title: Whole-exome sequencing identifies ADAM10 mutations as a cause of reticulate acropigmentation of Kitamura, a clinical entity distinct from Dowling-Degos disease.
abstract: Reticulate acropigmentation of Kitamura (RAK) is a rare genetic disorder of cutaneous pigmentation with an autosomal dominant pattern of inheritance and a high penetration rate. The characteristic skin lesions are reticulate, slightly depressed pigmented macules mainly affecting the dorsa of the hands and feet, which first appear before puberty and subsequently expand to the proximal limb and the trunk. To identify mutations that cause RAK, we performed exome sequencing of four family members in a pedigree with RAK. Fifty-three SNV/Indels were considered as candidate mutations after some condition narrowing. We confirmed the mutation status in each candidate gene of four other members in the same pedigree to find the gene that matched the mutation status and phenotype of each member. A mutation in ADAM10 encoding a zinc metalloprotease, a disintegrin and metalloprotease domain-containing protein 10 (ADAM10), was identified in the RAK family. ADAM10 is known to be involved in the ectodomain shedding of various substrates in the skin. Sanger sequencing of four additional unrelated RAK patients revealed four additional ADAM10 mutations. We identified a total of three truncating mutations, a splice site mutation and a missense mutation in ADAM10. We searched for mutations in the KRT5 gene, a causative gene for the similar pigmentation disorder Dowling-Degos disease (DDD), in all the patients and found no KRT5 mutation. These results reveal that mutations in ADAM10 are a cause of RAK and that RAK is an independent clinical entity distinct from DDD.
authors.affiliation: Department of Dermatology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Michihiro
authors.initials: M
authors.lastname: Kono
authors.forename: Kazumitsu
authors.initials: K
authors.lastname: Sugiura
authors.forename: Mutsumi
authors.initials: M
authors.lastname: Suganuma
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hayashi
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Takama
authors.forename: Tamio
authors.initials: T
authors.lastname: Suzuki
authors.forename: Kayoko
authors.initials: K
authors.lastname: Matsunaga
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Tomita
authors.forename: Masashi
authors.initials: M
authors.lastname: Akiyama
mesh_terms: D051722:ADAM Proteins / Q000235:genetics* / Q000378:metabolism*; D000072197:ADAM10 Protein; D000328:Adult; D000368:Aged; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics* / Q000378:metabolism*; D002478:Cells, Cultured; D059472:Exome; D005260:Female; D006801:Humans; D017495:Hyperpigmentation / Q000235:genetics* / Q000503:physiopathology; D054643:INDEL Mutation; D053555:Keratin-5 / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D010802:Phylogeny; D017422:Sequence Analysis, DNA; D020539:Sequence Analysis, Protein; D012873:Skin Diseases, Genetic / Q000235:genetics* / Q000503:physiopathology; D017444:Skin Diseases, Papulosquamous / Q000235:genetics* / Q000503:physiopathology; D055815:Young Adult
chemical_list: C503940:KRT5 protein, human; D053555:Keratin-5; D008565:Membrane Proteins; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human