TY - JOUR

T1 - Ancestral origins of the Machado-Joseph disease mutation

T2 - A worldwide haplotype study

AU - Gaspar, C.

AU - Lopes-Cendes, I.

AU - Hayes, S.

AU - Goto, J.

AU - Arvidsson, K.

AU - Dias, A.

AU - Silveira, I.

AU - Maciel, P.

AU - Coutinho, P.

AU - Lima, Manuela

AU - Zhou, Y. X.

AU - Soong, B. W.

AU - Watanabe, M.

AU - Giunti, P.

AU - Stevanin, G.

AU - Riess, O.

AU - Sasaki, H.

AU - Hsieh, M.

AU - Nicholson, G. A.

AU - Brunt, E.

AU - Higgins, J. J.

AU - Lauritzen, M.

AU - Tranebjaerg, L.

AU - Volpini, V.

AU - Wood, N.

AU - Ranum, L.

AU - Tsuji, S.

AU - Brice, A.

AU - Sequeiros, J.

AU - Rouleau, G. A.

PY - 2001/1/1

Y1 - 2001/1/1

N2 - 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 linkage-disequilibrium 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.

AB - 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 linkage-disequilibrium 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.

UR - http://www.scopus.com/inward/record.url?scp=0035125109&partnerID=8YFLogxK

U2 - 10.1086/318184

DO - 10.1086/318184

M3 - Journal article

C2 - 11133357

AN - SCOPUS:0035125109

VL - 68

SP - 523

EP - 528

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 2

ER -