The TRPV4 (transient receptor potential vanilloid 4) gene, located on chromosome 12, encodes for a protein that serves as an ion channel, typically found in the plasma membrane and is permeable to Ca2+. Abnormal regulation of Ca2+ can lead to inefficient muscle contraction. TRPV4 plays a major role in mechanosensation, as well as osmosensory functions in nerve endings, endothoelia, and alveoli. The TRPV4 protein consists of 871 amino acids with its N- and C- terminals facing intracellularly. The protein also contains six alpha helices that pass through the plasma membrane. Mutations in TRPV4 can result in the loss of its normal function, or a toxic gain of function. In the latter case, intracellular Ca2+ levels are increased, which results in abnormal regulation. Mechanism The ankyrin repeat domain (ARD) is a region located near the intracellular N-terminal of the TRPV4 protein and consists of six ankyrin repeats. Four missense mutations have been identified at three specific positions all located within the ARD. All of these mutations are due to the swapping out of arginine with a different amino acid. Arginine is highly polar and positively charged, while its replacements are less polar or nonpolar. Some of these identified amino acid substitutions are: * R296H, arginine to histidine substitution * R315W, arginine to tryptophan substitution * R316C, arginine to cysteine substitution * R594H, arginine to histidine substitution
Congenital distal spinal muscular atrophy
Congenital muscular dystrophy
Spinal muscular atrophies
Distal hereditary motor neuronopathies
Spinal muscular atrophy
Jokela type spinal muscular atrophy
Spinal muscular atrophy with lower extremity predominance 1
Monomelic amyotrophy