Abstract
Machado-Joseph disease (MJD, also known as spinocerebellar ataxia 3 or SCA3) is the most common dominant ataxia worldwide, with an overall average prevalence of 1–5/100,000. To this date, two major ancestral lineages have been found throughout the world. In China, the relative frequency of MJD among the SCAs reaches as high as 63%, however, little is known about its mutational origin in this country. We analyzed 50 families with MJD patients in two or more generations to study the hypothesis that new mutational events have occurred in this population. Haplotypes based on 20 SNPs have shown new genetic backgrounds segregating with MJD mutations in our cohort from China. We found the “Joseph-derived” lineage (Joseph lineage with a G variant in rs56268847) to be very common among Chinese MJD patients. Moreover, we estimated the time for the origin of this MJD SNP background based on STR diversity flanking the (CAG)n of ATXN3. It was surprising to find that the Chinese MJD population originated from 8,000 to 17,000 years ago, far earlier than the previous literature reports, which will be an important evidence to explain the origin, spread and founder effects of MJD.
Highlights
Machado-Joseph disease (MJD, OMIM#109150), known as spinocerebellar ataxia type 3 (SCA3), is one of the polyQ diseases
To determine the occurrence of new mutation events and clarify the spread of ancestral MJD lineages in different populations, genetic distances were determined using a total of 20 SNPs and 4 microsatellites for the purpose of haplotypes identification (Martins et al, 2012), little information on MJD haplotypes is available in China, the frequency of MJD is very high in this Asian population
We identified 13 disease-associated haplotypes in our cohort of Chinese MJD families
Summary
Machado-Joseph disease (MJD, OMIM#109150), known as spinocerebellar ataxia type 3 (SCA3), is one of the polyQ diseases It is a rare autosomal dominantly inherited neurodegenerative disease that causes progressive cerebellar ataxia, resulting in lacks of muscle control and coordination of the upper and lower extremities, with symptoms including dysarthria, dysphagia, pyramidal signs, progressive external ophthalmoplegia, and dystonia (Bettencourt and Lima, 2011; Costa Mdo and Paulson, 2012; Wang et al, 2015; Paulson et al, 2017). Four different SNP haplotypes were identified segregating with MJD expansions: A-C-A, A-G-A, G-G-A, and G-G-C (Gaspar et al, 2001) Following this discovery, a worldwide study of extended haplotypes was performed in 264 MJD families, and two major ancestral lineages were confirmed: the GTGGCA background or the Machado lineage, probably originated in Portugal; and the TTACAC or Joseph lineage, observed in 19 countries, including Japan (Martins et al, 2007). To determine the occurrence of new mutation events and clarify the spread of ancestral MJD lineages in different populations, genetic distances were determined using a total of 20 SNPs and 4 microsatellites for the purpose of haplotypes identification (Martins et al, 2012), little information on MJD haplotypes is available in China, the frequency of MJD is very high in this Asian population
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