A common founder mutation in FANCA underlies the world's highest prevalence of Fanconi anemia in Gypsy families from Spain.
Fanconi anemia (FA) is a genetic disease characterized by bone marrow failure and cancer predisposition. Here we have identified Spanish Gypsies as the ethnic group with the world's highest prevalence of FA (carrier frequency of 1/64-1/70). DNA sequencing of the FANCA gene in 8 unrelated Spanish Gypsy FA families after retroviral subtyping revealed a homozygous FANCA mutation (295C>T) leading to FANCA truncation and FA pathway disruption. This mutation appeared specific for Spanish Gypsies as it is not found in other Gypsy patients with FA from Hungary, Germany, Slovakia, and Ireland. Haplotype analysis showed that Spanish Gypsy patients all share the same haplotype. Our data thus suggest that the high incidence of FA among Spanish Gypsies is due to an ancestral founder mutation in FANCA that originated in Spain less than 600 years ago. The high carrier frequency makes the Spanish Gypsies a population model to study FA heterozygote mutations in cancer.
Callén
Elsa
E
Universitat Autònoma de Barcelona and the Hospital Meterno-Infantil Vall d'Hebron, Barcelona, Spain.
Casado
José A
JA
Tischkowitz
Marc D
MD
Bueren
Juan A
JA
Creus
Amadeu
A
Marcos
Ricard
R
Dasí
Angeles
A
Estella
Jesús M
JM
Muñoz
Arturo
A
Ortega
Juan J
JJ
de Winter
Johan
J
Joenje
Hans
H
Schindler
Detlev
D
Hanenberg
Helmut
H
Hodgson
Shirley V
SV
Mathew
Christopher G
CG
Surrallés
Jordi
J
D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D005192:Family Health; D005199:Fanconi Anemia / Q000453:epidemiology / Q000208:ethnology / Q000235:genetics*; D052217:Fanconi Anemia Complementation Group A Protein; D018703:Founder Effect; D006239:Haplotypes; D006801:Humans; D009154:Mutation; D017354:Point Mutation; D015995:Prevalence; D013030:Spain / Q000208:ethnology
D018389:Codon, Nonsense; D004268:DNA-Binding Proteins; C498471:FANCA protein, human; D052217:Fanconi Anemia Complementation Group A Protein