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From the Department of Neurology (Drs. Blumen, Nisipeanu, Inzelberg, and Carasso), Hillel Yaffe Medical Center, Hadera, Israel; the Rappaport Faculty of Medicine (Drs. Blumen and Inzelberg), The Technion, Haifa, Israel; the Department of Neurology (Drs. Korczyn, Chapman, and Asherov), Tel Aviv Medical Center, Tel Aviv, Israel; the Sieratzki Chair of Neurology (Dr. Korczyn), Tel Aviv University, Ramat Aviv, Israel; the Centre de Recherche du CHUM (Drs. Lavoie and Brais), Université de Montréal, Montreal, Quebec, Canada; the Centre for Research in Neurosciences (Drs. Medynski, Rouleau, and Brais), McGill University Health Center, Montreal, Quebec, Canada; the Departement des Sciences Neurologiques (Dr. Bouchard), Hôpital de l’Enfant-Jésus, Quebec, Canada; and INSERM (Dr. Tomé), Unité 523, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
Address correspondence and reprint requests to Dr. S.C. Blumen, Department of Neurology, Hillel Yaffe Medical Center, PO Box 169, Hadera, 38100 Israel; e-mail: neurology{at}hillel-yaffe.health.gov.il
OBJECTIVE: To determine whether all cases of oculopharyngeal muscular dystrophy (OPMD) among Bukhara Jews share the same founder mutation.
BACKGROUND: Autosomal dominant OPMD is caused by a (GCG)8–13 repeat expansion in the polyadenylation binding protein 2 (PABP2) gene. The disease has a worldwide distribution but is particularly prevalent in Bukhara Jews and in French Canadians, in whom it was introduced by three sisters in 1648.
METHODS: We established the size of the PABP2 mutation in 23 Bukhara Jewish patients belonging to eight unrelated families. In all families, we constructed haplotypes for the carrying chromosomes composed of the alleles for eight chromosome 14q polymorphic markers.
RESULTS: All patients share a (GCG)9 PABP2 mutation and a four-marker haplotype. Furthermore, a shared intron single nucleotide polymorphism (SNP) in the PABP2 gene 2.6Kb from the mutation was not observed in 22 families with (GCG)9 mutations from nine different countries. The smaller size of the chromosomal region in linkage disequilibrium around the mutation in Bukhara Jews, as compared with French Canadians, suggests a founder effect that occurred more than 350 years ago. Based on the Luria–Delbrück corrected "genetic clock," we estimate that the mutation appeared or was introduced once in the Bukhara Jewish population between AD 872 and 1512 (mean, AD 1243).
CONCLUSION: OPMD among Bukhara Jews is the result of a shared, historically distinct, PABP2 (GCG)9 mutation that likely arose or was introduced in this population at the time they first settled in Bukhara and Samarkand during the 13th or 14th centuries.
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X. Fan, P. Dion, J. Laganiere, B. Brais, and G. A. Rouleau Oligomerization of polyalanine expanded PABPN1 facilitates nuclear protein aggregation that is associated with cell death Hum. Mol. Genet., October 1, 2001; 10(21): 2341 - 2351. [Abstract] [Full Text] [PDF]
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