Abstract
Transient receptor potential (TRP) channels respond to various chemical and physical stimuli by mediating cation influx. The skin expresses abundant TRP channels of different subtypes, which play an essential role in the maintenance of skin functionality. Here, we report cases of mutations in TRPM4, which encodes TRPM4, a Ca 2+ -activated monovalent cation channel, as a cause of an autosomal dominant form of progressive symmetric erythrokeratodermia. In three separate families with progressive symmetric erythrokeratodermia, we identified two missense mutations (c.3099C>G and c.3119T>C) that produce p.Ile1033Met and p.Ile1040Thr, both of which are located in the S6 transmembrane domain of the TRPM4 protein. The substitutions are expected to directly affect activation gating of TRPM4 according to the cryo-EM structures. Electrophysiological studies of the mutants showed substantial hyperactivity, as evidenced by pronounced baseline activity, enhanced sensitivity to intracellular Ca 2+ , and an elevated resting membrane potential. In vitro studies showed enhanced proliferation in keratinocytes overexpressing either of the mutants. We also detected an up-regulation of markers for proliferation and differentiation of keratinocytes in the affected skin tissues. Our study identified TRPM4 as an important player in the pathogenesis of skin TRP channelopathies and a potential target for treatment of skin hyperkeratotic disorders.
| Original language | English (US) |
|---|---|
| Journal | Journal of Investigative Dermatology |
| DOIs | |
| State | Published - Jan 1 2019 |
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ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Dermatology
- Cell Biology
Cite this
Gain-of-Function Mutations in TRPM4 Activation Gate Cause Progressive Symmetric Erythrokeratodermia. / Wang, Huijun; Xu, Zhe; Lee, Bo Hyun; Vu, Simon; Hu, Linghan; Lee, Mingyang; Bu, Dingfang; Cao, Xu; Hwang, Samuel T; Yang, Yong; Zheng, Jie; Lin, Zhimiao.
In: Journal of Investigative Dermatology, 01.01.2019.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Gain-of-Function Mutations in TRPM4 Activation Gate Cause Progressive Symmetric Erythrokeratodermia
AU - Wang, Huijun
AU - Xu, Zhe
AU - Lee, Bo Hyun
AU - Vu, Simon
AU - Hu, Linghan
AU - Lee, Mingyang
AU - Bu, Dingfang
AU - Cao, Xu
AU - Hwang, Samuel T
AU - Yang, Yong
AU - Zheng, Jie
AU - Lin, Zhimiao
PY - 2019/1/1
Y1 - 2019/1/1
N2 - Transient receptor potential (TRP) channels respond to various chemical and physical stimuli by mediating cation influx. The skin expresses abundant TRP channels of different subtypes, which play an essential role in the maintenance of skin functionality. Here, we report cases of mutations in TRPM4, which encodes TRPM4, a Ca 2+ -activated monovalent cation channel, as a cause of an autosomal dominant form of progressive symmetric erythrokeratodermia. In three separate families with progressive symmetric erythrokeratodermia, we identified two missense mutations (c.3099C>G and c.3119T>C) that produce p.Ile1033Met and p.Ile1040Thr, both of which are located in the S6 transmembrane domain of the TRPM4 protein. The substitutions are expected to directly affect activation gating of TRPM4 according to the cryo-EM structures. Electrophysiological studies of the mutants showed substantial hyperactivity, as evidenced by pronounced baseline activity, enhanced sensitivity to intracellular Ca 2+ , and an elevated resting membrane potential. In vitro studies showed enhanced proliferation in keratinocytes overexpressing either of the mutants. We also detected an up-regulation of markers for proliferation and differentiation of keratinocytes in the affected skin tissues. Our study identified TRPM4 as an important player in the pathogenesis of skin TRP channelopathies and a potential target for treatment of skin hyperkeratotic disorders.
AB - Transient receptor potential (TRP) channels respond to various chemical and physical stimuli by mediating cation influx. The skin expresses abundant TRP channels of different subtypes, which play an essential role in the maintenance of skin functionality. Here, we report cases of mutations in TRPM4, which encodes TRPM4, a Ca 2+ -activated monovalent cation channel, as a cause of an autosomal dominant form of progressive symmetric erythrokeratodermia. In three separate families with progressive symmetric erythrokeratodermia, we identified two missense mutations (c.3099C>G and c.3119T>C) that produce p.Ile1033Met and p.Ile1040Thr, both of which are located in the S6 transmembrane domain of the TRPM4 protein. The substitutions are expected to directly affect activation gating of TRPM4 according to the cryo-EM structures. Electrophysiological studies of the mutants showed substantial hyperactivity, as evidenced by pronounced baseline activity, enhanced sensitivity to intracellular Ca 2+ , and an elevated resting membrane potential. In vitro studies showed enhanced proliferation in keratinocytes overexpressing either of the mutants. We also detected an up-regulation of markers for proliferation and differentiation of keratinocytes in the affected skin tissues. Our study identified TRPM4 as an important player in the pathogenesis of skin TRP channelopathies and a potential target for treatment of skin hyperkeratotic disorders.
UR - http://www.scopus.com/inward/record.url?scp=85061567021&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85061567021&partnerID=8YFLogxK
U2 - 10.1016/j.jid.2018.10.044
DO - 10.1016/j.jid.2018.10.044
M3 - Article
C2 - 30528822
AN - SCOPUS:85061567021
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
SN - 0022-202X
ER -