Population genetics and new insight into range of CAG repeats of spinocerebellar ataxia type 3 in the Han Chinese population.
Spinocerebellar ataxia type 3 (SCA3), also called Machado-Joseph disease (MJD), is one of the most common SCAs worldwide and caused by a CAG repeat expansion located in ATXN3 gene. Based on the CAG repeat numbers, alleles of ATXN3 can be divided into normal alleles (ANs), intermediate alleles (AIs) and expanded alleles (AEs). It was controversial whether the frequency of large normal alleles (large ANs) is related to the prevalence of SCA3 or not. And there were huge chaos in the comprehension of the specific numbers of the range of CAG repeats which is fundamental for genetic analysis of SCA3. To illustrate these issues, we made a novel CAG repeat ladder to detect CAG repeats of ATXN3 in 1003 unrelated Chinese normal individuals and studied haplotypes defined by three single nucleotide polymorphisms (SNPs) closed to ATXN3. We found that the number of CAG repeats ranged from 13 to 49, among them, 14 was the most common number. Positive skew, the highest frequency of large ANs and 4 AIs which had never been reported before were found. Also, AEs and large ANs shared the same haplotypes defined by the SNPs. Based on these data and other related studies, we presumed that de novo mutations of ATXN3 emerging from large ANs are at least one survival mechanisms of mutational ATXN3 and we can redefine the range of CAG repeats as: ANs≤44, 45 ≤AIs ≤49 and AEs≥50.
Department of Neurology and Research center of Neurology in Second Affiliated Hospital, and the Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, China; Department of Neurology and Institute of Neurology, First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
Shi-Rui
SR
Gan
Department of Neurology and Research center of Neurology in Second Affiliated Hospital, and the Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, China.
Wang
W
Ni
Department of Neurology and Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, Shanghai, China.
Yi
Y
Dong
Department of Neurology and Institute of Neurology, First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
Ning
N
Wang
Department of Neurology and Research center of Neurology in Second Affiliated Hospital, and the Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, China; Department of Neurology and Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, Shanghai, China.
Zhi-Ying
ZY
Wu
D000483:Alleles; D044466:Asian People; D000067699:Ataxin-3 / Q000235:genetics*; D002681:China; D005260:Female; D005820:Genetic Testing; D005828:Genetics, Population; D006239:Haplotypes; D006801:Humans; D017827:Machado-Joseph Disease / Q000235:genetics* / Q000473:pathology; D008297:Male; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D012097:Repressor Proteins / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
D012097:Repressor Proteins; C092341:ATXN3 protein, human; D000067699:Ataxin-3