Population genetics and new insight into range of CAG repeats of spinocerebellar ataxia type 3 in the Han Chinese population

PLoS One. 2015 Aug 12;10(8):e0134405. doi: 10.1371/journal.pone.0134405. eCollection 2015.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Asian People
  • Ataxin-3 / genetics*
  • China
  • Female
  • Genetic Testing
  • Genetics, Population*
  • Haplotypes
  • Humans
  • Machado-Joseph Disease / genetics*
  • Machado-Joseph Disease / pathology
  • Male
  • Mutation
  • Polymorphism, Single Nucleotide
  • Repressor Proteins / genetics*
  • Trinucleotide Repeat Expansion / genetics*

Substances

  • Repressor Proteins
  • ATXN3 protein, human
  • Ataxin-3

Grants and funding

This work was supported by The National Natural Science Foundation of China (http://www.nsfc.gov.cn/) to Z-Y Wu (81125009, Beijing) and S-R Gan (81100851, Beijing). This work was also supported by national key clinical specialty discipline construction program. The funding agencies played no role in the design and conduct of the study, collection, management, analysis and interpretation of the data, preparation, review, or approval of the manuscript and decision to submit the manuscript for publication.