title: Multiple self-healing squamous epithelioma is caused by a disease-specific spectrum of mutations in TGFBR1.
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.
authors.affiliation: Human Genetics Unit, University of Dundee College of Medicine, Dentistry and Nursing, Dundee, UK.
authors.forename: David R
authors.initials: DR
authors.lastname: Goudie
authors.forename: Mariella
authors.initials: M
authors.lastname: D'Alessandro
authors.forename: Barry
authors.initials: B
authors.lastname: Merriman
authors.forename: Hane
authors.initials: H
authors.lastname: Lee
authors.forename: Ildikó
authors.initials: I
authors.lastname: Szeverényi
authors.forename: Stuart
authors.initials: S
authors.lastname: Avery
authors.forename: Brian D
authors.initials: BD
authors.lastname: O'Connor
authors.forename: Stanley F
authors.initials: SF
authors.lastname: Nelson
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Coats
authors.forename: Arlene
authors.initials: A
authors.lastname: Stewart
authors.forename: Lesley
authors.initials: L
authors.lastname: Christie
authors.forename: Gabriella
authors.initials: G
authors.lastname: Pichert
authors.forename: Jean
authors.initials: J
authors.lastname: Friedel
authors.forename: Ian
authors.initials: I
authors.lastname: Hayes
authors.forename: Nigel
authors.initials: N
authors.lastname: Burrows
authors.forename: Sean
authors.initials: S
authors.lastname: Whittaker
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Gerdes
authors.forename: Sigurd
authors.initials: S
authors.lastname: Broesby-Olsen
authors.forename: Malcolm A
authors.initials: MA
authors.lastname: Ferguson-Smith
authors.forename: Chandra
authors.initials: C
authors.lastname: Verma
authors.forename: Declan P
authors.initials: DP
authors.lastname: Lunny
authors.forename: Bruno
authors.initials: B
authors.lastname: Reversade
authors.forename: E Birgitte
authors.initials: EB
authors.lastname: Lane
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism; D018389:Codon, Nonsense; D017124:Conserved Sequence; D017931:DNA Primers / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation; D056726:Genetic Association Studies; D006239:Haplotypes; D006801:Humans; D007636:Keratoacanthoma / Q000235:genetics / Q000378:metabolism; D008297:Male; D008382:Marfan Syndrome / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D020125:Mutation, Missense; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism
chemical_list: D018389:Codon, Nonsense; D017931:DNA Primers; D050505:Mutant Proteins; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human