RHBDF2 mutations are associated with tylosis, a familial esophageal cancer syndrome

Am J Hum Genet. 2012 Feb 10;90(2):340-6. doi: 10.1016/j.ajhg.2011.12.008. Epub 2012 Jan 19.


Tylosis esophageal cancer (TOC) is an autosomal-dominant syndrome characterized by palmoplantar keratoderma, oral precursor lesions, and a high lifetime risk of esophageal cancer. We have previously localized the TOC locus to a small genomic interval within chromosomal region 17q25. Using a targeted capture array and next-generation sequencing, we have now identified missense mutations (c.557T>C [p.Ile186Thr] and c.566C>T [p.Pro189Leu] in RHBDF2, which encodes the inactive rhomboid protease RHBDF2 (also known as iRhom2), as the underlying cause of TOC. We show that the distribution of RHBDF2 in tylotic skin is altered in comparison with that in normal skin, and immortalized tylotic keratinocytes have decreased levels of total epidermal growth factor receptor (EGFR) and display an increased proliferative and migratory potential relative to normal cells, even when normal cells are stimulated with exogenous epidermal growth factor. It would thus appear that EGFR signaling is dysregulated in tylotic cells. Furthermore, we also show an altered localization of RHBDF2 in both tylotic and sporadic squamous esophageal tumors. The elucidation of a role of RHBDF2 in growth-factor signaling in esophageal cancer will help to determine whether targeting this pathway in chemotherapy for this and other squamous cell carcinomas will be effective.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Carcinoma, Squamous Cell / genetics
  • Cell Growth Processes / genetics
  • Cell Movement / genetics
  • Chromosomes, Human, Pair 17 / genetics
  • ErbB Receptors / genetics
  • Esophageal Neoplasms / enzymology
  • Esophageal Neoplasms / genetics*
  • Esophageal Neoplasms / metabolism
  • Esophageal Neoplasms / pathology
  • Exons
  • Humans
  • Keratinocytes / metabolism
  • Keratoderma, Palmoplantar, Diffuse / enzymology
  • Keratoderma, Palmoplantar, Diffuse / genetics*
  • Keratoderma, Palmoplantar, Diffuse / metabolism
  • Keratoderma, Palmoplantar, Diffuse / pathology
  • Molecular Sequence Data
  • Mutation, Missense*
  • Pedigree
  • Phenotype
  • Sequence Alignment
  • Serine Endopeptidases
  • Serine Proteases / genetics*
  • Untranslated Regions


  • Untranslated Regions
  • EGFR protein, human
  • ErbB Receptors
  • Serine Proteases
  • Serine Endopeptidases
  • RHBDL2 protein, human