Kretz, Christine; Haumesser, Nicolas; Poirson, Claire; Toussaint, Anne; Greenleaf, Rebecca S.; Barger, Melissa A.; Mahoney, Lane J.; Kang, Peter B.; Zanoteli, Edmar; Vissing, John; Witting, Nanna; Echaniz-Laguna, Andoni; Wallgren-Pettersson, Carina; Dowling, James; Merlini, Luciano; Oldfors, Anders; Ousager, Lilian Bomme; Melki, Judith; Krause, Amanda; Jern, Christina; Oliveira, Acary S. B.; Petit, Florence; Jacquette, Aurelia; Chaussenot, Annabelle; Mowat, David; Leheup, Bruno; Cristofano, Michele; Aldea, Juan Jose Poza; Michel, Fabrice; Furby, Alain; Llona, Jose E. Barcena; Van Coster, Rudy; Bertini, Enrico; Urtizberea, Jon Andoni; Drouin-Garraud, Valerie; Beroud, Christophe; Prudhon, Bernard; Bedford, Melanie; Mathews, Katherine; Erby, Lori A. H.; Smith, Stephen A.; Roggenbuck, Jennifer; Crowe, Carol A.; Spitale, Allison Brennan; Johal, Sheila C.; Amato, Anthony A.; Demmer, Laurie A.; Jonas, Jessica; Darras, Basil T.; Bird, Thomas D.; Laurino, Mercy; Welt, Selman I.; Trotter, Cynthia; Guicheney, Pascale; Das, Soma; Mandel, Jean-Louis; Beggs, Alan H.; Laporte, Jocelyn

2012-01-01

350

Autosomal dominant polycystic kidney disease: Localization of the second gene to chromosome 4q13-q23  

SciTech Connect

At least two loci are known to exist for autosomal dominant polycystic kidney disease (ADPKD). One was localized to 16p, but the second less common locus has remained unlinked. Over 100 microsatellite markers, distributed across all chromosomes, have been typed on informative family members from the large Sicilian kindred in which the genetic heterogeneity was first discovered. Both the affected and the unaffected status of every family member used in the study were consulted in the successful localization of a second ADPKD gene to chromosome 4q. It was found to be flanked by the markers D4S231 and D4S414, defining a segment that spans about 9 cM. The new locus has been designated PKD4. This second localization will allow researchers to target another ADPKD gene for isolation in an effort to understand the pathogenesis of this common disorder. Furthermore, when flanking markers for the second ADPKD gene are used in conjunction with flanking markers for PKD1, the accuracy of the diagnosis of the subtype of ADPKD present in any particular family will be enhanced. This will improve the accuracy of linkage-based presymptomatic diagnoses by reducing the error due to genetic heterogeneity. 42 refs., 3 figs., 1 tab.

Kimberling, W.J.; Kumar, S.; Kenyon, J.B.; Connolly, C.J. (Creighton Univ. Medical School, Omaha, NE (United States)); Gabow, P.A. (Colorado Univ. Health Sciences Center, Denver, CO (United States)); Somlo, S. (Albert Einstein School of Medicine, Bronx, NY (United States))

1993-12-01

351

Why is genetic screening for autosomal dominant disorders underutilized in families? The case of hereditary hemorrhagic telangiectasia (HHT)  

PubMed Central

Purpose Appropriate management of autosomal dominant disorders reduces morbidity and mortality, but relies on identifying which family members are affected. Genetic testing may identify relatives needing follow-up, but is underutilized. We conducted this study to identify barriers to genetic testing for one disorder, hereditary hemorrhagic telangiectasia (HHT). Methods Surveys and on-line discussion groups with people from HHT families. Results Multiple barriers to HHT genetic testing were identified including lack of knowledge about genetic testing, problems with access, and emotional barriers. Many participants: did not understand the rationale for HHT testing or benefits of early detection; believed that genetic testing is expensive and not covered by insurance; believed that primary care providers don’t know how to order genetic testing. Access to HHT testing is limited by distance from an HHT Center or a genetics clinic. Emotional barriers include fear of insurance discrimination; denial of having HHT or being at risk; guilt and stigma. Conclusion Voluntary disease organizations should develop and disseminate brief educational materials that describe the rationale for genetic testing, and emphasize the benefits of early detection and treatment. In addition, laboratories offering genetic testing should provide support for primary care physicians to order and interpret genetic tests.

Bernhardt, Barbara A.; Zayac, Cara; Pyeritz, Reed E.

2011-01-01

352

Family with neurofibromatosis type 2 and autosomal dominant hearing loss: identification of carriers of the mutated NF2 gene.  

PubMed

A family is presented in which neurofibromatosis type 2 (NF2) and autosomal dominant hearing loss segregate in an apparently independent way. The presence of the latter condition caused anxiety in all family members at risk for NF2 in whom hearing loss became apparent. Previously, we identified a G-->A transition in the donor splice site of exon 5 of the NF2 gene in a family member with proven NF2. As expected, the mutation was present in two other family members who fulfilled the diagnostic criteria for NF2. Four out of five family members at risk for NF2 developed hearing loss. Two of these had the G-->A transition. The mutation was absent in the two other individuals with hearing loss and in the fifth family member without hearing loss or other clinical symptoms. In this family, the identification of the underlying NF2 gene mutation excluded NF2 as the cause of hearing loss in two potential carriers of the mutated gene. On the other hand, it enabled the identification of two carriers of the NF2 gene mutation who did not fulfill the diagnostic criteria for NF2. They will have to be monitored very carefully for the development of NF2-associated tumors. The consistent association within this family of a relatively mild clinical phenotype with the NF2 mutation, supports earlier suggestions that intrafamilial variability is small in NF2. PMID:7607639

Bijlsma, E K; Merel, P; Fleury, P; van Asperen, C J; Westerveld, A; Delattre, O; Thomas, G; Hulsebos, T J

1995-07-01

353

Mutation spectrum in the large GTPase dynamin 2, and genotype-phenotype correlation in autosomal dominant centronuclear myopathy.  

PubMed

Centronuclear myopathy (CNM) is a genetically heterogeneous disorder associated with general skeletal muscle weakness, type I fiber predominance and atrophy, and abnormally centralized nuclei. Autosomal dominant CNM is due to mutations in the large GTPase dynamin 2 (DNM2), a mechanochemical enzyme regulating cytoskeleton and membrane trafficking in cells. To date, 40 families with CNM-related DNM2 mutations have been described, and here we report 60 additional families encompassing a broad genotypic and phenotypic spectrum. In total, 18 different mutations are reported in 100 families and our cohort harbors nine known and four new mutations, including the first splice-site mutation. Genotype-phenotype correlation hypotheses are drawn from the published and new data, and allow an efficient screening strategy for molecular diagnosis. In addition to CNM, dissimilar DNM2 mutations are associated with Charcot-Marie-Tooth (CMT) peripheral neuropathy (CMTD1B and CMT2M), suggesting a tissue-specific impact of the mutations. In this study, we discuss the possible clinical overlap of CNM and CMT, and the biological significance of the respective mutations based on the known functions of dynamin 2 and its protein structure. Defects in membrane trafficking due to DNM2 mutations potentially represent a common pathological mechanism in CNM and CMT. PMID:22396310

Böhm, Johann; Biancalana, Valérie; Dechene, Elizabeth T; Bitoun, Marc; Pierson, Christopher R; Schaefer, Elise; Karasoy, Hatice; Dempsey, Melissa A; Klein, Fabrice; Dondaine, Nicolas; Kretz, Christine; Haumesser, Nicolas; Poirson, Claire; Toussaint, Anne; Greenleaf, Rebecca S; Barger, Melissa A; Mahoney, Lane J; Kang, Peter B; Zanoteli, Edmar; Vissing, John; Witting, Nanna; Echaniz-Laguna, Andoni; Wallgren-Pettersson, Carina; Dowling, James; Merlini, Luciano; Oldfors, Anders; Bomme Ousager, Lilian; Melki, Judith; Krause, Amanda; Jern, Christina; Oliveira, Acary S B; Petit, Florence; Jacquette, Aurélia; Chaussenot, Annabelle; Mowat, David; Leheup, Bruno; Cristofano, Michele; Poza Aldea, Juan José; Michel, Fabrice; Furby, Alain; Llona, Jose E Barcena; Van Coster, Rudy; Bertini, Enrico; Urtizberea, Jon Andoni; Drouin-Garraud, Valérie; Béroud, Christophe; Prudhon, Bernard; Bedford, Melanie; Mathews, Katherine; Erby, Lori A H; Smith, Stephen A; Roggenbuck, Jennifer; Crowe, Carol A; Brennan Spitale, Allison; Johal, Sheila C; Amato, Anthony A; Demmer, Laurie A; Jonas, Jessica; Darras, Basil T; Bird, Thomas D; Laurino, Mercy; Welt, Selman I; Trotter, Cynthia; Guicheney, Pascale; Das, Soma; Mandel, Jean-Louis; Beggs, Alan H; Laporte, Jocelyn

2012-04-04

354

Neuropsychological function in patients with a single gene mutation associated with autosomal dominant nocturnal frontal lobe epilepsy.  

PubMed

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a nonlesional condition associated with mutation of the gene coding for the alpha4 nicotinic acetylcholine receptor (nAChR). The nAChR modulates aspects of memory and attention. We examined the neuropsychological phenotype of ADNFLE, with a particular emphasis on understanding the impact on frontal lobe functions. We used standard clinical tests as well as focused measures of frontal lobe function in a well-defined group of patients with ADNFLE. Their performance was compared with that of a group of age-, sex-, and education-matched control participants. Patients with ADNFLE showed impairments on tasks requiring cognitive flexibility against a background of well-preserved intellectual abilities. In accord with existing research, verbal memory impairments were identified in the patient group; the level of impairment on these tasks correlated with disease-related factors. In our study of ADNFLE associated with one mutation, cognitive flexibility appears to be the core cognitive deficit. PMID:20189461

Wood, Amanda G; Saling, Michael M; Fedi, Marco; Berkovic, Samuel F; Scheffer, Ingrid E; Benjamin, Christopher; Reutens, David C

2010-02-26

355

Seizures and enhanced cortical GABAergic inhibition in two mouse models of human autosomal dominant nocturnal frontal lobe epilepsy.  

PubMed

Selected mutations in the human alpha4 or beta2 neuronal nicotinic acetylcholine receptor subunit genes cosegregate with a partial epilepsy syndrome known as autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). To examine possible mechanisms underlying this inherited epilepsy, we engineered two ADNFLE mutations (Chrna4(S252F) and Chrna4(+L264)) in mice. Heterozygous ADNFLE mutant mice show persistent, abnormal cortical electroencephalograms with prominent delta and theta frequencies, exhibit frequent spontaneous seizures, and show an increased sensitivity to the proconvulsant action of nicotine. Relative to WT, electrophysiological recordings from ADNFLE mouse layer II/III cortical pyramidal cells reveal a >20-fold increase in nicotine-evoked inhibitory postsynaptic currents with no effect on excitatory postsynaptic currents. i.p. injection of a subthreshold dose of picrotoxin, a use-dependent gamma-aminobutyric acid receptor antagonist, reduces cortical electroencephalogram delta power and transiently inhibits spontaneous seizure activity in ADNFLE mutant mice. Our studies suggest that the mechanism underlying ADNFLE seizures may involve inhibitory synchronization of cortical networks via activation of mutant alpha4-containing nicotinic acetylcholine receptors located on the presynaptic terminals and somatodendritic compartments of cortical GABAergic interneurons. PMID:17146052

Klaassen, Alwin; Glykys, Joseph; Maguire, Jamie; Labarca, Cesar; Mody, Istvan; Boulter, Jim

2006-12-04

356

Autosomal dominant nocturnal frontal-lobe epilepsy: genetic heterogeneity and evidence for a second locus at 15q24.  

PubMed

Autosomal dominant nocturnal frontal-lobe epilepsy (ADNFLE) is a recently identified partial epilepsy in which two different mutations have been described in the alpha4 subunit of the neuronal nicotinic acetylcholine receptor (CHRNA4). An additional seven families are presented in which ADNFLE is unlinked to the CHRNA4 region on chromosome 20q13.2. Seven additional sporadic cases showed no evidence of defective CHRNA4. One of the families showed evidence of linkage to 15q24, close to the CHRNA3/CHRNA5/CHRNB4 cluster (maximum LOD score of 3.01 with D15S152). Recombination between ADNFLE and CHRNA4, linkage to 15q24 in one family, and exclusion from 15q24 and 20q13.2 in others demonstrate genetic heterogeneity with at least three different genes for ADNFLE. The CHRNA4 gene and the two known CHRNA4 mutations are responsible for only a minority of ADNFLE. Although the ADNFLE phenotype is clinically homogeneous, there appear to be a variety of molecular defects responsible for this disorder, which will provide a challenge to the understanding of the basic mechanism of epileptogenesis. PMID:9758605

Phillips, H A; Scheffer, I E; Crossland, K M; Bhatia, K P; Fish, D R; Marsden, C D; Howell, S J; Stephenson, J B; Tolmie, J; Plazzi, G; Eeg-Olofsson, O; Singh, R; Lopes-Cendes, I; Andermann, E; Andermann, F; Berkovic, S F; Mulley, J C

1998-10-01

357

An insertion mutation of the CHRNA4 gene in a family with autosomal dominant nocturnal frontal lobe epilepsy.  

PubMed

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is the first, and to date only, idiopathic epilepsy for which a specific mutation has been found. A missense mutation in the critical M2 domain of the alpha4 subunit of the neuronal nicotinic acetylcholine receptor (CHRNA4) has been recently identified in one large Australian pedigree. Here we describe a novel mutation in the M2 domain of the CHRNA4 gene in a Norwegian family. Three nucleotides (GCT) were inserted at nucleotide position 776 into the coding region for the C-terminal end of the M2 domain. Physiological investigations of the receptor reconstituted with the mutated CHRNA4 subunit reveal that this insertion does not prevent the receptor function but increases its apparent affinity for ACh. In addition, this mutant receptor shows a significantly lower calcium permeability that, at the cellular level, may correspond to a loss of function. Comparison of the two mutations identified so far in families with ADNFLE illustrates that different mutations can result in similar phenotypes. PMID:9175743

Steinlein, O K; Magnusson, A; Stoodt, J; Bertrand, S; Weiland, S; Berkovic, S F; Nakken, K O; Propping, P; Bertrand, D

1997-06-01

358

Localization of a gene for autosomal dominant nocturnal frontal lobe epilepsy to chromosome 20q 13.2.  

PubMed

The epilepsies comprise a group of syndromes that are divided into generalized and partial (focal) types. Familial occurrence has long been recognized but progress in mapping epilepsy genes has been slow except for rare cases where the inheritance is easily determined from classical genetic studies. Linkage is established for three generalized syndromes: the EBN1 and EBN2 genes for benign familial neonatal convulsions (BFNC) map to chromosomes 20q and 8q (refs 2-5), the EPM1 gene for Unverricht-Lundborg disease maps to 21q (ref. 6) and the gene for the northern epilepsy syndrome maps to 8p (ref. 7). A claim for linkage of the EJM1 gene for the common generalized syndrome of juvenile myoclonic epilepsy to 6p is currently in dispute. Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) was recently described in five families. We now report the chromosomal assignment, to 20q13.2, for the gene for ADNFLE in one large Australian kindred with 27 affected individuals spanning six generations. PMID:7647781

Phillips, H A; Scheffer, I E; Berkovic, S F; Hollway, G E; Sutherland, G R; Mulley, J C

1995-05-01

359

[Generation of epilepsy animal model bearing a genetic abnormality identified in autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) of humans].  

PubMed

Nocturnal frontal lobe epilepsy is seen exclusively during sleep and is characterized by three distinct seizure phenotypes: paroxysmal arousals, paroxysmal dystonia, and episodic wandering. Mutations of CHRNA4, CHRNB2, or CHRNA2 genes encoding alpha4, beta2 or alpha2 subunits of neuronal nicotinic ACh receptor (nAChR) have been identified in the individuals with sporadic type NFLE and pedigrees with autosomal dominant type of NFLE (ADNFLE). In the past decade, various electrophysiological studies have analyzed the functional abnormalities of ADNFLE/NFLE mutant nAChR; however, the detailed pathogenesis of ADNFLE/NFLE has remained to be clarified. Therefore, to explore the pathogenesis of ADNFLE/NFLE, genetic animal models harboring ADNFLE mutant Chrna4 genes have recently been established. The face, construct and predictive validities have been demonstrated in a transgenic rat strain bearing the S284L mutant Chrna4 gene. The in vivo analyses of the functional abnormalities using genetic ADNFLE/NFLE animal models suggest the putative mechanisms of the ADNFLE/NFLE seizure onset during slow wave sleep. PMID:20297737

Okada, Motohiro

2010-02-01

360

The structure and composition of deciduous enamel affected by local hypoplastic autosomal dominant amelogenesis imperfecta resulting from an ENAM mutation.  

PubMed

In a group of families in northern Sweden, a mutation in the ENAM gene (predicted to produce a highly truncated protein) results in the local hypoplastic form of autosomal dominant amelogenesis imperfecta. In this study, sections of deciduous teeth from members of 3 of these families were examined by scanning electron microscopy (SEM) and the enamel mineral was analysed by energy dispersive X-ray spectroscopy (EDX). The sections were also probed with antibodies raised to a conserved sequence of the enamelin protein. Selected intact teeth were first analysed by digital imaging and ascribed with an 'Enamel Defects Index' (EDI) score. SEM of tooth sections revealed disrupted prism morphology and the prisms had a glass-like appearance in some areas. These areas of dysplasia were sometimes irregular but formed regular arrays in others. Comparison of EDI scores with SEM indicated that in one tooth the surface had no measurable defects but significant defects were present in the underlying enamel microstructure. SEM immunohistochemistry with the antibody raised to a fragment of the enamelin protein produced positive, but light, labelling throughout normal enamel. In dysplastic areas, however, the labelling intensity appeared to be reduced. The results indicate that the presence of functional enamelin in the correct amounts is necessary for correct prism morphogenesis. In addition, a combination of EDI and structural analysis indicate that defects in enamel microstructure are not necessarily visible as defects on the surface of the tooth, suggesting the possibility, at least, that some instances of under-diagnosis may occur. PMID:19923784

Shore, R C; Bäckman, B; Elcock, C; Brook, A H; Brookes, S J; Kirkham, J

2009-11-14

361

Clinical and Genetic Description of a Family With a High Prevalence of Autosomal Dominant Restless Legs Syndrome  

PubMed Central

OBJECTIVE: To conduct clinical and molecular genetic analyses of the members of an extended family in Central Indiana with a high prevalence of restless legs syndrome (RLS). PARTICIPANTS AND METHODS: From February 1, 2006, through August 31, 2008, we collected data from members of this family, which is of English descent. Genealogical methods were used to expand the family tree, and family members were screened with an RLS questionnaire. Telephone interviews and personal examinations were performed at Mayo Clinic and during a field trip to Central Indiana. Blood samples were collected for molecular genetic analysis. A follow-up telephone interview was conducted 1 year later. RESULTS: The family tree spans 7 generations with 88 living members, 30 of whom meet the criteria for diagnosis of RLS established by the International Restless Legs Syndrome Study Group. Three affected family members also have Parkinson disease or essential tremor. The mode of RLS inheritance is compatible with an autosomal dominant pattern. The affected family members do not exhibit linkage to the 5 known RLS loci or mutations in the RLS susceptibility genes MEIS1 and BTBD9. CONCLUSION: Of 88 members of this single extended family in Central Indiana, 30 were diagnosed as having RLS. Because our analysis shows that the disease is not linked to any of the known RLS loci or risk-associated genes, we postulate that members of this family may carry a gene mutation in a novel genetic locus.

Young, Jessica E.; Vilarino-Guell, Carles; Lin, Siong-Chi; Wszolek, Zbigniew K.; Farrer, Matthew J.

2009-01-01

362

Mutations in DNAJC5, Encoding Cysteine-String Protein Alpha, Cause Autosomal-Dominant Adult-Onset Neuronal Ceroid Lipofuscinosis  

PubMed Central

Autosomal-dominant adult-onset neuronal ceroid lipofuscinosis (ANCL) is characterized by accumulation of autofluorescent storage material in neural tissues and neurodegeneration and has an age of onset in the third decade of life or later. The genetic and molecular basis of the disease has remained unknown for many years. We carried out linkage mapping, gene-expression analysis, exome sequencing, and candidate-gene sequencing in affected individuals from 20 families and/or individuals with simplex cases; we identified in five individuals one of two disease-causing mutations, c.346_348delCTC and c.344T>G, in DNAJC5 encoding cysteine-string protein alpha (CSP?). These mutations—causing a deletion, p.Leu116del, and an amino acid exchange, p.Leu115Arg, respectively—are located within the cysteine-string domain of the protein and affect both palmitoylation-dependent sorting and the amount of CSP? in neuronal cells. The resulting depletion of functional CSP? might cause in parallel the presynaptic dysfunction and the progressive neurodegeneration observed in affected individuals and lysosomal accumulation of misfolded and proteolysis-resistant proteins in the form of characteristic ceroid deposits in neurons. Our work represents an important step in the genetic dissection of a genetically heterogeneous group of ANCLs. It also confirms a neuroprotective role for CSP? in humans and demonstrates the need for detailed investigation of CSP? in the neuronal ceroid lipofuscinoses and other neurodegenerative diseases presenting with neuronal protein aggregation.

Noskova, Lenka; Stranecky, Viktor; Hartmannova, Hana; Pristoupilova, Anna; Baresova, Veronika; Ivanek, Robert; Hulkova, Helena; Jahnova, Helena; van der Zee, Julie; Staropoli, John F.; Sims, Katherine B.; Tyynela, Jaana; Van Broeckhoven, Christine; Nijssen, Peter C.G.; Mole, Sara E.; Elleder, Milan; Kmoch, Stanislav

2011-01-01

363

Characterization of large rearrangements in autosomal dominant polycystic kidney disease and the PKD1/TSC2 contiguous gene syndrome  

PubMed Central

Large DNA rearrangements account for about 8% of disease mutations and are more common in duplicated genomic regions, where they are difficult to detect. Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in either PKD1 or PKD2. PKD1 is located in an intrachromosomally duplicated region. A tuberous sclerosis gene, TSC2, lies immediately adjacent to PKD1 and large deletions can result in the PKD1/TSC2 contiguous gene deletion syndrome. To rapidly identify large rearrangements, a multiplex ligation-dependent probe amplification assay was developed employing base-pair differences between PKD1 and the six pseudogenes to generate PKD1-specific probes. All changes in a set of 25 previously defined deletions in PKD1, PKD2 and PKD1/TSC2 were detected by this assay and we also found 14 new mutations at these loci. About 4% of the ADPKD patients in the CRISP study were found to have gross rearrangements, and these accounted for about a third of base-pair mutation negative families. Sensitivity of the assay showed that about 40% of PKD1/TSC contiguous gene deletion syndrome families contained mosaic cases. Characterization of a family found to be mosaic for a PKD1 deletion is discussed here to illustrate family risk and donor selection considerations. Our assay improves detection levels and the reliability of molecular testing of patients with ADPKD.

Consugar, Mark B.; Wong, Wai C.; Lundquist, Patrick A.; Rossetti, Sandro; Kubly, Vickie J.; Walker, Denise L.; Rangel, Laureano J.; Aspinwall, Richard; Niaudet, W. Patrick; Ozen, Seza; David, Albert; Velinov, Milen; Bergstralh, Eric J.; Bae, Kyongtae T.; Chapman, Arlene B.; Guay-Woodford, Lisa M.; Grantham, Jared J.; Torres, Vicente E.; Sampson, Julian R.; Dawson, Brian D.; Harris, Peter C.

2009-01-01

364

A novel mutation of the RP1 gene (Lys778ter) associated with autosomal dominant retinitis pigmentosa  

PubMed Central

Background: Besides the three known genes (RHO, RDS/Peripherin, NRL) involved in autosomal dominant retinitis pigmentosa (adRP), a fourth gene, RP1, has been recently identified. Initial reports suggest that mutations in the RP1 gene are the second most frequent cause of adRP. The clinical findings were described in a family with adRP and a novel mutation in the RP1 gene. Method: Index patients from 15 independent families with adRP in which RHO mutations had been excluded in previous examinations were screened for mutations in the RP1 gene by means of direct DNA sequencing. Evaluation of the RP1 phenotype in patients included funduscopy, kinetic perimetry, dark adapted final threshold test, standard electroretinography and, in one case, multifocal electroretinography. Results: One novel nonsense mutation (Lys778ter) in one of these 15 patients was detected. Cosegregation of the mutation with the disease phenotype could be established in the index patient's family. The phenotype comprises variable expression of clinical disease probably including one case of incomplete penetrance, a onset of symptoms beginning in adulthood, and evidence of regionally varying retinal function loss. Conclusion: The Lys778ter mutation localises inside the critical region harbouring all mutations described so far. The ophthalmic findings support previous observations that variation of disease expression appears as a typical feature of the RP1 phenotype.

Dietrich, K; Jacobi, F K; Tippmann, S; Schmid, R; Zrenner, E; Wissinger, B; Apfelstedt-Sylla, E

2002-01-01

365

Identification of a novel mutation in the enamalin gene in a family with autosomal-dominant amelogenesis imperfecta.  

PubMed

Amelogenesis imperfecta (AI) is a heterogeneous genetic disorder that affects the formation of the dental enamel matrix. Mutations in the enamelin (ENAM) gene have been found in patients with this disorder. The objective of this research was to identify the mutations reported in exons 4, 7 and 9 of the ENAM gene in a single Colombian family with autosomal-dominant AI and to establish the phenotype. The fragments of exons 4, 7 and 9 of the ENAM gene were amplified by polymerase chain reaction and direct sequencing was performed. A mutation was found in exon 9 where guanine was substituted by thymine in one of the alleles in position 817, generating a change of arginine to methionine in codon 179 of the protein. The mutation was only found in affected members of this family who presented with the severe, generalised hypoplastic phenotype in all teeth. The genotype/phenotype correlation for different AI subtypes has not been established. These results support a possible correlation between hypoplastic AI and mutations in the ENAM gene; however, identification of additional mutations could be helpful in establishing phenotype/genotype relationships. PMID:17316551

Gutierrez, Sandra Janeth; Chaves, Margarita; Torres, Diana M; Briceño, Ignacio

2007-02-21

366

The autosomal dominant familial exudative vitreoretinopathy locus maps on 11q and is closely linked to D11S533  

SciTech Connect

Autosomal dominant familial exudative vitreoretinopathy (adFEVR) is a hereditary disorder characterized by the incomplete vascularization of the peripheral retina. The primary biochemical defect in adFEVR is unknown. The adFEVR locus has tentatively been assigned to 11q by linkage studies. The authors report the results of an extended multipoint linkage analysis of two families with adFEVR by using five markers (INT2, D11S533, D11S527, D11S35, and CD3D) from 11q13-q23. Pairwise linkage data obtained in the two families were rather similar and hence have not provided evidence for genetic heterogeneity. The highest compiled two-point lod score (3.67, at a recombination fraction of .07) was obtained for the disease locus versus D11S533. Multipoint analyses showed that the adFEVR locus maps most likely, with a maximum location score of over 20, between D11S533/D11S526 and D11S35, at recombination rates of .147 and .104, respectively. Close linkage without recombination (maximum lod score 11.26) has been found between D11S533 and D11S526. 15 refs., 3 figs., 4 tabs.

Li, Yuen (Institut fuer Humangenetik, Luebeck (Germany) Zhejiang Medical Univ., Hangzhou (China)); Schwinger, D.; Gal, A. (Institut fuer Humangenetik, Luebeck (Germany)); Mueller, B. (Ludwig-Maximilians-Universitaet, Munich (Germany)); Fuhrmann, C.; Laqua, H. (Augenklinik der Medizinische Universitaet, Luebeck (Germany)); Humphries, P.

1992-10-01

367

A R54L Mutation of CRYAA Associated with Autosomal Dominant Nuclear Cataracts in a Chinese Family.  

PubMed

Abstract Purpose: To identify the genetic defect in a three-generation Chinese family with congenital cataracts. Methods: The phenotype of a three-generation Chinese family with congenital cataract was recruited. Detailed family history and clinical data of the family were recorded. Candidate genes sequencing was performed to screen out the disease-causing mutation. Bioinformatics analysis was performed to predict the function of mutant gene. Results: The phenotype of the family was identified as nuclear cataract. Direct sequencing revealed a c.161 G?>?T transversion in exon 1 of crystallin alpha-A (CRYAA). This mutation co-segregated with all affected individuals in the family and was not found in unaffected family members nor in the 100 unrelated controls. Bioinformatics analysis indicated that the 54th amino acid position was highly conserved and the mutation R54L caused an increase of local hydrophobicity around the substitution site. Conclusions: This study identified a novel disease-causing mutation c.161 G?>?T (p.R54L) in CRYAA in a Chinese family with autosomal dominant nuclear cataracts, this is the first report relating a G?>?T mutation in CRYAA leading to congenital nuclear cataract. PMID:24074001

Yang, Zhenfei; Su, Dongmei; Li, Qian; Ma, Zicheng; Yang, Fan; Zhu, Siquan; Ma, Xu

2013-09-27

368

Mitochondrial oxidative phosphorylation compensation may preserve vision in patients with OPA1-linked autosomal dominant optic atrophy.  

PubMed

Autosomal Dominant Optic Atrophy (ADOA) is the most common inherited optic atrophy where vision impairment results from specific loss of retinal ganglion cells of the optic nerve. Around 60% of ADOA cases are linked to mutations in the OPA1 gene. OPA1 is a fission-fusion protein involved in mitochondrial inner membrane remodelling. ADOA presents with marked variation in clinical phenotype and varying degrees of vision loss, even among siblings carrying identical mutations in OPA1. To determine whether the degree of vision loss is associated with the level of mitochondrial impairment, we examined mitochondrial function in lymphoblast cell lines obtained from six large Australian OPA1-linked ADOA pedigrees. Comparing patients with severe vision loss (visual acuity [VA]<6/36) and patients with relatively preserved vision (VA>6/9) a clear defect in mitochondrial ATP synthesis and reduced respiration rates were observed in patients with poor vision. In addition, oxidative phosphorylation (OXPHOS) enzymology in ADOA patients with normal vision revealed increased complex II+III activity and levels of complex IV protein. These data suggest that OPA1 deficiency impairs OXPHOS efficiency, but compensation through increases in the distal complexes of the respiratory chain may preserve mitochondrial ATP production in patients who maintain normal vision. Identification of genetic variants that enable this response may provide novel therapeutic insights into OXPHOS compensation for preventing vision loss in optic neuropathies. PMID:21731710

Van Bergen, Nicole J; Crowston, Jonathan G; Kearns, Lisa S; Staffieri, Sandra E; Hewitt, Alex W; Cohn, Amy C; Mackey, David A; Trounce, Ian A

2011-06-22

369

A cis-regulatory site downregulates PTHLH in translocation t(8;12)(q13;p11.2) and leads to Brachydactyly Type E.  

PubMed

Parathyroid hormone-like hormone (PTHLH) is an important chondrogenic regulator; however, the gene has not been directly linked to human disease. We studied a family with autosomal-dominant Brachydactyly Type E (BDE) and identified a t(8;12)(q13;p11.2) translocation with breakpoints (BPs) upstream of PTHLH on chromosome 12p11.2 and a disrupted KCNB2 on 8q13. We sequenced the BPs and identified a highly conserved Activator protein 1 (AP-1) motif on 12p11.2, together with a C-ets-1 motif translocated from 8q13. AP-1 and C-ets-1 bound in vitro and in vivo at the derivative chromosome 8 breakpoint [der(8) BP], but were differently enriched between the wild-type and BP allele. We differentiated fibroblasts from BDE patients into chondrogenic cells and found that PTHLH and its targets, ADAMTS-7 and ADAMTS-12 were downregulated along with impaired chondrogenic differentiation. We next used human and murine chondrocytes and observed that the AP-1 motif stimulated, whereas der(8) BP or C-ets-1 decreased, PTHLH promoter activity. These results are the first to identify a cis-directed PTHLH downregulation as primary cause of human chondrodysplasia. PMID:20015959

Maass, Philipp G; Wirth, Jutta; Aydin, Atakan; Rump, Andreas; Stricker, Sigmar; Tinschert, Sigrid; Otero, Miguel; Tsuchimochi, Kaneyuki; Goldring, Mary B; Luft, Friedrich C; Bähring, Sylvia

2009-12-16

370

Exclusion of linkage between autosomal dominant split hand/split foot and markers from chromosome 7q: Further evidence for genetic heterogeneity  

SciTech Connect

The split hand/split foot anomaly (SHSF) is a developmental defect of the distal limbs, specifically involving the central digital rays. Such a defect is usually inherited as an autosomal trait, although most cases occur sporadically. Penetrance of SHSF is extremely variable, ranging from apparent excess of affected offspring in some families to very low penetrance in others. One explanation for this variability is that of locus heterogeneity. More recently, we ascertained a family with normal chromosomes and a highly penetrant type of SHSF, segregating as an autosomal dominant trait, and investigated whether it could also be due to the putative limb-development mutant gene at the 7q locus. For this purpose, we studied linkage between the defect and highly polymorphic DNA markers from the 7q22 region. The results demonstrate that, in the highly penetrant family, autosomal dominant SHSF is caused by a mutant gene not linked with the putative locus in 7q22.1. Our data is in agreement with the findings of other groups and provide further evidence for genetic heterogeneity of autosomal dominant SHSF. 12 refs., 2 figs., 1 tab.

Gurrieri, F.; Genuardi, M.; Chiurazzi, P.; Neri, G. [Catholic Univ., Rome (Italy); Gillessen-Kaesbach, G. [Universitaetsklinikum, Essen (Germany)

1994-10-01

371

Pseudoachondroplasia: clinical diagnosis at different ages and comparison of autosomal dominant and recessive types. A review of 32 patients (26 kindreds).  

PubMed Central

This survey reviews the diagnosis (predominantly radiological) of 32 cases of pseudoachondroplasia from 26 kindreds and illustrates the natural history and varying appearance of the disordered bone growth from infancy to adult life. In addition, an attempt has been made to detect phenotypic differences between autosomal dominant and recessive types (excluding isolated cases), analysing 10 kindreds of dominant inheritance (three in the current survey, seven from published reports) and six of recessive inheritance (three in the current survey, three from published reports). There appears to be no clinical or radiographical feature which clearly distinguishes them, but, using height as a criterion of severity, among those with autosomal recessive inheritance there was a disproportionate number of the most severely affected cases and there also appears to be very little intrafamilial variation. It is possible that pseudoachondroplasia can be subdivided into autosomal dominant mild and severe and autosomal recessive mild and severe, but full delineation must await elucidation of the basic defect at biochemical and molecular levels. Images

Wynne-Davies, R; Hall, C M; Young, I D

1986-01-01

372

The Severe Autosomal Dominant Retinitis Pigmentosa Rhodopsin Mutant Ter349Glu Mislocalizes and Induces Rapid Rod Cell Death.  

PubMed

Mutations in the rhodopsin gene cause approximately one-tenth of retinitis pigmentosa cases worldwide, and most result in endoplasmic reticulum retention and apoptosis. Other rhodopsin mutations cause receptor mislocalization, diminished/constitutive activity, or faulty protein-protein interactions. The purpose of this study was to test for mechanisms by which the autosomal dominant rhodopsin mutation Ter349Glu causes an early, rapid retinal degeneration in patients. The mutation adds an additional 51 amino acids to the C terminus of the protein. Folding and ligand interaction of Ter349Glu rhodopsin were tested by ultraviolet-visible (UV-visible) spectrophotometry. The ability of the mutant to initiate phototransduction was tested using a radioactive filter binding assay. Photoreceptor localization was assessed both in vitro and in vivo utilizing fluorescent immunochemistry on transfected cells, transgenic Xenopus laevis, and knock-in mice. Photoreceptor ultrastructure was observed by transmission electron microscopy. Spectrally, Ter349Glu rhodopsin behaves similarly to wild-type rhodopsin, absorbing maximally at 500 nm. The mutant protein also displays in vitro G protein activation similar to that of WT. In cultured cells, mislocalization was observed at high expression levels whereas ciliary localization occurred at low expression levels. Similarly, transgenic X. laevis expressing Ter349Glu rhodopsin exhibited partial mislocalization. Analysis of the Ter349Glu rhodopsin knock-in mouse showed a rapid, early onset degeneration in homozygotes with a loss of proper rod outer segment development and improper disc formation. Together, the data show that both mislocalization and rod outer segment morphogenesis are likely associated with the human phenotype. PMID:23940033

Hollingsworth, T J; Gross, Alecia K

2013-08-12

373

Urinary Proteomic Biomarkers for Diagnosis and Risk Stratification of Autosomal Dominant Polycystic Kidney Disease: A Multicentric Study  

PubMed Central

Treatment options for autosomal dominant polycystic kidney disease (ADPKD) will likely become available in the near future, hence reliable diagnostic and prognostic biomarkers for the disease are strongly needed. Here, we aimed to define urinary proteomic patterns in ADPKD patients, which aid diagnosis and risk stratification. By capillary electrophoresis online coupled to mass spectrometry (CE-MS), we compared the urinary peptidome of 41 ADPKD patients to 189 healthy controls and identified 657 peptides with significantly altered excretion, of which 209 could be sequenced using tandem mass spectrometry. A support-vector-machine based diagnostic biomarker model based on the 142 most consistent peptide markers achieved a diagnostic sensitivity of 84.5% and specificity of 94.2% in an independent validation cohort, consisting of 251 ADPKD patients from five different centers and 86 healthy controls. The proteomic alterations in ADPKD included, but were not limited to markers previously associated with acute kidney injury (AKI). The diagnostic biomarker model was highly specific for ADPKD when tested in a cohort consisting of 481 patients with a variety of renal and extrarenal diseases, including AKI. Similar to ultrasound, sensitivity and specificity of the diagnostic score depended on patient age and genotype. We were furthermore able to identify biomarkers for disease severity and progression. A proteomic severity score was developed to predict height adjusted total kidney volume (htTKV) based on proteomic analysis of 134 ADPKD patients and showed a correlation of r?=?0.415 (p<0.0001) with htTKV in an independent validation cohort consisting of 158 ADPKD patients. In conclusion, the performance of peptidomic biomarker scores is superior to any other biochemical markers of ADPKD and the proteomic biomarker patterns are a promising tool for prognostic evaluation of ADPKD.

Kistler, Andreas D.; Serra, Andreas L.; Siwy, Justyna; Poster, Diane; Krauer, Fabienne; Torres, Vicente E.; Mrug, Michal; Grantham, Jared J.; Bae, Kyongtae T.; Bost, James E.; Mullen, William; Wuthrich, Rudolf P.; Mischak, Harald; Chapman, Arlene B.

2013-01-01

374

Molecular modelling of the interactions of carbamazepine and a nicotinic receptor involved in the autosomal dominant nocturnal frontal lobe epilepsy.  

PubMed

1. The normal and a mutant (S248F) human neuronal alpha4beta2 nicotinic receptors, and their interaction with the channel blocker carbamazepine (CBZ) have been modelled. The mutant, responsible for the autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), has an enhanced sensitivity to and a slower recovery from desensitization, a lower conductance, short open times, reduced calcium permeability, and is 3 fold more sensitive to CBZ, a drug used in the treatment of partial epilepsies. 2. Mutant channel properties are explained by the physicochemical properties of the two Phe248 side chains, including size and cation-pi interaction, and their dynamic behaviour. A defective mechanism of dehydration might be responsible for the reduced calcium influx. 3. Phe248 residues are the main component of CBZ binding sites in the mutant, while this is not true for Ser248 in the normal receptor. 4. A higher number of blocking binding sites and a predicted higher affinity found for CBZ in the mutant account for its differential sensitivity to CBZ. 5. Aromatic-aromatic interactions between CBZ and the two Phe248 account for the difference in affinity, which is at least 12 times higher for the mutant, depending on the method used for calculating K(i). 6. Normal vs mutant differences in K(i), enhanced by the higher number of blocking binding sites in the mutant, seem excessive compared to the differential sensitivities to CBZ experimentally found. The negative cooperativity suggested by a predicted overlapping of blocking and non-blocking binding sites gives an explanation, as overlapping is higher in the mutant. 7. For both types of receptors we found that the carbamyl group of the best blocking conformers of CBZ forms hydrogen bonds with serine residues, which may explain the fundamental role of that moiety for this molecule to act as antiepileptic drug. PMID:12110613

Ortells, M O; Barrantes, G E

2002-07-01

375

Properties of neuronal nicotinic acetylcholine receptor mutants from humans suffering from autosomal dominant nocturnal frontal lobe epilepsy.  

PubMed

1. Physiological and pharmacological properties of the human neuronal alpha4beta2 nicotinic AChR and mutants found in patients suffering from autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) were studied. 2. Investigations of nicotinic AChRs reconstituted in Xenopus oocytes with the control or mutated alpha4 subunits revealed that both mutation S248F as well as the Leucine insertion (776ins3) result in major but different changes in the physiological and pharmacological properties of the receptors. 3. Mutation S248F causes a decrease in apparent affinity to ACh of about 7 fold. In addition, this receptor already desensitizes during exposure to agonist concentration 3000 times lower than the control. 4. 776ins3 provokes a 10 fold increase of apparent ACh affinity, an increase in the IC50 caused by prolonged ACh exposures and a slowing down of the response decay. 5. At saturating ACh concentration cells expressing the S248F mutant display average currents that are about five times smaller than control. 6. When measured at very low concentration, agonist sensitivities of the control and mutated receptors to ACh, nicotine and epibatidine exhibit differences that match those observed for higher agonist concentrations. 7. Mutation 776ins3 increases the apparent efficacy to cytisine. 8. Data presented herein suggest that mutation S248F mainly affects the desensitization properties of the receptor while the leucine insertion (776ins3) increases the probability of transition to the active state. Although these mutations differentially affect the receptor properties they both result in reduced permeability to calcium and enhanced desensitization sensitivity that might account for the ADNFLE phenotype. PMID:9831911

Bertrand, S; Weiland, S; Berkovic, S F; Steinlein, O K; Bertrand, D

1998-10-01

376

Non-Image-Forming Light Driven Functions Are Preserved in a Mouse Model of Autosomal Dominant Optic Atrophy  

PubMed Central

Autosomal dominant optic atrophy (ADOA) is a slowly progressive optic neuropathy that has been associated with mutations of the OPA1 gene. In patients, the disease primarily affects the retinal ganglion cells (RGCs) and causes optic nerve atrophy and visual loss. A subset of RGCs are intrinsically photosensitive, express the photopigment melanopsin and drive non-image-forming (NIF) visual functions including light driven circadian and sleep behaviours and the pupil light reflex. Given the RGC pathology in ADOA, disruption of NIF functions might be predicted. Interestingly in ADOA patients the pupil light reflex was preserved, although NIF behavioural outputs were not examined. The B6; C3-Opa1Q285STOP mouse model of ADOA displays optic nerve abnormalities, RGC dendropathy and functional visual disruption. We performed a comprehensive assessment of light driven NIF functions in this mouse model using wheel running activity monitoring, videotracking and pupillometry. Opa1 mutant mice entrained their activity rhythm to the external light/dark cycle, suppressed their activity in response to acute light exposure at night, generated circadian phase shift responses to 480 nm and 525 nm pulses, demonstrated immobility-defined sleep induction following exposure to a brief light pulse at night and exhibited an intensity dependent pupil light reflex. There were no significant differences in any parameter tested relative to wildtype littermate controls. Furthermore, there was no significant difference in the number of melanopsin-expressing RGCs, cell morphology or melanopsin transcript levels between genotypes. Taken together, these findings suggest the preservation of NIF functions in Opa1 mutants. The results provide support to growing evidence that the melanopsin-expressing RGCs are protected in mitochondrial optic neuropathies.

Perganta, Georgia; Barnard, Alun R.; Katti, Christiana; Vachtsevanos, Athanasios; Douglas, Ron H.; MacLaren, Robert E.; Votruba, Marcela; Sekaran, Sumathi

2013-01-01

377

Somatotroph pituitary adenoma with acromegaly and autosomal dominant polycystic kidney disease: SSTR5 polymorphism and PKD1 mutation.  

PubMed

A 39-year-old woman with autosomal dominant polycystic kidney disease (ADPKD) presented with acromegaly and a pituitary macroadenoma. There was a family history of this renal disorder. She had undergone surgery for pituitary adenoma 6 years prior. Physical examination disclosed bitemporal hemianopsia and elevation of both basal growth hormone (GH) 106 ng/mL (normal 0-5) and insulin-like growth factor (IGF-1) 811 ng/mL (normal 48-255) blood levels. A magnetic resonance imaging scan disclosed a 3.0 cm sellar and suprasellar mass with both optic chiasm compression and left cavernous sinus invasion. Pathologic, cytogenetic, molecular and in silico analysis was undertaken. Histologic, immunohistochemical and ultrastructural studies of the lesion disclosed a sparsely granulated somatotroph adenoma. Standard chromosome analysis on the blood sample showed no abnormality. Sequence analysis of the coding regions of PKD1 and PKD2 employing DNA from both peripheral leukocytes and the tumor revealed the most common PKD1 mutation, 5014_5015delAG. Analysis of the entire SSTR5 gene disclosed the variant c.142C>A (p.L48M, rs4988483) in the heterozygous state in both blood and tumor, while no pathogenic mutations were noted in the MEN1, AIP, p27Kip1 and SSTR2 genes. To our knowledge, this is the fourth reported case of a GH-producing pituitary adenoma associated with ADPKD, but the first subjected to extensive morphological, ultrastructural, cytogenetic and molecular studies. The physical proximity of the PKD1 and SSTR5 genes on chromosome 16 suggests a causal relationship between ADPKD and somatotroph adenoma. PMID:21744088

Syro, Luis V; Sundsbak, Jamie L; Scheithauer, Bernd W; Toledo, Rodrigo A; Camargo, Mauricio; Heyer, Christina M; Sekiya, Tomoko; Uribe, Humberto; Escobar, Jorge I; Vasquez, Martin; Rotondo, Fabio; Toledo, Sergio P A; Kovacs, Kalman; Horvath, Eva; Babovic-Vuksanovic, Dusica; Harris, Peter C

2012-09-01

378

Chronic asymptomatic pyuria precedes overt urinary tract infection and deterioration of renal function in autosomal dominant polycystic kidney disease  

PubMed Central

Background Urinary tract infection (UTI) occurs in 30%-50% of individuals with autosomal dominant polycystic kidney disease (ADPKD). However, the clinical relevance of asymptomatic pyuria in ADPKD patients remains unknown. Methods We retrospectively reviewed medical records of 256 ADPKD patients who registered to the ADPKD clinic at Seoul National University Hospital from Aug 1999 to Aug 2010. We defined the asymptomatic pyuria as more than 5-9 white blood cells in high-power field with no related symptoms or signs of overt UTI. Patients were categorized into 2 groups depending on its duration and frequency: Group A included non-pyuria and transient pyuria patients; Group B included recurrent and persistent pyuria patients. The association between asymptomatic pyuria and both the development of overt UTI and the deterioration of renal function were examined. Results With a mean follow-up duration of 65.3 months, 176 (68.8%) out of 256 patients experienced 681 episodes of asymptomatic pyuria and 50 episodes of UTI. The annual incidence of asymptomatic pyuria was 0.492 episodes/patient/year. The patients in group B showed female predominance (58.5% vs. 42.0%, P=0.01) and experienced an upper UTI more frequently (hazard ratio: 4.612, 95% confidence interval: 1.735-12.258; P=0.002, adjusted for gender and hypertension). The annual change in estimated glomerular filtration rate (?eGFR) was significantly larger in magnitude in group B than in group A (-2.7±4.56 vs. -1.17±5.8, respectively; P=0.01). Age and Group B found to be the independent variables for ?eGFR and developing end-stage renal disease (16.0% vs. 4.3%, respectively; P=0.001). Conclusions Chronic asymptomatic pyuria may increase the risk of developing overt UTI and may contribute to declining renal function in ADPKD.

2013-01-01

379

Extended Follow-Up of Unruptured Intracranial Aneurysms Detected by Presymptomatic Screening in Patients with Autosomal Dominant Polycystic Kidney Disease  

PubMed Central

Summary Background and objectives Autosomal dominant polycystic kidney disease (ADPKD) patients have an increased risk for intracranial aneurysms (IAs). The importance of screening for unruptured IAs (UIAs) depends on their risks for growth and rupture. Design, setting, participants, & measurements ADPKD patients with UIAs found by presymptomatic screening with magnetic resonance angiography (MRA) during 1989 to 2009 were followed initially at 6 months and annually, and less frequently after demonstration of stability. Results Forty-five saccular aneurysms were detected in 38 patients from 36 families. Most were small (median diameter 3.5 mm) and in the anterior circulation (84%). Median age at diagnosis was 49 years. During cumulative imaging follow-up of 243 years, one de novo UIA was detected and increased in size from 2 to 4.4 mm over 144 months and two UIAs grew from 4.5 to 5.9 mm and 4.7 to 6.2 mm after 69 and 184 months, respectively. Seven patients did not have imaging follow-up. No change was detected in the remaining 28 patients. During cumulative clinical follow-up of 316 years, no aneurysm ruptured. Five patients died from unrelated causes and two were lost to follow-up after 8 and 120 months. Three patients underwent surgical clipping. Conclusions Most UIAs detected by presymptomatic screening in ADPKD patients are small and in the anterior circulation. Growth and rupture risks are not higher than those of UIAs in the general population. These data support very selective screening for UIAs in ADPKD patients, and widespread screening is not indicated.

Irazabal, Maria V.; Huston, John; Kubly, Vickie; Rossetti, Sandro; Sundsbak, Jamie L.; Hogan, Marie C.; Harris, Peter C.; Brown, Robert D.

2011-01-01

380

A novel autosomal dominant condition consisting of congenital heart defects and low atrial rhythm maps to chromosome 9q  

PubMed Central

Congenital heart defects (CHDs) occur mostly sporadic, but familial CHD cases have been reported. Mutations in several genes, including NKX2.5, GATA4 and NOTCH1, were identified in families and patients with CHD, but the mechanisms underlying CHD are largely unknown. We performed genome-wide linkage analysis in a large four-generation family with autosomal dominant CHD (including atrial septal defect type I and II, tetralogy of Fallot and persistent left superior vena cava) and low atrial rhythm, a unique phenotype that has not been described before. We obtained phenotypic information including electrocardiography, echocardiography and DNA of 23 family members. Genome-wide linkage analysis on 12 affected, 5 unaffected individuals and 1 obligate carrier demonstrated significant linkage only to chromosome 9q21–33 with a multipoint maximum LOD score of 4.1 at marker D9S1690, between markers D9S167 and D9S1682. This 48-c critical interval corresponds to 39?Mb and contains 402 genes. Sequence analysis of nine candidate genes in this region (INVS, TMOD1, TGFBR1, KLF4, IPPK, BARX1, PTCH1, MEGF9 and S1PR3) revealed no mutations, nor were genomic imbalances detected using array comparative genomic hybridization. In conclusion, we describe a large family with CHD and low atrial rhythm with a significant LOD score to chromosome 9q. The phenotype is representative of a mild form of left atrial isomerism or a developmental defect of the sinus node and surrounding tissue. Because the mechanisms underlying CHD are largely unknown, this study represents an important step towards the discovery of genes implied in cardiogenesis.

van de Meerakker, Judith B A; van Engelen, Klaartje; Mathijssen, Inge B; Lekanne dit Deprez, Ronald H; Lam, Jan; Wilde, Arthur A M; Baars, Marieke J H; Mannens, Marcel M A M; Mulder, Barbara J M; Moorman, Antoon F M; Postma, Alex V

2011-01-01

381

Bidirectional encroachment of collagen into the tunica media in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy  

PubMed Central

Arteries in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) are susceptible to smooth muscle loss and fibrosis, but the molecular components underlying these dramatic vascular changes are not well characterized. The purpose of this study was to investigate the distribution of collagen isoforms in the cerebral vessels of North American CADASIL patients with classical NOTCH3 mutations. Expression of type I-VI collagen in brains obtained at autopsy from six CADASIL patients with cysteine-altering mutations in NOTCH3 was compared to control brain expression. We identified a consistent increase of type I, III, IV, and VI collagen in CADASIL brains. Strong accumulation of type I, III, IV and VI collagen was noted in all calibers of vessels, including small and medium-sized leptomeningeal arteries, small penetrating white matter arteries, and capillaries. Within leptomeningeal arteries, where we could define the three tunicae of each vessel, we found distinct collagen subtype distribution patterns in CADASIL. Type I and III collagen were largely found in either adventitial/medial or transmural locations. Type IV collagen was strictly intimal/medial. Type VI collagen was adventitial or adventitial/medial. Within the thickened penetrating arteries of CADASIL patients, all four collagens extended through most of the arterial wall. We observed increased staining of capillaries in CADASIL for type I, IV, and VI collagen. In conclusion, brain vascular collagen subtypes are increased in CADASIL in multiple layers of all sizes of arteries, with disease-specific changes most prominent in the tunica media and thickened small penetrating vessels. In diseased arteries, type I, III, and VI collagen spreads from an external location (adventitia) into the vascular media, while type IV collagen accumulates in an internal pattern (intima and media). These observations are consistent with a pathological role for collagen accumulation in the vascular media in CADASIL.

Dong, Hairong; Blaivas, Mila; Wang, Michael M.

2012-01-01

382

Mutations in SNRPE, which encodes a core protein of the spliceosome, cause autosomal-dominant hypotrichosis simplex.  

PubMed

Hypotrichosis simplex (HS) comprises a group of hereditary isolated alopecias that are characterized by a diffuse and progressive loss of hair starting in childhood and shows a wide phenotypic variability. We mapped an autosomal-dominant form of HS to chromosome 1q31.3-1q41 in a Spanish family. By direct sequencing, we identified the heterozygous mutation c.1A>G (p.Met1?) in SNRPE that results in loss of the start codon of the transcript. We identified the same mutation in a simplex HS case from the UK and an additional mutation (c.133G>A [p.Gly45Ser]) in a simplex HS case originating from Tunisia. SNRPE encodes a core protein of U snRNPs, the key factors of the pre-mRNA processing spliceosome. The missense mutation c.133G>A leads to a glycine to serine substitution and is predicted to disrupt the structure of SNRPE. Western blot analyses of HEK293T cells expressing SNRPE c.1A>G revealed an N-terminally truncated protein, and therefore the mutation might result in use of an alternative in-frame downstream start codon. Subcellular localization of mutant SNRPE by immunofluorescence analyses as well as incorporation of mutant SNRPE proteins into U snRNPs was found to be normal, suggesting that the function of U snRNPs in splicing, rather than their biogenesis, is affected. In this report we link a core component of the spliceosome to hair loss, thus adding another specific factor in the complexity of hair growth. Furthermore, our findings extend the range of human phenotypes that are linked to the splicing machinery. PMID:23246290

Pasternack, Sandra M; Refke, Melanie; Paknia, Elham; Hennies, Hans Christian; Franz, Thomas; Schäfer, Niklas; Fryer, Alan; van Steensel, Maurice; Sweeney, Elizabeth; Just, Miquel; Grimm, Clemens; Kruse, Roland; Ferrándiz, Carlos; Nöthen, Markus M; Fischer, Utz; Betz, Regina C

2012-12-13

383

Autosomal dominant retinitis pigmentosa: exclusion of the gene from the short arm of chromosome 1 including the region surrounding the rhesus locus.  

PubMed Central

Members of a large Irish pedigree exhibiting early-onset autosomal dominant retinitis pigmentosa (ADRP) were typed for the rhesus blood group and nine DNA markers on chromosome 1. Close linkage between the ADRP locus and any of the marker loci was excluded using two-point analysis. With use of the sex-averaged maps of Dracopoli et al. and Donis-Keller et al. and a strategy of rolling multipoint analyses, support was gained for the exclusion of ADRP from a 224-cM region of the chromosome, including almost the entire short arm. The disease locus was significantly excluded from within at least 50 cM of the rhesus locus and, as a loose linkage between these two genes has been suggested by other studies, this result may support the possibility of genetic heterogeneity within the autosomal dominant subgroup of retinitis pigmentosa.

Bradley, D G; Farrar, G J; Sharp, E M; Kenna, P; Humphries, M M; McConnell, D J; Daiger, S P; McWilliam, P; Humphries, P

1989-01-01

384

Autosomal dominant spinocerebellar ataxia with sensory axonal neuropathy (SCA4): clinical description and genetic localization to chromosome 16q22.1.  

PubMed Central

The hereditary ataxias represent a clinically and genetically heterogeneous group of neurodegenerative disorders. Various classification schemes based on clinical criteria are being replaced as molecular characterization of the ataxias proceeds; so far, seven distinct autosomal dominant hereditary ataxias have been genetically mapped in the human genome. We report linkage to chromosome 16q22.1 for one of these genes (SCA4) in a five-generation family with an autosomal dominant, late-onset spinocerebellar ataxia; the gene is tightly linked to the microsatellite marker D16S397 (LOD score = 5.93 at theta = .00). In addition, we present clinical and electrophysiological data regarding the distinct and previously unreported phenotype consisting of ataxia with the invariant presence of a prominent axonal sensory neuropathy.

Flanigan, K.; Gardner, K.; Alderson, K.; Galster, B.; Otterud, B.; Leppert, M. F.; Kaplan, C.; Ptacek, L. J.

1996-01-01

385

Autosomal dominant cerebellar ataxia type I. Nerve conduction and evoked potential studies in families with SCA1, SCA2 and SCA3  

Microsoft Academic Search

Summary Forty-one patients suffering from autosomal dominant cerebellar ataxia type I (ADCA-I) were subjected to a genotype-phenotype correlation analysis using molecular genetic assignment to the spinocerebellar ataxia type 1, 2 or 3 (SCA1, -2 or -3) genetic locus, clinical examination and nerve conduction as well as evoked potential studies. Pyramidal tract signs, pale discs, and dysphagia were more frequent in

M. Abele; K. Burk; F. Andres; H. Topka; F. Laccone; S. Bosch; A. Brice; G. Cancel; J. Dichgans; T. Klockgether

1997-01-01

386

Molecular heterogeneity of autosomal dominant cerebellar ataxia: analysis of flanking microsatellites of the spinocerebellar ataxia 1 locus in a northern European family unequivocally demonstrates non-linkage  

Microsoft Academic Search

This study addresses the question whether the different forms of autosomal dominant cerebellar ataxia (ADCA) are related to different ethnic\\/geographical regions in Europe. One mutation in families originating from Holland, Prussia and Italy has previously been localized to chromosome 6p (SCA1 locus), whereas the mutation in families of Iberic origin has been excluded from chromosome 6p. In a Danish five-generation

Astrid Lunkes; Suzana Gispert I; Jiirgen Enczmann; Georg Auburger

1993-01-01

387

Spectrum and prevalence of autosomal dominant spinocerebellar ataxia in Hokkaido, the northern island of Japan: a study of 113 Japanese families  

Microsoft Academic Search

Autosomal dominant cerebellar ataxia (ADCA) is a genetically heterogeneous group of neurodegenerative disorders. To shed further\\u000a light on the clinical and genetic spectrum of ADCA in Japan, we conducted a study to determine the frequency of a new variety\\u000a of different subtypes of SCAs among ADCA patients. This current study was carried out from April 1999 to December 2006 on

Ichiro Yabe

2007-01-01

388

Identification of CAG repeat-containing genes expressed in human brain as candidate genes for autosomal dominant spinocerebellar ataxias and other neurodegenerative diseases  

Microsoft Academic Search

To obtain novel candidate genes for autosomal dominant spinocerebellar ataxia and other neurodegenerative disorders in which\\u000a gene mutations remain unidentified, we screened a human fetal brain cDNA library using (CAG)10 repeat probes. Sixteen cDNAs were isolated and mapped to chromosomes 1, 2, 3, 6, 9, 13, 15, 16, 22, and X. Although we failed\\u000a to detect abnormal CAG repeat expansion

Masaji Tachikawa; Yoshitaka Nagai; Koichiro Nakamura; Kazuhiro Kobayashi; Tsutomu Fujiwara; Hye-Jung Han; Yuko Nakabayashi; Yaeko Ichikawa; Jun Goto; Ichiro Kanazawa; Yusuke Nakamura; Tatsushi Toda

2002-01-01

389

Autosomal dominant cerebellar ataxia type I. MRI-based volumetry of posterior fossa structures and basal ganglia in spinocerebellar ataxia types 1, 2 and 3  

Microsoft Academic Search

Summary Twenty-six patients suffering from autosomal dominant cerebellar ataxia type I were subjected to a genotype- phenotype correlation analysis using molecular genetic assignment to the genetic loci for spinocerebellar ataxia type 1, 2 or 3 (SCA1, SCA2, SCA3) and MRI-based volumetry of posterior fossa structures and basal ganglia nuclei. There was significant atrophy of the cerebellum and brainstem in all

T. Klockgether; M. Skalej; D. Wedekind; A. R. Luft; D. Welte; J. B. Schulz; M. Abele; K. Burk; F. Laccone; A. Brice; J. Dichgans

1998-01-01

390

Autosomal-dominant, prelingual, nonprogressive sensorineural hearing loss: localization of the gene (DFNA8) to chromosome 11q by linkage in an Austrian family  

Microsoft Academic Search

A four-generation family suffering from an autosomal-dominant, congenital, nonprogressive, nonsyndromic hearing loss was found in a rural region of Austria. The hearing loss was moderate to severe, a pure tone audiogram showing a U-shaped form with maximum loss at 2,000 Hz. An initial genome search led to a lod score of 3.01 with markers on chromosome 15. This locus was

K. Kirschhofer; J. B. Kenyon; D. M. Hoover; P. Franz; K. Weipoltshammer; F. Wachtler; W. J. Kimberling

1998-01-01

391

Molecular analysis of autosomal dominant hereditary ataxias in the Indian population: high frequency of SCA2 and evidence for a common founder mutation  

Microsoft Academic Search

Expansion of CTG\\/CAG trinucleotide repeats has been shown to cause a number of autosomal dominant cerebellar ataxias (ADCA) such as SCA1, SCA2, SCA3\\/MJD, SCA6, SCA7, SCA8 and DRPLA. There is a wide variation in the clinical phenotype and prevalence of these ataxias in different populations. An analysis of ataxias in 42 Indian families indicates that SCA2 is the most frequent

Quasar Saleem; Shweta Choudhry; Mitali Mukerji; Leena Bashyam; M. V. Padma; A. Chakravarthy; M. C. Maheshwari; S. Jain; S. K. Brahmachari

2000-01-01

392

A new locus on 3p23–p25 for an autosomal-dominant limb-girdle muscular dystrophy, LGMD1H  

Microsoft Academic Search

Limb-girdle muscular dystrophies (LGMDs) are a genetically heterogeneous group of neuromuscular disorders with a selective or predominant involvement of shoulder and pelvic girdles. We clinically examined 19 members in a four-generation Italian family with autosomal-dominant LGMD. A total of 11 subjects were affected. Clinical findings showed variable expressivity in terms of age at onset and disease severity. Five subjects presented

Luigi Bisceglia; Stefano Zoccolella; Alessandra Torraco; Maria Rosaria Piemontese; Rosa Dell'Aglio; Angela Amati; Patrizia De Bonis; Lucia Artuso; Massimiliano Copetti; Filippo Maria Santorelli; Luigi Serlenga; Leopoldo Zelante; Enrico Bertini; Vittoria Petruzzella

2010-01-01

393

HNF1A gene polymorphisms and cardiovascular risk factors in individuals with late-onset autosomal dominant diabetes: a cross-sectional study  

Microsoft Academic Search

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a genetically heterogeneous disease, hepatocyte nuclear factor-1 homeobox A (HNF1A) single-nucleotide polymorphisms (SNPs) playing a minor role in its pathogenesis. HNF1A is a frequent cause of monogenic diabetes, albeit with early-onset. Some uncommon subgroups like late-onset autosomal dominant diabetes mellitus (LOADDM) may present peculiar inheritance patterns with a stronger familial component. This study

Fernando MA Giuffrida; Gilberto K Furuzawa; Teresa S Kasamatsu; Marcos M Oliveira; Andre F Reis; Sergio A Dib

2009-01-01

394

Strong homophilic interactions of the Ig-like domains of polycystin-1, the protein product of an autosomal dominant polycystic kidney disease gene, PKD1  

Microsoft Academic Search

The 14 kb mRNA of the polycystic kidney disease gene PKD1 encodes a novel large (~460 kDa) protein, polycystin-1, of unknown function that is responsible for autosomal dominant polycystic kidney disease (ADPKD). The unique organization of multiple adhe- sive domains of polycystin-1, including 16 Ig-like domains (or PKD domains) suggests that it may play an important role in cell-cell\\/cell-matrix interactions.

Oxana Ibraghimov-Beskrovnaya; Nikolay O. Bukanov; Lincoln C. Donohue; William R. Dackowski; Katherine W. Klinger; Gregory M. Landes

2000-01-01

395

Exclusion of Insulin Receptor Substrate 2 (IRS-2) As a Major Locus for Early-Onset Autosomal Dominant Type 2 Diabetes  

Microsoft Academic Search

We investigated whether variability at the insulin receptor substrate (IRS)-2 locus plays a role in the eti- ology of early-onset autosomal dominant type 2 dia- betes. By means of radiation hybrid mapping, we placed the human IRS-2 gene on 13q at 8.6 cRays from SHGC- 37358. Linkage between diabetes and two polymorphic markers located in this region (D13S285 and D13S1295)

Arsun Bektas; James H. Warram; Morris F. White; Andrzej S. Krolewski; Alessandro Doria

1999-01-01

396

Cleavage of polycystin-1 requires the receptor for egg jelly domain and is disrupted by human autosomal-dominant polycystic kidney disease 1-associated mutations  

Microsoft Academic Search

Polycystin-1 plays an essential role in renal tubular morphogenesis, and disruption of its function causes cystogenesis in human autosomal-dominant polycystic kidney disease (ADPKD). We demonstrated that polycystin-1 undergoes cleavage at G protein coupled receptor proteolytic site in a process that requires the receptor for egg jelly domain. Most of the N-terminal fragment remains tethered at the cell surface, although a

Feng Qian; Alessandra Boletta; Anil K. Bhunia; Hangxue Xu; Lijuan Liu; Ali K. Ahrabi; Terry J. Watnick; Fang Zhou; Gregory G. Germino

2002-01-01

397

A gene for autosomal dominant juvenile amyotrophic lateral sclerosis ( ALS4? ) localizes to a 500-kb interval on chromosome 9q34  

Microsoft Academic Search

Amyotrophic lateral sclerosis (ALS) denotes a heterogeneous group of neurodegenerative disorders affecting upper and lower\\u000a motor neurons. ALS4 is a juvenile-onset, autosomal dominant form of ALS that is characterized by slow progression, distal\\u000a limb weakness and amyotrophy, and pyramidal signs associated with severe loss of motor neurons in the brain and spinal cord.\\u000a The \\u000a ALS4\\u000a locus was recently mapped by

I. P. Blair; C. L. Bennett; A. Abel; B. A. Rabin; J. W. Griffin; K. H. Fischbeck; D. R. Cornblath; P. F. Chance

2000-01-01

398

Identification of lamin A\\/C ( LMNA ) gene mutations in Korean patients with autosomal dominant Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy 1B  

Microsoft Academic Search

Mutations in the LMNA gene encoding lamins A and C by alternative splicing have been found to cause at least four different kinds of genetic disorders:\\u000a autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD2; MIM 181350); limb-girdle muscular dystrophy type 1B (LGMD1B;\\u000a MIM 159001); dilated cardiomyopathy type 1A (CMD1A; MIM 115200); and familial partial lipodystrophy (FPLD; MIM 151660). Recently,\\u000a we have studied

Chang-Seok Ki; Jong Seo Hong; Gyu-Young Jeong; Kyoung Ju Ahn; Kwang-Mo Choi; Duk-Kyung Kim; Jong-Won Kim

2002-01-01

399

Refinement of the Gene Locus for Autosomal Dominant Medullary Cystic Kidney Disease Type 1 (MCKD1) and Construction of a Physical and Partial Transcriptional Map of the Region  

Microsoft Academic Search

Autosomal dominant medullary cystic kidney disease (MCKD) is an adult onset tubulointerstitial nephropathy that leads to salt wasting and end-stage renal failure. A gene locus (MCKD1) has been mapped on chromosome 1q21. Here we report on a large MCKD1 family of British origin linked to the MCKD1 locus. Haplotype analysis performed with markers spanning the previously reported critical MCKD1 region

A. Fuchshuber; S. Kroiss; S. Karle; S. Berthold; K. Huck; C. Burton; N. Rahman; M. Koptides; C. Deltas; E. Otto; F. Rüschendorf; T. Feest; F. Hildebrandt

2001-01-01

400

A model for the initiation and progression of non-chromaffin paragangliomas: An autosomal dominant disorder with genetic heterogeneity and genomic imprinting  

Microsoft Academic Search

Non-chromaffin paragangliomas are autosomal dominantly inherited tumors of the head and neck region (frequency: 1:30,000). Genomic imprinting influences the expression of the disorder. Tumor development is restricted to offspring of male disease gene carriers. By linkage analysis and haplotyping of a single family, in which the pattern of inheritance is consistent with genomic imprinting, we have mapped the gene to

E. C. M. Mariman; S. E. C. van Beersum; H. H. Ropers

1994-01-01

401

Twinkle mutations associated with autosomal dominant progressive external ophthalmoplegia lead to impaired helicase function and in vivo mtDNA replication stalling  

Microsoft Academic Search

Mutations in the mitochondrial helicase Twinkle underlie autosomal dominant progressive external ophthal- moplegia (PEO), as well as recessively inherited infantile-onset spinocerebellar ataxia and rare forms of mito- chondrial DNA (mtDNA) depletion syndrome. Familial PEO is typically associated with the occurrence of multiple mtDNA deletions, but the mechanism by which Twinkle dysfunction induces deletion formation has been under debate. Here we

Steffi Goffart; Helen M. Cooper; Henna Tyynismaa; Sjoerd Wanrooij; Anu Suomalainen; Johannes N. Spelbrink

2009-01-01

402

A novel activating mutation (C129S) in the calcium-sensing receptor gene in a Japanese family with autosomal dominant hypocalcemia  

Microsoft Academic Search

Autosomal dominant hypocalcemia can be caused by activating mutations of the calcium-sensing receptor (CaSR) gene. We experienced two patients (proband and her daughter) with hypocalcemia caused by a missense mutation of the CaSR gene. The proband, aged 25, showed hypocalcemia and hypoparathyroidism from infancy. She had been diagnosed as having idiopathic\\u000a hypoparathyroidism and had been treated with calcitriol. She gave

Haruhiko Hirai; Shigeo Nakajima; Akimitsu Miyauchi; Kumi Nishimura; Nobuhiko Shimizu; Masaaki Shima; Toshimi Michigami; Keiichi Ozono; Shintaro Okada

2001-01-01

403

Detection of the single nucleotide polymorphism causing feline autosomal-dominant polycystic kidney disease in Persians from the UK using a novel real-time PCR assay  

Microsoft Academic Search

Autosomal-dominant polycystic kidney disease (AD-PKD) is the most prevalent inherited genetic disease of cats, particularly affecting Persians. Until recently the condition has been diagnosed by renal ultrasound screening. With the identification of the genetic mutation responsible for AD-PKD it is now possible to use advanced molecular techniques to screen for the disease. We have developed a rapid, sensitive and specific

Chris R. Helps; Séverine Tasker; Frances J. Barr; Sheila J. Wills; Timothy J. Gruffydd-Jones

2007-01-01

404

Activation of MAPK in hearts of EMD null mice: similarities between mouse models of X-linked and autosomal dominant Emery Dreifuss muscular dystrophy  

Microsoft Academic Search

Emery-Dreifuss muscular dystrophy (EDMD) is an inherited disorder characterized by slowly progressive skeletal muscle weakness in a humero-peroneal distribution, early contractures and prominent cardiomyopa- thy with conduction block. Mutations in EMD, encoding emerin, and LMNA, encoding A-type lamins, respecti- vely, cause X-linked and autosomal dominant EDMD. Emerin and A-type lamins are proteins of the inner membrane of the nuclear envelope.

Antoine Muchir; Paul Pavlidis; Gisele Bonne; Yukiko K. Hayashi; Howard J. Worman

2007-01-01

405

Therapeutic benefit derived from RNAi-mediated ablation of IMPDH1 transcripts in a murine model of autosomal dominant retinitis pigmentosa (RP10)  

Microsoft Academic Search

Mutations within the inosine 50-monophosphate dehydrogenase 1 (IMPDH1) gene cause the RP10 form of autosomal dominant retinitis pigmentosa (adRP), an early-onset retinopathy resulting in extensive visual handicap owing to progressive death of photoreceptors. Apart from the prevalence of RP10, estimated to account for 5-10% of cases of adRP in United States and Europe, two observations render this form of RP

Lawrence C. S. Tam; Anna-Sophia Kiang; Avril Kennan; Paul F. Kenna; Naomi Chadderton; Marius Ader; Arpad Palfi; Aileen Aherne; Carmen Ayuso; Matthew Campbell; Alison Reynolds; Alex McKee; Marian M. Humphries; G. Jane Farrar; Pete Humphries

2008-01-01

406

Identification of a locus for autosomal dominant high myopia on chromosome 5p13.3-p15.1 in a Chinese family  

PubMed Central

Purpose Myopia and its extreme form, high myopia, are common vision disorders worldwide, especially in Asia. Identifying genetic markers is a useful step toward understanding the genetic basis of high myopia, particularly in the Chinese population, where it is highly prevalent. This study was conducted to provide evidence of linkage for autosomal dominant high myopia to a locus on chromosome 5p13.3-p15.1 in a large Chinese family. Methods After clinical evaluation, genomic DNA from 29 members of this family was genotyped. A genome-wide screen was then performed using 382 markers with an average inter-marker distance of 10 cM, and two-point linkage was analyzed using the MLINK program. Mutation analysis of the candidate genes was performed using direct sequencing. Results Linkage to the known autosomal dominant high myopia loci was excluded. The genome-wide screening identified a maximum two-point LOD score of 3.71 at ?=0.00 with the microsatellite marker D5S502. Fine mapping and haplotype analysis defined a critical region of 11.69 cM between D5S2096 and D5S1986 on chromosome 5p13.3-p15.1. Sequence analysis of the candidate genes inside the linked region did not identify any causative mutations. Conclusions A genetic locus was mapped to chromosome 5p13.3-p15.1 in a large Chinese family with autosomal dominant high myopia.

Ma, Jun-Hua; Shen, Shu-Hong; Zhang, Guo-Wei; Zhao, Dong-Sheng; Xu, Chao; Pan, Chun-Ming; Jiang, He; Wang, Zhi-Quan

2010-01-01

407

Nicotine normalizes intracellular subunit stoichiometry of nicotinic receptors carrying mutations linked to autosomal dominant nocturnal frontal lobe epilepsy.  

PubMed

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is linked with high penetrance to several distinct nicotinic receptor (nAChR) mutations. We studied (alpha4)(3)(beta2)(2) versus (alpha4)(2)(beta2)(3) subunit stoichiometry for five channel-lining M2 domain mutations: S247F, S252L, 776ins3 in alpha4, V287L, and V287M in beta2. alpha4 and beta2 subunits were constructed with all possible combinations of mutant and wild-type (WT) M2 regions, of cyan and yellow fluorescent protein, and of fluorescent and nonfluorescent M3-M4 loops. Sixteen fluorescent subunit combinations were expressed in N2a cells. Förster resonance energy transfer (FRET) was analyzed by donor recovery after acceptor photobleaching and by pixel-by-pixel sensitized emission, with confirmation by fluorescence intensity ratios. Because FRET efficiency is much greater for adjacent than for nonadjacent subunits and the alpha4 and beta2 subunits occupy specific positions in nAChR pentamers, observed FRET efficiencies from (alpha4)(3)(beta2)(2) carrying fluorescent alpha4 subunits were significantly higher than for (alpha4)(2)(beta2)(3); the converse was found for fluorescent beta2 subunits. All tested ADNFLE mutants produced 10 to 20% increments in the percentage of intracellular (alpha4)(3)(beta2)(2) receptors compared with WT subunits. In contrast, 24- to 48-h nicotine (1 muM) exposure increased the proportion of (alpha4)(2)(beta2)(3) in WT receptors and also returned subunit stoichiometry to WT levels for alpha4S248F and beta2V287L nAChRs. These observations may be relevant to the decreased seizure frequency in patients with ADNFLE who use tobacco products or nicotine patches. Fluorescence-based investigations of nAChR subunit stoichiometry may provide efficient drug discovery methods for nicotine addiction or for other disorders that result from dysregulated nAChRs. PMID:19237585

Son, Cagdas D; Moss, Fraser J; Cohen, Bruce N; Lester, Henry A

2009-02-23

408

Functional characteristics of three new germline mutations of the thyrotropin receptor gene causing autosomal dominant toxic thyroid hyperplasia  

SciTech Connect

We report three unrelated families in which hyperthyroidism associated with thyroid hyperplasia was transmitted in an autosomal dominant fashion, in the absence of signs of autoimmunity. Exon 10 of the TSH receptor gene was directly sequenced after PCR amplification from DNA of peripheral leukocytes. In one family, a C to A transversion resulted in an S505R substitution in the third transmembrane segment; in the second, an A to T transversion caused an N650Y substitution in the sixth transmembrane segment; and in the third family, an A to G transition resulted in an N670S substitution in the seventh transmembrane segment. When expressed by transfection in COS-7 cells, each mutated receptor displayed an increase in constitutive stimulation of cAMP production; no effect on basal accumulation of inositol phosphates (IP) could be detected. In binding studies, cells transfected with wild-type of mutated receptors showed similar levels of expression, with the mutated receptors displaying similar or slightly increased affinity for bovine TSH (bTSH) binding. Cells transfected with S505R and N650Y mutants showed a similar cAMP maximal TSH-stimulated accumulation over the cells transfected with the wild type, whereas N670S transfectants showed a blunted response with an increase in EC{sub 50}. A higher IP response to 100 mU/mL bTSH over that obtained with the wild-type receptor was obtained in cells transfected with N650Y; in contrast, cells transfected with S505R showed a blunted IP production (50% less), and the N670S mutant completely lost the ability to stimulate IP accumulation in response to bTSH. The differential effects of individual mutations on stimulation by bTSH of cAMP or IP accumulation suggest that individual mutant receptors may achieve different active conformations with selective abilities to couple to G{sub s}{alpha} and to G{sub q}{alpha}. 17 refs., 8 figs.

Tonacchera, M.; Van Sande, J.; Cetani, F. [Universite Libre de Bruxelles, Brussels (Belgium)] [and others

1996-02-01

409

Sirolimus ameliorates the enhanced expression of metalloproteinases in a rat model of autosomal dominant polycystic kidney disease  

Microsoft Academic Search

Background. Remodelling of matrix and tubular basement membranes (TBM) is a characteristic of polycystic kid- ney disease. We hypothesized that matrix and TBM degra- dation by metalloproteinases (MMPs) could promote cyst formation. We therefore investigated the renal expression of MMPs in the Han:SPRD rat model of autosomal domi- nant polycystic kidney disease (ADPKD) and examined the effect of sirolimus treatment

C. Berthier; Patricia R. Wahl; M ichel Le Hir; Hans-Peter Marti; Ulrich Wagner; Hubert Rehrauer; Andreas L. Serra

2008-01-01

410

Molecular genetic diagnosis of autosomal dominant polycystic kidney disease in a newborn with bilateral cystic kidneys detected prenatally and multiple skeletal malformations.  

PubMed Central

We report a case of an unusual prenatal presentation of polycystic kidneys associated with multiple skeletal limb defects, including polydactyly, syndactyly, bilateral agenesis of the tibia, and club foot. The ultrasonographic picture was consistent with a diagnosis of polycystic kidney disease, either the adult onset autosomal dominant type (ADPKD) or the early onset autosomal recessive form (ARPKD). However, there was a positive family history for ADPKD. Linkage analysis was performed in 10 family members, of whom four were affected, using six flanking DNA markers tightly linked to the PKD1 locus on chromosome 16p, and one marker linked to the putative PKD2 locus on chromosome 2p. Lod score determinations indicated that the affected gene in the family is most likely PKD1. The patient inherited the disease linked haplotype from his affected mother. Images

Turco, A E; Padovani, E M; Chiaffoni, G P; Peissel, B; Rossetti, S; Marcolongo, A; Gammaro, L; Maschio, G; Pignatti, P F

1993-01-01

411

Recurrent Mutation in the First Zinc Finger of the Orphan Nuclear Receptor NR2E3 Causes Autosomal Dominant Retinitis Pigmentosa  

PubMed Central

Autosomal dominant retinitis pigmentosa” (adRP) refers to a genetically heterogeneous group of retinal dystrophies, in which 54% of all cases can be attributed to 17 disease loci. Here, we describe the localization and identification of the photoreceptor cell-specific nuclear receptor gene NR2E3 as a novel disease locus and gene for adRP. A heterozygous mutation c.166G?A (p.Gly56Arg) was identified in the first zinc finger of NR2E3 in a large Belgian family affected with adRP. Overall, this missense mutation was found in 3 families affected with adRP among 87 unrelated families with potentially dominant retinal dystrophies (3.4%), of which 47 were affected with RP (6.4%). Interestingly, affected members of these families display a novel recognizable NR2E3-related clinical subtype of adRP. Other mutations of NR2E3 have previously been shown to cause autosomal recessive enhanced S-cone syndrome, a specific retinal phenotype. We propose a different pathogenetic mechanism for these distinct dominant and recessive phenotypes, which may be attributed to the dual key role of NR2E3 in the regulation of photoreceptor-specific genes during rod development and maintenance.

Coppieters, Frauke; Leroy, Bart P.; Beysen, Diane; Hellemans, Jan; De Bosscher, Karolien; Haegeman, Guy; Robberecht, Kirsten; Wuyts, Wim; Coucke, Paul J.; De Baere, Elfride

2007-01-01

412

Successfully Treated Escherichia coli-Induced Emphysematous Cyst Infection with Combination of Intravenous Antibiotics and Intracystic Antibiotics Irrigation in a Patient with Autosomal Dominant Polycystic Kidney Disease  

PubMed Central

A 62-yr-old woman with an autosomal dominant polycystic kidney disease (ADPKD) was admitted to our hospital for further evaluation of intermittent fever, nausea and left flank discomfort. The computed tomography (CT) scan revealed a gas-forming, infectious cyst of approximately 8.1 cm in size in left kidney lower pole. Escherichia coli was identified from the cyst fluid culture examination. Her symptoms improved only after the concomitant use of intravenous ciprofloxacin and an intracystic irrigation of ciprofloxacin through a percutaneous cystostomy drainage. Our case presents the successfully treated emphysematous cyst infection with combination of intravenous antibiotics and intracystic antibiotic therapy instead of surgical management.

Kim, Hyunsuk; Cho Park, Hayne; Lee, Sunhwa; Lee, Jungsil; Cho, Chungyun; Kim, Dong Ki; Hwang, Young-Hwan; Oh, Kook-Hwan

2013-01-01

413

A novel locus DFNA59 for autosomal dominant nonsyndromic hearing loss maps at chromosome 11p14.2–q12.3  

Microsoft Academic Search

Autosomal dominant nonsyndromic hearing loss (ADNSHL) accounts for about one-fifth of hereditary hearing loss in humans. In\\u000a the present study, we have analyzed a three-generation family with 14 of its members manifesting ADNSHL, using a genome-wide\\u000a linkage mapping approach. We found a novel locus DFNA59 between the D11S929 and D11S480 markers in the chromosome location 11p14.2–q12.3. The highest two-point lod

Arunima Chatterjee; Rajeev Jalvi; Nishtha Pandey; R. Rangasayee; Anuranjan Anand

2009-01-01

414

Association of chromosome 2q36.1-36.3 and autosomal dominant transmission in ankylosing spondylitis: results of genetic studies across generations of Han Chinese families  

PubMed Central

Background: Ankylosing spondylitis (AS) is a chronic, potentially crippling, spondyloarthropathy with strong genetic components affecting approximately 0.3% of the population. Its exact genetic mechanism and mode of transmission, however, remains obscure. Methods and results: The authors conducted a genome wide scan on 75 individuals across multiple generations of three Han Chinese families affected with AS. Segregation analysis and pedigree investigation suggested an autosomal dominant inheritance. Pairwise logarithm of odds (LOD) scores were calculated using LINKAGE package for the obtained genotypes. High resolution mapping was then performed based on markers with significant LOD scores. To minimise the number of crossovers in each family, haplotype were constructed and assigned. Two of the pedigrees shared one candidate region for AS on 2q36.1–2q36.3 spanning 6-cM (maximum heterogeneity LOD score of 12.41 at marker D2S2228), while the other showed strong linkage to the HLA-B region. Conclusions: This is the first report which proposes one of the new genetic models of autosomal dominant transmission in AS. The breakthrough in the identification of linkage to chromosome 2q36.1–2q36.3 and the HLA-B region highlights the future potential of more comprehensive genetic studies of determinants of disease risk.

Gu, J; Huang, J; Li, C; Zhao, L; Huang, F; Liao, Z; Li, T; Wei, Q; Lin, Z; Pan, Y; Huang, J; Wang, X; Lin, Q; Lu, C; Wu, Y; Cao, S; Wu, J; Xu, H; Yu, B; Shen, Y

2009-01-01

415

Genomewide search and genetic localization of a second gene associated with autosomal dominant branchio-oto-renal syndrome: clinical and genetic implications.  

PubMed Central

Branchio-oto-renal (BOR) syndrome is characterized by ear malformations, cervical fistulas, hearing loss, and renal anomalies. It is an autosomal dominant disorder with variable clinical manifestations. The most common features of BOR syndrome are branchial, hearing, and renal anomalies. However, many affected subjects have been observed with branchial-cleft anomalies and hearing loss but without renal anomalies, a condition called "branchio-otic" (BO) syndrome. It is logical to question whether the BOR and BO syndromes are allelic or whether they represent distinct genetic entities. We identified a very large extended family whose members had branchial and hearing anomalies associated with commissural lip pits that segregated in an autosomal dominant fashion. Using a genomewide search strategy, we identified genetic linkage, with a maximum LOD score of 4.81 at recombination fraction 0, between the BO phenotype and polymorphic marker D1S2757 in the genetic region of chromosome 1q31. This is the first report of linkage for a second gene associated with BOR syndrome. The findings have important clinical implications and will provide insight into the genetic basis of BOR syndrome.

Kumar, S; Deffenbacher, K; Marres, H A; Cremers, C W; Kimberling, W J

2000-01-01

416

Mapping of the locus for autosomal dominant amelogenesis imperfecta (AIH2) to a 4-Mb YAC contig on chromosome 4q11-q21  

SciTech Connect

Amelogenesis imperfecta (Al) is a clinically and genetically heterogeneous group of inherited enamel defects. We recently mapped a locus for autosomal dominant local hypoplastic amelogenesis imperfecta (AIH2) to the long arm of chromosome 4. The disease gene was localized to a 17.6-cM region between the markers D4S392 and D4S395. The albumin gene (ALB), located in the same interval, was a candidate gene for autosomal dominant AI (ADAI) since albumin has a potential role in enamel maturation. Here we describe refined mapping of the AIH2 locus and the construction of marker maps by radiation hybrid mapping and yeast artificial chromosome (YAC)-based sequence tagged site-content mapping. A radiation hybrid map consisting of 11 microsatellite markers in the 5-cM interval between D4S409 and D4S1558 was constructed. Recombinant haplotypes in six Swedish ADAI families suggest that the disease gene is located in the interval between D4S2421 and ALB. ALB is therefore not likely to be the disease-causing gene. Affected members in all six families share the same allele haplotypes, indicating a common ancestral mutation in all families. The AIH2 critical region is less than 4 cM and spans a physical distance of approximately 4 Mb as judged from radiation hybrid maps. A YAC contig over the AIH2 critical region including several potential candidate genes was constructed. 35 refs., 4 figs., 1 tab.

Kaerrman, C.; Holmgren, G.; Forsman, K. [Univ. Hospital, Umea (Sweden)]|[Univ. of Umea (Sweden)] [and others

1997-01-15

417

Two double non allelic heterozygotes for autosomal dominant polycystic kidney disease at loci PKD1 and PKD4 are not more affected than heterozygous relatives  

SciTech Connect

We describe a family in which both members of a non-consanguineous couple are affected by autosomal dominant polycystic kidney disease (ADPKD). They have three affected children without obvious clinical differences, and three affected grand-children. Two different morbid loci for this disease have been localized, PKD1 on chromosome 16p and PKD4 on chromosome 4q. There were four a priori mating possibilities for this couple: PKD1xPKD1, PKD1xPKD4 or PKD4xPKD1 and PKD4xPKD4. We demonstrate by linkage analysis that: (i) the father is heterozygous at the PKD1 locus (most probably a de novo mutation); (ii) the mother is heterozygous at the PKD4 locus. The abnormal alleles segregates as follows: one child has the abnormal PKD1, another child has the abnormal PKD4 while the third child is a compound heterozygote for both abnormal PKD1 and PKD4 alleles, which were both transmitted to one offspring. The clinical status of these subjects is similar to the status of their relatives in the same age range, suggesting that both PKD1 and PKD4 are truly dominant disease. As there is no other example of such a situation for heterogeneous dominant diseases, we discuss this issue and some possible pathogenic processes by comparison with the similar problem of expressivity in homozygotes for dominant diseases.

Bachner, L.; Vinet, M.C.; Kaplan, J.C. [ICGM-INSERM U129-CHU Cochin 24, Paris (France)] [and others

1994-09-01

418

Field resistance of codling moth against Cydia pomonella granulovirus (CpGV) is autosomal and incompletely dominant inherited.  

PubMed

The current appearance of local codling moth populations with resistance to Cydia pomonella granulovirus (CpGV) is an impediment to continuous CpGV application. Therefore, crossing experiments have been performed in order to gain information about the inheritance of resistance. Evidence is presented that the observed field resistance is stably inherited even under non-selective conditions in the laboratory. Offspring of reciprocal F(1) crosses between a susceptible ('S') and a resistant ('R') strain and backcrosses between F(1) and S were bioassayed at different CpGV concentrations. The resistant strain showed 100 times lower susceptibility in 7-day bioassays. The responses of the reciprocal crosses (male S x female R and female S x male R) did not differ significantly, indicating that resistance is autosomally inherited. The median lethal concentration for the F(1) progeny was intermediate between those of its parental strains. Mortality data obtained from the backcrosses suggested that inheritance of resistance is due to a non-additive, polygenic trait. PMID:16908027

Eberle, Karolin E; Jehle, Johannes A

2006-09-05

419

Do not trust the pedigree: reduced and sex-dependent penetrance at a novel mutation hotspot in ATL1 blurs autosomal dominant inheritance of spastic paraplegia.  

PubMed

The hereditary spastic paraplegias (HSPs), a group of neurodegenerative movement disorders, are among the genetically most heterogeneous clinical conditions. Still, the more than 50 forms known so far apparently explain less than 80% of cases. The present study identified two large HSP families, which seemed to show an autosomal recessive and an X-linked inheritance pattern. A set of genetic analyses including exome sequencing revealed plausible mutations only when assuming incomplete/sex-dependent penetrance of adjacent alterations in the autosomal dominant HSP gene ATL1 (c.1243C>T and c.1244G>A, respectively). By screening of additional HSP patients for the presence of these alterations, we identified three more cases and obtained additional evidence for reduced penetrance. Bisulfate sequencing and haplotype analysis indicated that c.1243C and c.1244G constitute a mutational hotspot. Our findings suggest that misinterpretation of inheritance patterns and, consequently, misselection of candidate genes to be screened in gene-focused approaches contribute to the apparently missing heritability in HSP and, potentially, in other genetically heterogeneous disorders. PMID:23483706

Varga, Rita-Eva; Schüle, Rebecca; Fadel, Hicham; Valenzuela, Irene; Speziani, Fiorella; Gonzalez, Michael; Rudenskaia, Galina; Nürnberg, Gudrun; Thiele, Holger; Altmüller, Janine; Alvarez, Victoria; Gamez, Josep; Garbern, James Y; Nürnberg, Peter; Zuchner, Stephan; Beetz, Christian

2013-04-05

420

Report of a kindred with x-linked (or autosomal dominant sex-limited) 46, XY partial gonadal dysgenesis  

SciTech Connect

The condition termed 46, XY complete gonadal dysgenesis is characterized by the lack of testicular determination with resulting streak gonads, normal Mullerian structures, and female external genitalia. In the partial form, there is incomplete testicular determination with a wide range in the degree of ambiguous genitalia and sexual duct development. The authors evaluated a kindred in which a partial form of 46, XY gonadal dysgenesis occurred in four subjects from two generations. Pedigree analysis indicated an X-linked or possibly an autosomal sex-limited mode of inheritance. All affected subjects were ascertained because of ambiguous genitalia with minimal virilization. At 10 days of age, the proband had a subnormal plasma level of testosterone, and at 4 months, there was no rise in plasma T after stimulation with hCG. At laparotomy, a dysgenetic gonad was found on the right side, but no gonad was found on the left side. A vas deferens was present on the right, indicating the presence of functional leydig cells early in fetal life. In the other affected subjects, gonadal tissue was also limited to one side of the abdomen and showed poorly developed seminiferous tubules. The sex-determining region Y gene, which encodes the testis-determining factor, was present and unaltered in the genomic DNA of all affected subjects. Duplication of the distal short arm of the X-chromosome has been associated with 46, XY complete gonadal dysgenesis in some patients. In the authors studies, Southern blot analysis revealed that sequences of the distal short arm of the X-chromosome were present in single copy, excluding a large duplication in this area of the X. Several kindreds with familial 46, XY complete gonadal dysgenesis have been reported; five of them had evidence of an X-linked mode of inheritance. The authors study of a kindred with 46, XY partial gonadal dysgenesis further supports the role of an X chromosome gene in testicular determination. 44 refs., 1 fig., 3 tabs.

Fechner, P.Y.; Marcantonio, S.M.; Ogata, T.; Rosales, T.O.; Smith, K.D.; Goodfellow, P.N.; Migeon, C.J.; Berkovitz, G.D. (Johns Hopkins Univ. School of Medicine, Baltimore, MD (United States))

1993-05-01

421

Mice with a D190N Mutation in the Gene Encoding Rhodopsin: A Model for Human Autosomal-Dominant Retinitis Pigmentosa  

PubMed Central

Rhodopsin is the G protein–coupled receptor in charge of initiating signal transduction in rod photoreceptor cells upon the arrival of the photon. D190N (RhoD190n), a missense mutation in rhodopsin, causes autosomal-dominant retinitis pigmentosa (adRP) in humans. Affected patients present hyperfluorescent retinal rings and progressive rod photoreceptor degeneration. Studies in humans cannot reveal the molecular processes causing the earliest stages of the condition, thus necessitating the creation of an appropriate animal model. A knock-in mouse model with the D190N mutation was engineered to study the pathogenesis of the disease. Electrophysiological and histological findings in the mouse were similar to those observed in human patients, and the hyperfluorescence pattern was analogous to that seen in humans, confirming that the D190N mouse is an accurate model for the study of adRP.

Sancho-Pelluz, Javier; Tosi, Joaquin; Hsu, Chun-Wei; Lee, Frances; Wolpert, Kyle; Tabacaru, Mirela R; Greenberg, Jonathan P; Tsang, Stephen H; Lin, Chyuan-Sheng

2012-01-01

422

Mutational analysis of nicotinic acetylcholine receptor beta2 subunit gene (CHRNB2) in a representative cohort of Italian probands affected by autosomal dominant nocturnal frontal lobe epilepsy.  

PubMed

Twenty-four autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) probands were analyzed for the presence of V287L and V287M mutations in the CHRNB2 gene, which have been recently associated with the disease. In all patients, the involvement of the two additional loci reported as being associated with ADNFLE (CHRNA4 gene and chromosome 15q24 region) had been previously excluded. Mutational screening was performed by sequencing a polymerase chain reaction-amplified CHRNB2 DNA fragment, spanning the whole exon 5, which contains the V287L and V287M mutations and codes for approximately 65% of the mature protein. In none of the patients were mutations in the analyzed region of CHRNB2 found. These data, obtained in the largest ADNFLE cohort so far analyzed, demonstrate the rarity of the identified CHRNB2 mutations in ADNFLE patients. PMID:11952766

Duga, Stefano; Asselta, Rosanna; Bonati, Maria Teresa; Malcovati, Massimo; Dalprà, Leda; Oldani, Alessandro; Zucconi, Marco; Ferini-Strambi, Luigi; Tenchini, Maria Luisa

2002-04-01

423

[18F-FDG PET/CT diagnosis of liver cyst infection in a patient with autosomal dominant polycystic kidney disease and fever of unknown origin].  

PubMed

The diagnosis, localization and treatment of infected cysts in the kidney or liver of patients with autosomal dominant polycystic kidney disease (ADPKD) remain a clinical challenge. We report the findings of (18)F-FDG PET-CT in an ADPKD diagnosed patient who required renal transplantation five years before and in his follow up presented repeated episodes of bacteriemia without known focus on radiological tests performed. The (18)F-FDG PET-CT scan showed numerous hypermetabolic images with focal or ring-shaped morphology related to the content and the wall of some hepatic cysts. The increased metabolic activity was localized on segments VI and VII. We proceeded to drainage of one cyst in segment VI, removing 110 cc of purulent fluid which grew E. Coli BLEE. The (18)F-FDG PET/CT scan should be included in the diagnostic algorithm for detecting infected liver cysts in patients with ADPKD and fever of unknown origin. PMID:23153986

Banzo, J; Ubieto, M A; Gil, D; Prats, E; Razola, P; Tardín, L; Andrés, A; Rambalde, E F; Ayala, S M; Cáncer, L; Velilla, J

2012-11-13

424

Clinical variability of the cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy phenotype in two siblings of a large family showing the same mutation  

PubMed Central

A 44-year-old Albanian male was consulted and diagnosed with dementia. His magnetic resonance imaging suggested diffuse white matter changes. The suspicion of cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) was raised, and a genetic analysis confirmed such a suspicion through uncovering a pathogenic mutation at the level of exon 4 (c.475C>T) of chromosome 19. The patient came from a large family of 13 children, all of whom underwent clinical, genetic, and imaging examination. The pathogenic mutation was found present only in his eldest sister (50 years old), and she presented also very suggestive signs of CADASIL in her respective imaging study, but without any clinically significant counterpart. All other siblings were free from clinical and radiological signs of the disorder. Our opinion was that we were dealing with a mutation showing a very low level of penetrance, with only two siblings affected in a large Albanian family with 13 children.

Vyshka, Gentian; Kruja, Jera

2013-01-01

425

Clinical aspects of an autosomal dominantly inherited hearing impairment linked to the DFNA60 locus on chromosome 2q23.1-2q23.3.  

PubMed

A total of 64 loci for autosomal dominant non-syndromic hearing impairment have been described, and the causative genes have been identified for 24 of these. The present study reports on the clinical characteristics of an autosomal dominantly inherited hearing impairment that is linked to a region within the DFNA60 locus located on chromosome 2 in q22.1-24.1. A pedigree spanning four generations was established with 13 affected individuals. Linkage analysis demonstrated that the locus extended over a 2.96 Mb region flanked by markers D2S2335 and D2S2275. The audiograms mainly showed a distinctive U-shaped configuration. Deterioration of hearing started at a wide age range, from 12 to 40 years. Cross-sectional analysis showed rapid progression of hearing impairment from mild to severe, between the ages of 40 and 60 years, a phenomenon that is also observed in DFNA9 patients. The results of the individual longitudinal analyses were generally in line with those obtained by the cross-sectional analysis. Speech recognition scores related to the level of hearing impairment (PTA1,2,4 kHz) appeared to be fairly similar to those of presbyacusis patients. It is speculated that hearing impairment starting in mid-life, as shown by DFNA60 patients, could play a role in the development of presbyacusis. Furthermore, speech recognition did not deteriorate appreciably before the sixth decade of life. We conclude that DFNA60 should be considered in hearing impaired patients who undergo a rapid progression in middle age and are negative for DFNA9. Furthermore, cochlear implantation resulted in good rehabilitation in two DFNA60 patients. PMID:23538131

van Beelen, E; Schraders, M; Huygen, P L M; Oostrik, J; Plantinga, R F; van Drunen, W; Collin, R W J; Kooper, D P; Pennings, R J E; Cremers, C W R J; Kremer, H; Kunst, H P M