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A novel TRPA1 variant is associated with carbamazepine‐responsive cramp‐fasciculation syndrome
Author(s) -
Nirenberg M.J.,
Chaouni R.,
Biller T.M.,
Gilbert R.M.,
PaisánRuiz C.
Publication year - 2018
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/cge.13040
Subject(s) - channelopathy , fasciculation , medicine , transient receptor potential channel , hyperreflexia , exome sequencing , anesthesia , genetics , receptor , mutation , gene , biology
Cramp‐fasciculation syndrome ( CFS ) is a rare muscle hyperexcitability syndrome that presents with muscle cramps, fasciculations, and stiffness, as well as pain, fatigue, anxiety, hyperreflexia, and paresthesias. Although familial cases have been reported, a genetic etiology has not yet been identified. We performed whole‐exome sequencing followed by validation and cosegregation analyses on a father‐son pair with CFS . Both subjects manifested other hypersensitivity‐hyperexcitability symptoms, including asthma, gastroesophageal reflux, migraine, restless legs syndrome, tremor, cold hyperalgesia, and cardiac conduction defects. Most symptoms improved with carbamazepine, consistent with an underlying cation channelopathy. We identified a variant in the transient receptor potential ankyrin A1 channel ( TRPA1 ) gene that selectively cosegregated with CFS and the other hypersensitivity‐hyperexcitability symptoms. This variant (c. 2755C >T) resulted in a premature stop codon at amino acid 919 (p.Arg919*) in the outer pore of the channel. TRPA1 is a widely distributed, promiscuous plasmalemmal cation channel that is strongly implicated in the pathophysiology of the specific hypersensitivity‐hyperexcitability symptoms observed in these subjects. Thus, we have identified a novel TRPA1 variant that is associated with CFS as part of a generalized hypersensitivity‐hyperexcitability disorder. These findings clarify the diverse functional roles of TRPA1 , and underscore the importance of this channel as a potential therapeutic target.