title: Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome.
abstract: Olmsted syndrome (OS) is a rare congenital disorder characterized by palmoplantar and periorificial keratoderma, alopecia in most cases, and severe itching. The genetic basis for OS remained unidentified. Using whole-exome sequencing of case-parents trios, we have identified a de novo missense mutation in TRPV3 that produces p.Gly573Ser in an individual with OS. Nucleotide sequencing of five additional affected individuals also revealed missense mutations in TRPV3 (which produced p.Gly573Ser in three cases and p.Gly573Cys and p.Trp692Gly in one case each). Encoding a transient receptor potential vanilloid-3 cation channel, TRPV3 is primarily expressed in the skin, hair follicles, brain, and spinal cord. In transfected HEK293 cells expressing TRPV3 mutants, much larger inward currents were recorded, probably because of the constitutive opening of the mutants. These gain-of-function mutations might lead to elevated apoptosis of keratinocytes and consequent skin hyperkeratosis in the affected individuals. Our findings suggest that TRPV3 plays essential roles in skin keratinization, hair growth, and possibly itching sensation in humans and selectively targeting TRPV3 could provide therapeutic potential for keratinization or itching-related skin disorders.
authors.affiliation: Department of Dermatology, Peking University First Hospital, Beijing, China.
authors.forename: Zhimiao
authors.initials: Z
authors.lastname: Lin
authors.forename: Quan
authors.initials: Q
authors.lastname: Chen
authors.forename: Mingyang
authors.initials: M
authors.lastname: Lee
authors.forename: Xu
authors.initials: X
authors.lastname: Cao
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Donglai
authors.initials: D
authors.lastname: Ma
authors.forename: Long
authors.initials: L
authors.lastname: Chen
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Hu
authors.forename: Huijun
authors.initials: H
authors.lastname: Wang
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Wang
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.forename: Xuanzhu
authors.initials: X
authors.lastname: Liu
authors.forename: Liping
authors.initials: L
authors.lastname: Guan
authors.forename: Yiquan
authors.initials: Y
authors.lastname: Tang
authors.forename: Haizhen
authors.initials: H
authors.lastname: Yang
authors.forename: Ping
authors.initials: P
authors.lastname: Tu
authors.forename: Dingfang
authors.initials: D
authors.lastname: Bu
authors.forename: Xuejun
authors.initials: X
authors.lastname: Zhu
authors.forename: KeWei
authors.initials: K
authors.lastname: Wang
authors.forename: Ruoyu
authors.initials: R
authors.lastname: Li
authors.forename: Yong
authors.initials: Y
authors.lastname: Yang
mesh_terms: D000293:Adolescent; D000328:Adult; D000505:Alopecia / Q000235:genetics*; D000595:Amino Acid Sequence; D017209:Apoptosis / Q000235:genetics; D002461:Cell Line, Transformed; D002648:Child; D059472:Exome; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007645:Keratoderma, Palmoplantar / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D011537:Pruritus / Q000235:genetics*; D013577:Syndrome; D050916:TRPV Cation Channels / Q000235:genetics*; D014162:Transfection / Q000379:methods; D055815:Young Adult
chemical_list: D050916:TRPV Cation Channels; C459445:TRPV3 protein, human