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

David R Goudie, Mariella D'Alessandro, Barry Merriman, Hane Lee, Ildikó Szeverényi, Stuart Avery, Brian D O'Connor, Stanley F Nelson, Stephanie E Coats, Arlene Stewart, Lesley Christie, Gabriella Pichert, Jean Friedel, Ian Hayes, Nigel Burrows, Sean Whittaker, Anne-Marie Gerdes, Sigurd Broesby-Olsen, Malcolm A Ferguson-Smith, Chandra VermaDeclan P Lunny, Bruno Reversade, E Birgitte Lane

Research output: Contribution to journalLetterResearchpeer-review

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.
Original languageEnglish
JournalNature Genetics
Volume43
Issue number4
Pages (from-to)365-9
Number of pages5
ISSN1061-4036
DOIs
Publication statusPublished - 2011

Keywords

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

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  • Cite this

    Goudie, D. R., D'Alessandro, M., Merriman, B., Lee, H., Szeverényi, I., Avery, S., O'Connor, B. D., Nelson, S. F., Coats, S. E., Stewart, A., Christie, L., Pichert, G., Friedel, J., Hayes, I., Burrows, N., Whittaker, S., Gerdes, A-M., Broesby-Olsen, S., Ferguson-Smith, M. A., ... Lane, E. B. (2011). Multiple self-healing squamous epithelioma is caused by a disease-specific spectrum of mutations in TGFBR1. Nature Genetics, 43(4), 365-9. https://doi.org/10.1038/ng.780