ClinVar

In a family with HMSN2C (606071) originally reported by Donaghy and Kennett (1999), Klein et al. (2011) identified a heterozygous 694C-T transition in exon 4 of the TRPV4 gene, resulting in an arg232-to-cys (R232C) substitution in a conserved residue in the ankyrin-repeat domain. In vitro functional expression studies showed that the mutant protein had the same subcellular localization as wildtype in HEK293 cells and localized to the plasma membrane similar to wildtype in HeLa cells. In HEK293 cells, the mutant protein caused increased agonist-induced channel activity and increased basal intracellular calcium concentrations compared to wildtype. HeLa cells expressing the mutant protein showed increased cell death, which could be suppressed by the TRPV antagonist ruthenium red. The mutation was not found in 800 controls.

Astrea et al. (2012) identified an R232C mutation in an 11-year-old girl with congenital distal spinal muscular atrophy (600175). She had proximal and distal muscle weakness, atrophy of the distal leg muscles, and clubfoot. MRI of the thighs and calf muscles showed extensive fatty atrophy with preservation of the biceps femoris in the lateral thighs and of the medial gastrocnemius in the posteromedial calves. This pattern was distinct when compared to a patient with non-TRPV4 SMA.