A novel autosomal dominant spinocerebellar ataxia (SCA22) linked to chromosome 1p21‐q23
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TLDR
A four-generation Chinese pedigree segregating an autosomal dominant phenotype for cerebellar ataxia is ascertained and clinically characterized and is characterized by a slowly progressive, pure cerebellum without involvement of the brainstem.Abstract:
The autosomal dominant cerebellar ataxias (ADCA) are a clinically, pathologically and genetically heterogeneous group of disorders. Ten responsible genes have been identified for spinocerebellar ataxia types SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA10, SCA12 and SCA17, and dentatorubral pallidoluysian atrophy (DRPLA). The mutation is caused by an expansion of a CAG, CTG or ATTCT repeat sequence of these genes. Six additional loci, SCA4, SCA5, SCA11, SCA13, SCA14 and SCA16 have also been mapped. The growing heterogeneity of the autosomal dominant forms of these diseases shows that the genetic aetiologies of at least 20% of ADCA have yet to be elucidated. We ascertained and clinically characterized a four-generation Chinese pedigree segregating an autosomal dominant phenotype for cerebellar ataxia. Direct mutation analysis, linkage analysis for all known SCA loci and a genome-wide linkage study were performed. Direct mutation analysis excluded SCA1, 2, 3, 6, 7, 8, 10, 12, 17 and DRPLA, and genetic linkage analysis excluded SCA4, 5, 11, 13, 14 and 16. The genome-wide linkage study suggested linkage to a locus on chromosome 1p21-q23, with the highest two-point LOD score at D1S1167 (Zmax = 3.46 at theta = 0.00). Multipoint analysis and haplotype reconstruction traced this novel SCA locus (SCA22) to a 43.7-cM interval flanked by D1S206 and D1S2878 (Zmax = 3.78 under four liability classes, and 2.67 using affected-only method). The age at onset ranged from 10 to 46 years. All affected members had gait ataxia with variable features of dysarthria and hyporeflexia. Head MRI showed homogeneous atrophy of the cerebellum without involvement of the brainstem. In six parent-child pairs, median onset occurred 10 years earlier in offspring than in their parents, suggesting anticipation. This family is distinct from other families with SCA and is characterized by a slowly progressive, pure cerebellar ataxia.read more
Citations
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Journal ArticleDOI
Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis.
TL;DR: The identification of ataxia genes raises hope that essential pathogenetic mechanisms causing SCA will become more and more apparent, and will enable the development of rational therapies for this group of disorders, which currently can only be treated symptomatically.
Journal ArticleDOI
Brain pathology of spinocerebellar ataxias
TL;DR: The genetic and clinical background of the known SCAs are reported, the state of neuropathological investigations of brain tissue from SCA patients in the final disease stages are presented, and detailed molecular and pathogenetic consequences remain to be determined.
Journal ArticleDOI
The wide spectrum of spinocerebellar ataxias (SCAs).
TL;DR: It is estimated that extensive genetic testing leads to the identification of the causative gene in about 60–75 % of cases, and the development of relevant animal models of SCAs is bringing hope for effective therapies in human.
Journal ArticleDOI
Molecular pathogenesis of spinocerebellar ataxias
TL;DR: The latest evidence for the proposed molecular processes to the pathogenesis of dominantly inherited spinocerebellar ataxias and the current therapeutic strategies is reviewed.
Journal ArticleDOI
Mutations in KCND3 cause spinocerebellar ataxia type 22
Yi-Chung Lee,Alexandra Durr,Karen Majczenko,Yen Hua Huang,Yu Chao Liu,Cheng Chang Lien,Pei-Chien Tsai,Yaeko Ichikawa,Jun Goto,Marie Lorraine Monin,Jun Li,Ming Yi Chung,Emeline Mundwiller,Vikram G. Shakkottai,Tze Tze Liu,Christelle Tesson,Yi-Chun Lu,Alexis Brice,Shoji Tsuji,Margit Burmeister,Giovanni Stevanin,Bing-Wen Soong +21 more
TL;DR: In this article, the causative gene in SCA22, an autosomal dominant cerebellar ataxia mapped to chromosome 1p21-q23, was identified.
References
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Book
Molecular Cloning: A Laboratory Manual
TL;DR: Molecular Cloning has served as the foundation of technical expertise in labs worldwide for 30 years as mentioned in this paper and has been so popular, or so influential, that no other manual has been more widely used and influential.
Journal Article
Parametric and nonparametric linkage analysis: a unified multipoint approach.
TL;DR: It is shown that NPL is robust to uncertainty about mode of inheritance, is much more powerful than commonly used nonparametric methods, and loses little power relative to parametric linkage analysis, and appears to be the method of choice for pedigree studies of complex traits.
Journal ArticleDOI
CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1
Yoshiya Kawaguchi,Toshihiro Okamoto,Masafumi Taniwaki,Megumi Aizawa,Miho Inoue,Sadao Katayama,Hideshi Kawakami,Shigenobu Nakamura,Masaki Nishimura,Ichiro Akiguchi,Jun Kimura,Shuh Narumiya,Akira Kakizuka +12 more
TL;DR: Southern blot analyses and genomic cloning demonstrates the existence of related genes, raising the possibility that similar abnormalities in related genes may give rise to diseases similar to Machado-Joseph disease.
Journal ArticleDOI
Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1.
Harry T. Orr,Ming Yi Chung,Sandro Banfi,Thomas J. Kwiatkowski,Antonio Servadio,Arthur L. Beaudet,Alanna E. McCall,Lisa A. Duvick,Laura P.W. Ranum,Huda Y. Zoghbi +9 more
TL;DR: There is a direct correlation between the size of the (CAG)n repeat expansion and the age–of–onset of SCA1, with larger alleles occurring in juvenile cases.
Journal ArticleDOI
Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the α(1A)-voltage-dependent calcium channel
Olga Zhuchenko,Jennifer Bailey,Penelope E. Bonnen,T. Ashizawa,T. Ashizawa,David W. Stockton,Christopher I. Amos,William B. Dobyns,S. H. Subramony,Huda Y. Zoghbi,Cheng Chi Lee +10 more
TL;DR: It is concluded that a small polyglutamine expansion in the human α1A calcium channel is most likely the cause of a newly classified autosomal dominant spinocerebellar ataxia, SCA6.
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