A single Mediterranean, possibly Jewish, origin for the Val59Gly CDKN2A mutation in four melanoma-prone families.
We have screened for CDKN2A germline mutations in 49 Jewish families with two or more cases of melanoma. The Val59Gly mutation, one of the three different alterations identified among these families, was also detected independently in two kindreds from France and one from Spain. The impact of the Val59Gly substitution on the function of the cyclin-dependent kinase inhibitor p16(INK4a), a product of the CDKN2A gene, was assessed by protein-protein interaction and cell proliferation assays and related to potential structural alterations predicted by molecular modeling. Seven microsatellite markers in the vicinity of the CDKN2A gene were used to determine whether the mutation in these families is identical by descent, or represents a mutational hotspot in the CDKN2A gene. Our results show that the Val59Gly substitution impairs p16(INK4a) function, and this dysfunction is consistent with structural predictions. All melanoma-affected individuals tested in the families under study harbor this mutation. Interestingly, the Israeli pedigree includes an affected individual who is homozygous for the Val59Gly mutation. A common haplotype of microsatellite markers has been demonstrated for mutation carriers in all four pedigrees. The Israeli pedigree and one of the French melanoma families are of Moroccan and Tunisian Jewish descent, respectively, and the other families originate from regions of France and Spain close to the Pyrenees. We conclude that the Val59Gly mutation is a major contributor to melanoma risk in the families under study and that it may derive from a single ancestral founder of Mediterranean (possibly Jewish) origin.
Yakobson
Emanuel
E
Clinical Biochemistry Laboratory, Tel Aviv Sourasky Medical Center, 6 Weizmann Street, Tel Aviv 64239, Israel.
Eisenberg
Shlomit
S
Isacson
Ruth
R
Halle
David
D
Levy-Lahad
Efrat
E
Catane
Raphael
R
Safro
Mark
M
Sobolev
Vladimir
V
Huot
Thomas
T
Peters
Gordon
G
Ruiz
Anna
A
Malvehy
Josep
J
Puig
Suzana
S
Chompret
Agnes
A
Avril
Marie-Fracoise
MF
Shafir
Raphael
R
Peretz
Hava
H
Bressac-de Paillerets
Brigitte
B
D002874:Chromosome Mapping; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000737:chemistry*; D019942:Genes, p16; D020022:Genetic Predisposition to Disease; D006801:Humans; D007585:Jews / Q000235:genetics*; D019083:Mediterranean Region; D008545:Melanoma / Q000235:genetics*; D018895:Microsatellite Repeats; D010375:Pedigree; D018807:Polymorphism, Single-Stranded Conformational; D011487:Protein Conformation
D019941:Cyclin-Dependent Kinase Inhibitor p16