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Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma.
- Source :
-
Nature genetics [Nat Genet] 2014 May; Vol. 46 (5), pp. 482-6. Date of Electronic Publication: 2014 Mar 30. - Publication Year :
- 2014
-
Abstract
- Although CDKN2A is the most frequent high-risk melanoma susceptibility gene, the underlying genetic factors for most melanoma-prone families remain unknown. Using whole-exome sequencing, we identified a rare variant that arose as a founder mutation in the telomere shelterin gene POT1 (chromosome 7, g.124493086C>T; p.Ser270Asn) in five unrelated melanoma-prone families from Romagna, Italy. Carriers of this variant had increased telomere lengths and numbers of fragile telomeres, suggesting that this variant perturbs telomere maintenance. Two additional rare POT1 variants were identified in all cases sequenced in two separate Italian families, one variant per family, yielding a frequency for POT1 variants comparable to that for CDKN2A mutations in this population. These variants were not found in public databases or in 2,038 genotyped Italian controls. We also identified two rare recurrent POT1 variants in US and French familial melanoma cases. Our findings suggest that POT1 is a major susceptibility gene for familial melanoma in several populations.
- Subjects :
- Amino Acid Sequence
Base Sequence
Computational Biology
Exome genetics
France
Humans
In Situ Hybridization, Fluorescence
Italy
Molecular Sequence Data
Pedigree
Sequence Alignment
Sequence Analysis, DNA
Shelterin Complex
Skin Neoplasms
Telomere-Binding Proteins chemistry
United States
Melanoma, Cutaneous Malignant
Genetic Predisposition to Disease genetics
Melanoma genetics
Models, Molecular
Mutation, Missense genetics
Neoplasms, Connective Tissue genetics
Telomere Homeostasis genetics
Telomere-Binding Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1546-1718
- Volume :
- 46
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Nature genetics
- Publication Type :
- Academic Journal
- Accession number :
- 24686846
- Full Text :
- https://doi.org/10.1038/ng.2941