Identification of a novel TRPA1 mutation associated with carbamazepine-responsive cramp-fasciculation syndrome (S45.008)

Objective: To identify a genetic cause for familial cramp-fasciculation syndrome (CFS). Background: CFS is a muscle hyperexcitability syndrome that may present not only with muscle cramps, stiffness, and fasciculations, but also with pain, generalized fatigue, anxiety, hyperreflexia, and paresthesias. The clinical features of CFS and improvement with carbamazepine suggest that it may represent a cation channelopathy. Although familial cases have been reported, a genetic etiology for CFS has yet to be identified. Design/Methods: Whole exome sequencing was performed on a father-son pair with carbamazepine-responsive CFS. After filtering for common genetic variations, only seven candidate single nucleotide variants were validated and found to be present in both affected subjects. Disease segregation analyses carried out in four unaffected family members were used to reduce this to a single disease-segregating mutation. An ethnicity-matched control population was used to assess the pathogenicity of this mutation. Results: We identified a novel mutation in the transient receptor potential ankyrin 1 ion channel ( TRPA1; MIM #615040) gene in subjects with CFS. This disease-segregating TRPA1 mutation (c.2755C>T) resulted in a premature stop codon at amino-acid 919 (p.Arg919Stop), and was found to be absent in the control population. TRPA1 is a widely distributed, promiscuous plasmalemmal cation channel activated by endogenous and environmental irritants. TRPA1 has been associated with the pathogenesis of pain, paresthesias, and inflammation, and is therefore under investigation as a potential therapeutic target for pain and muscle cramps. The identified mutation was localized to the putative selectivity filter of TRPA1 , a region implicated in the pore dilatation process, and thus the degree to which TRPA1 is activated by noxious stimuli. Conclusions: Autosomal dominant CFS is associated with a novel mutation in the putative selectivity filter of TRPA1 . These findings further clarify the functional role of human TRPA1 , and underscore the importance of this ion channel as a potential therapeutic target. Study Supported by: This work was supported by the National Institute of Neurological Disorders and Stroke of the National Institute of Health (R01NS079388). MJN also receives support from the New York Stem Cell Foundation. Disclosure: Dr. Biller has nothing to disclose. Dr. Paisan-Ruiz has nothing to disclose. Dr. Gilbert has nothing to disclose. Dr. Chaouni has nothing to disclose. Dr. Nirenberg has nothing to disclose.