POT1 loss-of-function variants predispose to familial melanoma

Nat Genet. 2014 May;46(5):478-481. doi: 10.1038/ng.2947. Epub 2014 Mar 30.

Abstract

Deleterious germline variants in CDKN2A account for around 40% of familial melanoma cases, and rare variants in CDK4, BRCA2, BAP1 and the promoter of TERT have also been linked to the disease. Here we set out to identify new high-penetrance susceptibility genes by sequencing 184 melanoma cases from 105 pedigrees recruited in the UK, The Netherlands and Australia that were negative for variants in known predisposition genes. We identified families where melanoma cosegregates with loss-of-function variants in the protection of telomeres 1 gene (POT1), with a proportion of family members presenting with an early age of onset and multiple primary tumors. We show that these variants either affect POT1 mRNA splicing or alter key residues in the highly conserved oligonucleotide/oligosaccharide-binding (OB) domains of POT1, disrupting protein-telomere binding and leading to increased telomere length. These findings suggest that POT1 variants predispose to melanoma formation via a direct effect on telomeres.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Australia
  • Base Sequence
  • Genetic Predisposition to Disease / genetics*
  • Humans
  • Melanoma / genetics*
  • Models, Molecular*
  • Molecular Sequence Data
  • Netherlands
  • Pedigree
  • Protein Binding
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Alignment
  • Sequence Analysis, DNA
  • Skin Neoplasms
  • Telomere / chemistry
  • Telomere / genetics
  • Telomere / metabolism*
  • Telomere-Binding Proteins / chemistry
  • Telomere-Binding Proteins / genetics*
  • Telomere-Binding Proteins / metabolism
  • United Kingdom

Substances

  • POT1 protein, human
  • Telomere-Binding Proteins

Supplementary concepts

  • Melanoma, Cutaneous Malignant