Homozygous TRPV4 loss-of-function mutation causes a severe form of distal Hereditary Motor Neuropathy (dHMN)

Objective: Hereditary neuropathies form a group of genetic disorders with a broad range of phenotypes, mode of inheritance and causative genes. The objective of this study is to identify the genetic cause of disease in a congenital form of distal hereditary motor neuropathy (dHMN). Methods: A 2-year-old boy was diagnosed with arthrogryposis multiplex congenital, severe skeletal abnormalities, torticollis, vocal cord paralysis and diminished lower limb movement. Whole exome sequencing was performed on the proband and family members. Structure modeling and functional studies were performed to validate pathogenicity of the identified variant. Results: Whole exome sequencing revealed a biallelic homozygous mutation in the TRPV4 gene (c.281C>T; p.S94L). The identification of a novel recessive mutation in TRPV4 extends the spectrum of mutations in recessive forms of the TRPV4-associated disease. Structural modeling and functional studies were performed on p.S94L and other previously identified TRPV4 variants in different protein domains. 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 alternations in trafficking and/or channel sensitivity. Functional studies show that p.S94L reduces TRPV4 protein stability and therefore involves a loss-of-function mechanism. Conclusion: This study identifies a novel biallelic mutation in TRPV4 as a cause of the recessive form of congenital form of distal hereditary motor neuropathy (dHMN).