Gain-of-Function Mutations in TRPM4 Activation Gate Cause Progressive Symmetric Erythrokeratodermia

J Invest Dermatol. 2019 May;139(5):1089-1097. doi: 10.1016/j.jid.2018.10.044.

Huijun Wang ¹, Zhe Xu ², Bo Hyun Lee ³, Simon Vu ³, Linghan Hu ¹, Mingyang Lee ⁴, Dingfang Bu ⁴, Xu Cao ⁴, Samuel Hwang ⁵, Yong Yang ⁶, Jie Zheng ⁷, Zhimiao Lin ⁸

Affiliations

1 Department of Dermatology, Peking University First Hospital, Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China; Peking-Tsinghua Center for Life Sciences, Beijing, China; Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.
2 Department of Dermatology, Shunyi Maternal and Children's Hospital of Beijing Children's Hospital, Beijing, China; Department of Dermatology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.
3 Department of Physiology and Membrane Biology, University of California-Davis, Davis, California, USA.
4 Department of Dermatology, Peking University First Hospital, Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China.
5 Department of Dermatology, University of California-Davis, Davis, California, USA.
6 Department of Dermatology, Peking University First Hospital, Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China; Peking-Tsinghua Center for Life Sciences, Beijing, China.
7 Department of Physiology and Membrane Biology, University of California-Davis, Davis, California, USA. Electronic address: jzheng@ucdavis.edu.
8 Department of Dermatology, Peking University First Hospital, Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China. Electronic address: zhimiaolin@bjmu.edu.cn.

PMID: 30528822 DOI: 10.1016/j.jid.2018.10.044

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 CA²⁺-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 CA²⁺, 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.

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