Copyright © 1999 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 64, Issue 4, 1063-1070, 1 April 1999
doi:10.1086/302340
Ancestral Origins and Worldwide Distribution of the PRNP 200K Mutation Causing Familial Creutzfeldt-Jakob Disease
Hee Suk Lee1, Nyamkhishig Sambuughin1, Larisa Cervenakova2, 4, Joab Chapman5, Maurizio Pocchiari7, Svetlana Litvak1, Hai Yan Qi1, Herbert Budka8, Teodoro del Ser9, Hisako Furukawa10, Paul Brown2, D. Carleton Gajdusek2, 11, Jeffrey C. Long3, Amos D. Korczyn6 and Lev G. Goldfarb1, 
, 
1 Clinical Neurogenetics Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD
2 Laboratory of Central Nervous System Studies, National Institute of Neurological Disorders and Stroke, Bethesda, MD
3 Laboratory of Neurogenetics, National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD
4 American Red Cross J. H. Holland Laboratory, Rockville, MD
5 Department of Physiology and Pharmacology, Ramat Aviv, Israel
6 Sieratzki Chair of Neurology, Department of Neurology, Tel Aviv University, Ramat Aviv, Israel
7 Laboratory of Virology, Instituto Superiore di Sanita, Rome
8 Institute of Neurology, University of Vienna, Vienna
9 Seccion de Neurologia, Hospital Severo Ochoa Leganes, Madrid
10 Department of Neuropathology, Kyushu University, Maidashi, Japan; and
11 Centre National de la Recherche Scientifique, Institut Alfred Fessard, Gif-sur-Yvette, France
Address for correspondence and reprints: Dr. Lev Goldfarb, National Institutes of Health Clinical Neurogenetics Unit, Room 4B37, Building 10, 10 Center Drive MSC 1361, Bethesda, MD 20892-1361.Abstract
Creutzfeldt-Jakob disease (CJD) belongs to a group of prion diseases that may be infectious, sporadic, or hereditary. The 200K point mutation in the PRNP gene is the most frequent cause of hereditary CJD, accounting for >70% of families with CJD worldwide. Prevalence of the 200K variant of familial CJD is especially high in Slovakia, Chile, and Italy, and among populations of Libyan and Tunisian Jews. To study ancestral origins of the 200K mutation–associated chromosomes, we selected microsatellite markers flanking the PRNP gene on chromosome 20p12-pter and an intragenic single-nucleotide polymorphism at the PRNP codon 129. Haplotypes were constructed for 62 CJD families originating from 11 world populations. The results show that Libyan, Tunisian, Italian, Chilean, and Spanish families share a major haplotype, suggesting that the 200K mutation may have originated from a single mutational event, perhaps in Spain, and spread to all these populations with Sephardic migrants expelled from Spain in the Middle Ages. Slovakian families and a family of Polish origin show another unique haplotype. The haplotypes in families from Germany, Sicily, Austria, and Japan are different from the Mediterranean or eastern European haplotypes. On the bais of this study, we conclude that founder effect and independent mutational events are responsible for the current geographic distribution of hereditary CJD associated with the 200K mutation.
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