title: A single Mediterranean, possibly Jewish, origin for the Val59Gly CDKN2A mutation in four melanoma-prone families.
abstract: 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.
authors.affiliation: Clinical Biochemistry Laboratory, Tel Aviv Sourasky Medical Center, 6 Weizmann Street, Tel Aviv 64239, Israel.
authors.forename: Emanuel
authors.initials: E
authors.lastname: Yakobson
authors.forename: Shlomit
authors.initials: S
authors.lastname: Eisenberg
authors.forename: Ruth
authors.initials: R
authors.lastname: Isacson
authors.forename: David
authors.initials: D
authors.lastname: Halle
authors.forename: Efrat
authors.initials: E
authors.lastname: Levy-Lahad
authors.forename: Raphael
authors.initials: R
authors.lastname: Catane
authors.forename: Mark
authors.initials: M
authors.lastname: Safro
authors.forename: Vladimir
authors.initials: V
authors.lastname: Sobolev
authors.forename: Thomas
authors.initials: T
authors.lastname: Huot
authors.forename: Gordon
authors.initials: G
authors.lastname: Peters
authors.forename: Anna
authors.initials: A
authors.lastname: Ruiz
authors.forename: Josep
authors.initials: J
authors.lastname: Malvehy
authors.forename: Suzana
authors.initials: S
authors.lastname: Puig
authors.forename: Agnes
authors.initials: A
authors.lastname: Chompret
authors.forename: Marie-Fracoise
authors.initials: MF
authors.lastname: Avril
authors.forename: Raphael
authors.initials: R
authors.lastname: Shafir
authors.forename: Hava
authors.initials: H
authors.lastname: Peretz
authors.forename: Brigitte
authors.initials: B
authors.lastname: Bressac-de Paillerets
mesh_terms: 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
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16