Hereditary sensory and autonomic neuropathy type V (HSAN5) is a condition that primarily affects the sensory nerve cells (sensory neurons), which transmit information about sensations such as pain, temperature, and touch. These sensations are impaired in people with HSAN5.

The signs and symptoms of HSAN5 appear early, usually at birth or during infancy. People with HSAN5 lose the ability to feel pain, heat, and cold. Deep pain perception, the feeling of pain from injuries to bones, ligaments, or muscles, is especially affected in people with HSAN5. Because of the inability to feel deep pain, affected individuals suffer repeated severe injuries such as bone fractures and joint injuries that go unnoticed. Repeated trauma can lead to a condition called Charcot joints, in which the bones and tissue surrounding joints are destroyed.

Mutations in the NGF gene cause HSAN5. The NGF gene provides instructions for making a protein called nerve growth factor beta (NGFβ) that is important in the development and survival of nerve cells (neurons), including sensory neurons. The NGFβ protein functions by attaching (binding) to its receptors, which are found on the surface of neurons. Binding of the NGFβ protein to its receptor transmits signals to the cell to grow and to mature and take on specialized functions (differentiate). This binding also blocks signals in the cell that initiate the process of self-destruction (apoptosis). Additionally, NGFβ signaling plays a role in pain sensation. Mutation of the NGF gene leads to the production of a protein that cannot bind to the receptor and does not transmit signals properly. Without the proper signaling, sensory neurons die and pain sensation is altered, resulting in the inability of people with HSAN5 to feel pain.

Normal Function

The NGF gene provides instructions for making a protein called nerve growth factor beta (NGFβ). This protein is important in the development and survival of nerve cells (neurons), especially those that transmit pain, temperature, and touch sensations (sensory neurons). The NGFβ protein functions by attaching (binding) to its receptors, which initiates signaling pathways inside the cell. The NGFβ protein can bind to two different receptors, the NTRK1 receptor or the p75NTR receptor. Both receptors are found on the surface of sensory neurons and other types of neurons. The binding of the NGFβ protein to the NTRK1 receptor signals these neurons to grow and to mature and take on specialized functions (differentiate). This binding also blocks signals that initiate the process of self-destruction (apoptosis). Additionally, NGFβ signaling through NTRK1 plays a role in pain sensation. It is less clear what binding with the p75NTR receptor signals. Studies suggest that p75NTR signaling can help sensory neurons grow and differentiate but can also trigger apoptosis.

Health Conditions Related to Genetic Changes

Hereditary sensory and autonomic neuropathy type V

At least one mutation in the NGF gene has been reported to cause hereditary sensory and autonomic neuropathy type V (HSAN5), a condition characterized by the inability to feel pain and sense hot and cold. This mutation changes a single protein building block (amino acid) in the NGFβ protein. The amino acid arginine is replaced with the amino acid tryptophan at position 100 (written as Arg100Trp or R100W). Studies show that the mutated NGFβ protein cannot bind to the p75NTR receptor and that it alters the signaling through the NTRK1 receptor. In addition, people with HSAN5 have a reduced number of sensory neurons. However, the mechanism by which mutation of the NGF gene leads to the inability to feel pain and temperature sensations is unclear. Although the NGFβ protein is important in many types of neurons, only sensory neurons appear to be affected in people with HSAN5.

Other Names for This Gene

• beta-nerve growth factor
• beta-nerve growth factor precursor
• Beta-NGF
• HSAN5
• nerve growth factor (beta polypeptide)
• nerve growth factor, beta subunit
• NGF_HUMAN
• NGFB

Genomic Location

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

HSAN5 is very rare. Only a few people with the condition have been identified.