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Novel Insights From History and Polymorphism Studies

Uma Mittal, MSc; Achal K. Srivastava, DM; Satish Jain, DM; Sanjeev Jain, MD; Mitali Mukerji, PhD

Arch Neurol. 2005;62:637-640.

Background  The ACA haplotype is associated with 72% of the expanded repeats in Machado-Joseph disease (MJD) worldwide and has been traced to a Portuguese ancestry. It is present in only 5% of the normal chromosomes in the Portuguese population.

Objective  To trace the origin of expanded alleles of MJD in the Indian population.

Methods  We performed CAG repeat size determination and haplotype analysis for 9 families with MJD and 263 unrelated chromosomes with unexpanded CAG sequences from the Indian population.

Results  All the expanded alleles were exclusively associated with the ACA haplotype in the Indian population. Interestingly, this haplotype was very common in normal alleles (40%) as compared with the Portuguese population (5%) and was significantly associated with large normal alleles (Pearson ²₁ = 87.1, P<.001) in the Indian population. We also observed a rare intermediate allele of MJD with the ACA haplotype but with a CAG variant instead of CAA at the sixth position in the repeat tract.

Conclusions  Overrepresentation of the ACA haplotype in large normal alleles in India as compared with the Portuguese population suggests that the expansion-prone large normal alleles with the ACA haplotype may have been introduced in the Portuguese population through admixture with South Asian populations. Detailed haplotype analysis of a CAG variant within the repeat tract in an intermediate allele of MJD suggests a mechanism of gene conversion in the expansion.

Author Affiliations: Functional Genomics Unit, Institute of Genomics and Integrative Biology, New Delhi (Ms Mittal and Dr Mukerji), Neuroscience Centre, All India Institute of Medical Sciences, New Delhi (Drs Srivastava and Satish Jain), and Molecular Genetics Laboratory, Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bangalore (Dr Sanjeev Jain), India. Dr Satish Jain is now with the Indian Epilepsy Centre, New Delhi.