Loss-of-function mutations in the keratin 5 gene lead to Dowling-Degos disease

Am J Hum Genet. 2006 Mar;78(3):510-9. doi: 10.1086/500850. Epub 2006 Jan 19.


Dowling-Degos disease (DDD) is an autosomal dominant genodermatosis characterized by progressive and disfiguring reticulate hyperpigmentation of the flexures. We performed a genomewide linkage analysis of two German families and mapped DDD to chromosome 12q, with a total LOD score of 4.42 ( theta =0.0) for marker D12S368. This region includes the keratin gene cluster, which we screened for mutations. We identified loss-of-function mutations in the keratin 5 gene (KRT5) in all affected family members and in six unrelated patients with DDD. These represent the first identified mutations that lead to haploinsufficiency in a keratin gene. The identification of loss-of-function mutations, along with the results from additional functional studies, suggest a crucial role for keratins in the organization of cell adhesion, melanosome uptake, organelle transport, and nuclear anchorage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Biological Transport
  • Cell Adhesion / genetics
  • Chromosomes, Human, Pair 12 / genetics*
  • Epidermolysis Bullosa Simplex / genetics*
  • Epidermolysis Bullosa Simplex / pathology
  • Female
  • Haploidy
  • Humans
  • Keratin-5
  • Keratins / analysis
  • Keratins / genetics*
  • Male
  • Melanosomes / metabolism
  • Molecular Sequence Data
  • Mutation, Missense*
  • Organelles / metabolism
  • Pedigree
  • Skin / chemistry
  • Skin / pathology


  • KRT5 protein, human
  • Keratin-5
  • Keratins

Associated data

  • RefSeq/NM_000424
  • RefSeq/NP_000415