Loss-of-Function Mutations in the Keratin 5 Gene Lead to Dowling-Degos Disease

• Published in: American journal of human genetics Vol. 78; no. 3; pp. 510 - 519
• Main Authors: Betz, Regina C., Planko, Laura, Eigelshoven, Sibylle, Hanneken, Sandra, Pasternack, Sandra M., Büssow, Heinrich, Van Den Bogaert, Kris, Wenzel, Joerg, Braun-Falco, Markus, Rütten, Arno, Rogers, Michael A., Ruzicka, Thomas, Nöthen, Markus M., Magin, Thomas M., Kruse, Roland
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01.03.2006; University of Chicago Press; Cell Press; The American Society of Human Genetics
• Subjects: Base Sequence; Biological and medical sciences; Biological Transport; Cell Adhesion - genetics; Chromosomes, Human, Pair 12 - genetics; Deoxyribonucleic acid; Dermatology; DNA; Epidermolysis Bullosa Simplex - genetics; Epidermolysis Bullosa Simplex - pathology; Female; General aspects. Genetic counseling; Genes; Genetics; Haploidy; Humans; Keratin-5; Keratins - analysis; Keratins - genetics; Male; Medical genetics; Medical sciences; Melanosomes - metabolism; Molecular Sequence Data; Mutation; Mutation, Missense; Organelles - metabolism; Pedigree; Pigmentary diseases of the skin; Skin - chemistry; Skin - pathology; Skin diseases; Human; Dowling Degos disease; Loss function; Keratin; Skin disease; Gene; Genetics; Mutation
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/500850

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 (θ=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.