In human, there are many TRPV4-associated disorders (see MIM:605427), currently grouped into two classes: neuromuscular disorders and skeletal dysplasias. All exhibit autosomal dominant inheritance. This model investigates TRPV4-associated neuromuscular disorders, which include hereditary motor and sensory neuropathy, type IIC (HMSN2C, MIM:606071, FBhh0001241), neuronopathy, distal hereditary motor, autosomal dominant 8 (HMND8, MIM:600175, FBhh0001242), and scapuloperoneal spinal muscular atrophy (SPSMA, MIM:181405, FBhh0001243). HMSN2C, HMND8, and SPSMA are described as allelic disorders with overlapping phenotypes.
UAS constructs of the human Hsap\TRPV4 gene have been introduced into flies, including wild-type and variants implicated in disease. Variant(s) implicated in human disease tested (as transgenic human gene, TRPV4): R269C and R232C variant forms of the human gene have been introduced into flies. These variants are implicated in both HMSN2C and HMN8; the R269C variant is also implicated in SPSMA. See the 'Disease-Implicated Variants' table below.
Pan-neuronal expression of the Hsap\TRPV4 R269C or R232C variant results in an unexpanded wing phenotype in adults. In larvae, axonal and dendritic degeneration phenotypes and axonal mitochondrial transport defects are observed. Using suppression of the unexpanded wing phenotype for genetic screens, downstream modifiers have been identified.
A construct carrying both the R269C variant and a second mutation known to block the TRPV4 ion-conducting pore fails to produce the expanded wing and larval neurodegenerative phenotypes. Thus, neuronal dysfunction and degeneration caused by this neuropathogenic TRPV4 mutant is dependent on a functional channel pore, consistent with a gain-of-function mechanism of toxicity. TRPV4 antagonists are suggested as potential pharmaceutical therapeutics.
[updated Feb. 2024 by FlyBase; FBrf0222196]
The TRPV4-associated disorders, previously considered to be clinically distinct phenotypes before their molecular basis was discovered, are now grouped into neuromuscular disorders and skeletal dysplasias. [Gene Reviews, TRPV4-Associated Disorders; 2020.08.16]
In TRPV4-associated neuromuscular disorders, peripheral nerve degeneration results in muscle weakness, particularly of limb, diaphragm, and vocal fold muscles, the latter of which can be life threatening. They are strikingly variable in severity, ranging from severe, congenital onset to mild, late adult onset. The mutations are dominantly inherited missense mutations and each is capable of causing a wide spectrum of disease severities even within the same family (FBrf0245808 and references cited therein).
Congenital distal spinal muscular atrophy (CDSMA), scapuloperoneal spinal muscular atrophy (SPSMA), and Charcot-Marie-Tooth disease type 2C (CMT2C) are inherited degenerative diseases of the peripheral nervous system caused by mutations in the gene encoding the transient receptor potential vanilloid 4 (TRPV4) cation channel (FBrf0245808 and references cited therein).
Neuronopathy, distal hereditary motor, type VIII (HMN8) and hereditary motor and sensory neuropathy, type IIC (HMSN2C) are allelic disorders with overlapping phenotypes. Both are caused by heterozygous mutation in the TRVP4 gene. [from MIM:606071 and MIM:600175; 2020.08.16]
TRPV4 encodes a member of the OSM9-like transient receptor potential channel (OTRPC) subfamily in the transient receptor potential (TRP) superfamily of ion channels. The encoded protein is a Ca2+-permeable, nonselective cation channel that is thought to be involved in osmotic sensitivity and mechanosensitivity. [Gene Cards, TRPV4; 2020.08.16]
Many to many: multiple related genes in both species.
