Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder originally described in families
of Portuguese-Azorean ancestry. The cloning of the MJD1 gene allowed identification of the disease in many
other populations, and MJD is now known to be the most common cause of dominant spinocerebellar ataxia. The
hypothesis that its present world distribution could result from the spread of an original founder mutation has
been raised, both at historical and molecular levels. In the present study, we tested this hypothesis by linkagedisequilibrium
analysis of tightly linked polymorphisms and by haplotype comparison, in 249 families from different
countries. We typed five microsatellite markers surrounding the MJD1 locus (D14S1015, D14S995, D14S973,
D14S1016, and D14S977), and three intragenic single–base-pair polymorphisms (A669TG/G669TG, C987GG/G987GG,
and TAA1118/TAC1118). The results show two different haplotypes, specific to the island of origin, in families of
Azorean extraction. In families from mainland Portugal, both Azorean haplotypes can be found. The majority of
the non-Portuguese families also share the same intragenic haplotype seen in the families coming from the island
of Flores, but at least three other haplotypes were seen. These findings suggest two introductions of the mutation
into the Portuguese population. Worldwide, the sharing of one intragenic haplotype by the majority of the families
studied implies a founder mutation in MJD.
Relation:
American journal of human genetics, 68(2), 523-528
