RT Journal Article SR Electronic T1 Homozygous TRPV4 mutation causes congenital distal spinal muscular atrophy and arthrogryposis JF Neurology Genetics JO Neurol Genet FD Lippincott Williams & Wilkins SP e312 DO 10.1212/NXG.0000000000000312 VO 5 IS 2 A1 Jose Velilla A1 Michael Mario Marchetti A1 Agnes Toth-Petroczy A1 Claire Grosgogeat A1 Alexis H. Bennett A1 Nikkola Carmichael A1 Elicia Estrella A1 Basil T. Darras A1 Natasha Y. Frank A1 Joel Krier A1 Rachelle Gaudet A1 Vandana A. Gupta A1 , YR 2019 UL http://ng.neurology.org/content/5/2/e312.abstract AB Objective To identify the genetic cause of disease in a form of congenital spinal muscular atrophy and arthrogryposis (CSMAA).Methods A 2-year-old boy was diagnosed with arthrogryposis multiplex congenita, severe skeletal abnormalities, torticollis, vocal cord paralysis, and diminished lower limb movement. Whole-exome sequencing (WES) was performed on the proband and family members. In silico modeling of protein structure and heterologous protein expression and cytotoxicity assays were performed to validate pathogenicity of the identified variant.Results WES revealed a homozygous mutation in the TRPV4 gene (c.281C>T; p.S94L). The identification of a recessive mutation in TRPV4 extends the spectrum of mutations in recessive forms of the TRPV4-associated disease. p.S94L and other previously identified TRPV4 variants in different protein domains were compared in structural modeling and functional studies. In silico structural modeling suggests that the p.S94L mutation is in the disordered N-terminal region proximal to important regulatory binding sites for phosphoinositides and for PACSIN3, which could lead to alterations in trafficking and/or channel sensitivity. Functional studies by Western blot and immunohistochemical analysis show that p.S94L increased TRPV4 activity-based cytotoxicity and resultant decreased TRPV4 expression levels, therefore involves a gain-of-function mechanism.Conclusions This study identifies a novel homozygous mutation in TRPV4 as a cause of the recessive form of CSMAA.CMT=Charcot-Marie-Tooth; cryoEM=cryoelectron microscopy; CSMAA=congenital spinal muscular atrophy and arthrogryposis; dHMN=distal hereditary motor neuropathy; PIP2=phosphatidylinositol 4,5-bisphosphate; PRR=proline-rich region; SPSMA=scapuloperoneal spinal muscular atrophy; TRPV=transient receptor potential vanilloid; WES=whole-exome sequencing; WT=wild-type