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Linkage disequilibrium analysis in Machado-Joseph disease patients of different ethnic origins
C Gaspar1, I Lopes-Cendes, A L DeStefano
1Centre for Research in Neuroscience, McGill University, Montreal General Hospital Research Institute, Quebec, Canada.
Abstract:
Machado-Joseph disease (MJD) is an autosomal dominant spinocerebellar degeneration originally described in families of Portuguese-Azorean ancestry. The hypothesis that its present world distribution could result from the spread of an original founder mutation has been raised. To test this possibility we have conducted a linkage disequilibrium study of markers segregating with the MJD1 locus in a total of 64 unrelated families of different geographical origins. Significant association was detected between the MJD1 locus and marker alleles at loci D14S280, D14S1050 and D14S81. All affected individuals, except one Chinese family, had allele 3 (237 bp) at D14S280. This finding is consistent with a founder effect in our MJD population. However, distinct haplotypes were observed in patients originating from the two Azorean islands showing the highest disease prevalence; therefore, the possible existence of more than one founder mutation can not be excluded with the markers currently available.
Insights
Machado-Joseph disease (MJD) may stem from a single founder mutation, as indicated by genetic marker associations in most affected families. However, distinct genetic patterns on two Azorean islands suggest multiple origins might exist.
Area of Science:
- Genetics
- Neurology
- Population Studies
Background:
- Machado-Joseph disease (MJD), an autosomal dominant spinocerebellar degeneration, was first identified in Portuguese-Azorean populations.
- The global distribution of MJD suggests a potential founder effect originating from a single mutation event.
Purpose of the Study:
- To investigate the hypothesis of a common founder mutation for Machado-Joseph disease.
- To analyze the genetic origins and distribution of MJD across diverse geographical populations.
Main Methods:
- Conducted a linkage disequilibrium study involving 64 unrelated families with MJD from various geographical locations.
- Examined genetic markers, specifically D14S280, D14S1050, and D14S81, associated with the MJD1 locus.
Main Results:
- Significant associations were found between the MJD1 locus and markers at D14S280, D14S1050, and D14S81.
- Allele 3 (237 bp) at D14S280 was present in nearly all affected individuals, supporting a founder effect.
- Distinct haplotypes were identified in patients from two high-prevalence Azorean islands, suggesting potential multiple founder mutations.
Conclusions:
- The findings are consistent with a founder effect for Machado-Joseph disease in the studied population.
- The presence of distinct haplotypes indicates that more than one founder mutation may be responsible for MJD, particularly within the Azorean archipelago.