Loss-of-function mutations in the keratin 5 gene lead to Dowling-Degos disease.
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.
Betz
Regina C
RC
Institute of Human Genetics, University of Bonn, D-53111 Bonn, Germany. regina.betz@uni-bonn.de
Planko
Laura
L
Eigelshoven
Sibylle
S
Hanneken
Sandra
S
Pasternack
Sandra M
SM
Bussow
Heinrich
H
Van Den Bogaert
Kris
K
Wenzel
Joerg
J
Braun-Falco
Markus
M
Rutten
Arno
A
Rogers
Michael A
MA
Ruzicka
Thomas
T
Nöthen
Markus M
MM
Magin
Thomas M
TM
Kruse
Roland
R
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
C503940:KRT5 protein, human; D053555:Keratin-5; D007633:Keratins