Ancestral origins of the prion protein gene D178N mutation in the Basque Country.
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.
Rodríguez-Martínez
Ana B
AB
Unidad de Genómica: Banco de ADN y Genotipado, Facultad de Farmacia, Universidad del País Vasco, Vitoria-Gasteiz, Spain.
Barreau
Christian
C
Coupry
Isabelle
I
Yagüe
Jordi
J
Sánchez-Valle
Raquel
R
Galdós-Alcelay
Luis
L
Ibáñez
Agustín
A
Digón
Antón
A
Fernández-Manchola
Ignacio
I
Goizet
Cyril
C
Castro
Azucena
A
Cuevas
Nerea
N
Alvarez-Alvarez
Maite
M
de Pancorbo
Marian M
MM
Arveiler
Benoît
B
Zarranz
Juan J
JJ
D000682:Amyloid / Q000235:genetics*; D007562:Creutzfeldt-Jakob Syndrome / Q000235:genetics*; D004249:DNA Damage; D018703:Founder Effect; D005828:Genetics, Population; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D040582:Inheritance Patterns; D034062:Insomnia, Fatal Familial / Q000235:genetics*; D016133:Polymerase Chain Reaction; D000072002:Prion Proteins; D011328:Prions; D011498:Protein Precursors / Q000235:genetics*; D012042:Registries / Q000706:statistics & numerical data*; D013030:Spain
D000682:Amyloid; C512656:PRNP protein, human; D000072002:Prion Proteins; D011328:Prions; D011498:Protein Precursors