Loss-of-function mutations in the keratin 5 gene lead to Dowling-Degos disease by Betz Regina C, Planko Laura, Eigelshoven Sibylle, Hanneken Sandra, Pasternack Sandra M, Bussow Heinrich, Van Den Bogaert Kris, Wenzel Joerg, Braun-Falco Markus, Rutten Arno, Rogers Michael A, Ruzicka Thomas, Nöthen Markus M, Magin Thomas M, Kruse Roland in American journal of human genetics (2006).

[PMID: 16465624] PubMed


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.

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