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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&gt;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.

Homozygous TRPV4 mutation causes congenital distal spinal muscular atrophy and arthrogryposis