title: Two p16 (CDKN2A) germline mutations in 30 Israeli melanoma families.
abstract: Germline mutations in the p16 (CDKN2A) tumour suppressor gene have been linked to inherited predisposition to malignant melanoma (MM). Variable frequencies of p16 germline mutations were reported in different collections of melanoma families but it can be as high as 50%. Here we describe the results of p16 mutation screening in 30 melanoma kindreds in Israel. The entire coding region of the p16 gene, including exons 1, 2 and 3, flanking exon/intron junctions, and a portion of the 3' untranslated (UTR) region of the gene were examined by single-stranded conformation polymorphism (SSCP) analysis and direct sequencing. Two p16 germline mutations were identified: G101W, which has been previously observed in a number of melanoma kindreds, and G122V, a novel missense mutation. Thus, the frequency of mutations identified in this collection of Israeli families was 7%. Functional analysis indicated that the novel G122V variant retained some capacity to interact with cyclin dependent kinases (CDKs) in vitro, yet it was significantly impaired in its ability to cause a G1 cell cycle arrest in human diploid fibroblasts. This partial loss of function is consistent with the predicted impact of G122V substitution on the 3-dimensional structure of the p16 protein.
authors.affiliation: Laboratory of Clinical Biochemistry, Tel Aviv University Sourasky Medical Center, Israel.
authors.forename: E
authors.initials: E
authors.lastname: Yakobson
authors.forename: P
authors.initials: P
authors.lastname: Shemesh
authors.forename: E
authors.initials: E
authors.lastname: Azizi
authors.forename: E
authors.initials: E
authors.lastname: Winkler
authors.forename: N
authors.initials: N
authors.lastname: Lassam
authors.forename: D
authors.initials: D
authors.lastname: Hogg
authors.forename: S
authors.initials: S
authors.lastname: Brookes
authors.forename: G
authors.initials: G
authors.lastname: Peters
authors.forename: M
authors.initials: M
authors.lastname: Lotem
authors.forename: A
authors.initials: A
authors.lastname: Zlotogorski
authors.forename: M
authors.initials: M
authors.lastname: Landau
authors.forename: M
authors.initials: M
authors.lastname: Safro
authors.forename: R
authors.initials: R
authors.lastname: Shafir
authors.forename: E
authors.initials: E
authors.lastname: Friedman
authors.forename: H
authors.initials: H
authors.lastname: Peretz
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019943:Amino Acid Substitution; D001665:Binding Sites; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D019942:Genes, p16 / Q000235:genetics*; D005820:Genetic Testing; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D007557:Israel / Q000453:epidemiology; D008297:Male; D008545:Melanoma / Q000208:ethnology / Q000235:genetics*; D008875:Middle Aged; D008958:Models, Molecular; D010375:Pedigree; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D017422:Sequence Analysis, DNA; D012878:Skin Neoplasms / Q000208:ethnology / Q000235:genetics*