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

Abstract

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.

• Authors: Regina C Betz, Laura Planko, Sibylle Eigelshoven, Sandra Hanneken, Sandra M Pasternack, Heinrich Bussow, Kris Van Den Bogaert, Joerg Wenzel, Markus Braun-Falco, Arno Rutten, Michael A Rogers, Thomas Ruzicka, Markus M Nöthen, Thomas M Magin, Roland Kruse
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 78 Issue 3 Pg. 510-9 (Mar 2006) ISSN: 0002-9297 [Print] United States
• PMID: 16465624 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• KRT5 protein, human
• Keratin-5
• Keratins

Topics

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