Multiple self-healing squamous epithelioma is caused by a disease-specific spectrum of mutations in TGFBR1

Nat Genet. 2011 Feb 27;43(4):365-9. doi: 10.1038/ng.780.

Abstract

Multiple self-healing squamous epithelioma (MSSE), also known as Ferguson-Smith disease (FSD), is an autosomal-dominant skin cancer condition characterized by multiple squamous-carcinoma-like locally invasive skin tumors that grow rapidly for a few weeks before spontaneously regressing, leaving scars. High-throughput genomic sequencing of a conservative estimate (24.2 Mb) of the disease locus on chromosome 9 using exon array capture identified independent mutations in TGFBR1 in three unrelated families. Subsequent dideoxy sequencing of TGFBR1 identified 11 distinct monoallelic mutations in 18 affected families, firmly establishing TGFBR1 as the causative gene. The nature of the sequence variants, which include mutations in the extracellular ligand-binding domain and a series of truncating mutations in the kinase domain, indicates a clear genotype-phenotype correlation between loss-of-function TGFBR1 mutations and MSSE. This distinguishes MSSE from the Marfan syndrome-related disorders in which missense mutations in TGFBR1 lead to developmental defects with vascular involvement but no reported predisposition to cancer.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Base Sequence
  • Carcinoma / genetics
  • Carcinoma / metabolism
  • Codon, Nonsense
  • Conserved Sequence
  • DNA Primers / genetics
  • Female
  • Frameshift Mutation
  • Genetic Association Studies
  • Haplotypes
  • Humans
  • Keratoacanthoma / genetics
  • Keratoacanthoma / metabolism
  • Male
  • Marfan Syndrome / genetics
  • Models, Molecular
  • Molecular Sequence Data
  • Mutant Proteins / chemistry
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism
  • Mutation*
  • Mutation, Missense
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases / chemistry
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Serine-Threonine Kinases / metabolism
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / chemistry
  • Receptors, Transforming Growth Factor beta / genetics*
  • Receptors, Transforming Growth Factor beta / metabolism
  • Sequence Homology, Amino Acid
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / metabolism

Substances

  • Codon, Nonsense
  • DNA Primers
  • Mutant Proteins
  • Receptors, Transforming Growth Factor beta
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type I
  • TGFBR1 protein, human

Supplementary concepts

  • Keratoacanthoma familial

Associated data

  • RefSeq/NM_001024847
  • RefSeq/NM_004612
  • RefSeq/NP_001015961
  • RefSeq/NP_004603
  • RefSeq/NP_036907
  • RefSeq/NP_571065
  • RefSeq/NT_008470
  • RefSeq/NT_022517