Ancestral origins of the prion protein gene D178N mutation in the Basque Country |
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Authors: | Ana B Rodríguez-Martínez Christian Barreau Isabelle Coupry Jordi Yagüe Raquel Sánchez-Valle Luis Galdós-Alcelay Agustín Ibáñez Antón Digón Ignacio Fernández-Manchola Cyril Goizet Azucena Castro Nerea Cuevas Maite Alvarez-Alvarez Marian M de Pancorbo Benoît Arveiler Juan J Zarranz |
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Institution: | (1) Unidad de Genómica: Banco de ADN y Genotipado, Facultad de Farmacia, Universidad del País Vasco, Paseo de la Universidad, 7. 01006 Vitoria-Gasteiz, Spain;(2) Institut de Biochimie et Génétique Cellulaires, UMR 5095 CNRS-Université Victor Segalen Bordeaux 2, 1 Rue Camille Saint Saëns, 33077 Bordeaux Cedex, France;(3) Laboratoire de Génétique Humaine, Développement et Cancer, Université Victor Segalen Bordeaux 2, 146 Rue Léo Saignat, 33076 Bordeaux Cedex, France;(4) Servei d Immunologia, Unitat de Biodiagnostic de la Malatia de Creutzfeld-Jacob I d altres Malaties per Prions, Hospital Clinic, Barcelona, Spain;(5) Servicio de Neurología, Hospital de Txagorritxu, Vitoria Gasteiz, Alava, Spain;(6) Servicio de Neurología, Hospital de Santiago, Vitoria Gasteiz, Alava, Spain;(7) Servicio de Neurología, Hospital Donostia, Donosti, Guipuzcoa, Spain;(8) Hôpital Pellegrin, Service de Neurologie, Université Victor Segalen Bordeaux 2, France;(9) Datagene, Edificio BEAZ, Sangroniz 6, Sondika, Bizkaia, Spain;(10) Servicio de Neurologia, Hospital de Cruces, Cruces-Barakaldo , Bizkaia, Spain |
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Abstract: | Fatal familial insomnia (FFI) and familial Creutzfeldt-Jakob disease (fCJD) are familial prion diseases with autosomal dominant inheritance of the D178N mutation. FFI has been reported in at least 27 pedigrees around the world. Twelve apparently unrelated FFI and fCJD pedigrees with the characteristic D178N mutation have been reported in the Prion Diseases Registry of the Basque Country since 1993. The high incidence of familial prion diseases in this region may reflect a unique ancestral origin of the chromosome carrying this mutation. In order to investigate this putative founder effect, we developed happy typing , a new approach to the happy mapping method, which consists of the physical isolation of large haploid genomic DNA fragments and their analysis by the Polymerase Chain Reaction in order to perform haplotypic analysis instead of pedigree analysis. Six novel microsatellite markers, located in a 150-kb genomic segment flanking the PRNP gene were characterized for typing haploid DNA fragments of 285 kb in size. A common haplotype was found in patients from the Basque region, strongly suggesting a founder effect. We propose that happy typing constitutes an efficient method for determining disease-associated haplotypes, since the analysis of a single affected individual per pedigree should provide sufficient evidence. |
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