TRPV4

The TRPV4 gene provides instructions for making a protein that acts as a calcium channel. This channel, which transports positively charged atoms of calcium (calcium ions) across cell membranes and into cells, is found in many types of cells and tissues. Studies suggest that the TRPV4 channel plays a role in the development of bones and cartilage, the tough but flexible tissue that makes up much of the skeleton during early development. It may also be involved in maintaining the body's water balance (osmoregulation). The TRPV4 channel likely has additional functions in other body systems, but these functions have not been identified.

Charcot-Marie-Tooth disease - caused by mutations in the TRPV4 gene

At least five mutations in the TRPV4 gene have been found to cause Charcot-Marie-Tooth disease type 2C (also called hereditary motor and sensory neuropathy type 2C). This condition affects the peripheral nerves, which connect the brain and spinal cord to muscles and to sensory cells that detect sensations such as touch, pain, heat, and sound. Charcot-Marie-Tooth disease type 2C causes problems with movement and sensation.

The TRPV4 gene mutations responsible for Charcot-Marie-Tooth disease type 2C each change a single protein building block (amino acid) in the TRPV4 calcium channel. Studies suggest that these mutations overactivate the channel, increasing the amount of calcium that can flow into cells. It is unclear why this change affects the nervous system specifically and how it is related to the particular neurological problems associated with this condition.

metatropic dysplasia - caused by mutations in the TRPV4 gene

At least 10 mutations in the TRPV4 gene have been identified in people with metatropic dysplasia, a skeletal disorder characterized by short stature (dwarfism) with other skeletal abnormalities. Most of these mutations change single amino acids in the TRPV4 calcium channel. However, a few mutations insert or delete pieces of DNA in the TRPV4 gene.

Studies suggest that the TRPV4 gene mutations that cause metatropic dysplasia overactivate the TRPV4 calcium channel. The resulting increase in calcium in cartilage-forming cells (chondrocytes) may disrupt the early development of cartilage and bone. However, it remains unclear why these mutations affect chondrocytes specifically and how changes in TRPV4 channel activity result in the particular skeletal abnormalities associated with metatropic dysplasia.

other disorders - caused by mutations in the TRPV4 gene

Mutations in the TRPV4 gene cause a variety of other conditions, most of which affect the developing skeleton or the nervous system.

In addition to metatropic dysplasia, skeletal disorders associated with TRPV4 gene mutations include autosomal dominant brachyolmia; spondylometaphyseal dysplasia, Kozlowski type; spondyloepiphyseal dysplasia, Maroteaux type; and parastremmatic dysplasia. These related conditions involve combinations of short stature, abnormal side-to-side and back-to-front curvature of the spine (kyphoscoliosis), and other problems with developing bones.

Mutations in the TRPV4 gene also cause neurological disorders. In addition to Charcot-Marie-Tooth disease type 2C, this spectrum of related conditions includes congenital distal spinal muscular atrophy, which is characterized by weakness of muscles in the legs and pelvis, and scapuloperoneal spinal muscular atrophy, which involves weakness and wasting (atrophy) of muscles in the shoulders and lower legs.

Most of the TRPV4 gene mutations that cause these skeletal and neurological disorders change single amino acids in the TRPV4 calcium channel. These mutations likely increase the activity of the channel, although some research suggests that the mutations may have different effects on channel function in different tissues. Certain TRPV4 gene mutations have been found to cause skeletal disorders in some people and neurological disorders in others. Additionally, some TRPV4 gene mutations can cause both skeletal and neurological features in the same individual. Researchers are working to determine how TRPV4 gene mutations can cause this wide variety of signs and symptoms.

Another bone disorder, known as familial digital arthropathy-brachydactyly, has also been associated with mutations in the TRPV4 gene. This condition is characterized by arthritis in the joints of the fingers and toes (arthropathy) and shortened fingers and toes (brachydactyly). The mutations that cause this condition appear to disrupt the function of the TRPV4 calcium channel, preventing it from transporting calcium ions effectively. It is unclear how a loss of channel function leads to the specific features of this condition.

Common variations (polymorphisms) in the TRPV4 gene have been associated with two additional disorders: hyponatremia, which is a condition of water imbalance that can cause dangerous brain swelling, and chronic obstructive pulmonary disease (COPD), a common lung disease that causes difficulty breathing. It has not yet been determined how differences in the function of the TRPV4 calcium channel are related to these two conditions.

Because mutations in the TRPV4 gene are associated with such a wide array of conditions, some researchers have proposed referring to all TRPV4-related disorders as TRPV4-associated peripheral neuropathy and bony dysplasias (TRPV4-PNAB) or TRPV4-opathies.