PT  - JOURNAL ARTICLE
AU  - Jose Velilla
AU  - Michael Mario Marchetti
AU  - Agnes Toth-Petroczy
AU  - Claire Grosgogeat
AU  - Alexis H. Bennett
AU  - Nikkola Carmichael
AU  - Elicia Estrella
AU  - Basil T. Darras
AU  - Natasha Y. Frank
AU  - Joel Krier
AU  - Rachelle Gaudet
AU  - Vandana A. Gupta
ED  - ,
TI  - Homozygous <em>TRPV4</em> mutation causes congenital distal spinal muscular atrophy and arthrogryposis
AID  - 10.1212/NXG.0000000000000312
DP  - 2019 Apr 01
TA  - Neurology Genetics
PG  - e312
VI  - 5
IP  - 2
4099  - http://ng.neurology.org/content/5/2/e312.short
4100  - http://ng.neurology.org/content/5/2/e312.full
SO  - Neurol Genet2019 Apr 01; 5
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