title: 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.affiliation: Institute of Human Genetics, University of Bonn, D-53111 Bonn, Germany. regina.betz@uni-bonn.de
authors.forename: Regina C
authors.initials: RC
authors.lastname: Betz
authors.forename: Laura
authors.initials: L
authors.lastname: Planko
authors.forename: Sibylle
authors.initials: S
authors.lastname: Eigelshoven
authors.forename: Sandra
authors.initials: S
authors.lastname: Hanneken
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Pasternack
authors.forename: Heinrich
authors.initials: H
authors.lastname: Bussow
authors.forename: Kris
authors.initials: K
authors.lastname: Van Den Bogaert
authors.forename: Joerg
authors.initials: J
authors.lastname: Wenzel
authors.forename: Markus
authors.initials: M
authors.lastname: Braun-Falco
authors.forename: Arno
authors.initials: A
authors.lastname: Rutten
authors.forename: Michael A
authors.initials: MA
authors.lastname: Rogers
authors.forename: Thomas
authors.initials: T
authors.lastname: Ruzicka
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Magin
authors.forename: Roland
authors.initials: R
authors.lastname: Kruse
mesh_terms: D001483:Base Sequence; D001692:Biological Transport; D002448:Cell Adhesion / Q000235:genetics; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics*; D016110:Epidermolysis Bullosa Simplex / Q000235:genetics* / Q000473:pathology; D005260:Female; D006238:Haploidy; D006801:Humans; D053555:Keratin-5; D007633:Keratins / Q000032:analysis / Q000235:genetics*; D008297:Male; D020460:Melanosomes / Q000378:metabolism; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D015388:Organelles / Q000378:metabolism; D010375:Pedigree; D012867:Skin / Q000737:chemistry / Q000473:pathology
chemical_list: C503940:KRT5 protein, human; D053555:Keratin-5; D007633:Keratins