NEFH

The NEFH gene provides instructions for making a protein component (subunit) of neurofilaments, which are essential for the structure of nerve cells. Neurofilaments are assembled from three different protein subunits called light, medium, and heavy. The heavy subunit is produced from the NEFH gene.

Neurofilaments form a structural framework that helps to define the shape and size of nerve cells. Cross-linking or bridging between neurofilaments maintains the diameter of nerve cells, which is important for the conduction of nerve impulses. Neurofilaments are particularly abundant in motor neurons, which are specialized nerve cells in the brain and spinal cord that control muscle movement.

The heavy subunit is made up of three regions: the head, which regulates assembly of neurofilaments; a coiled midsection; and a tail with branches that interact with other proteins (including other neurofilaments). The tail region has a segment called the KSP motif that plays an important role in regulating the functions of neurofilaments.

amyotrophic lateral sclerosis - increased risk from variations of the NEFH gene

Mutations in the NEFH gene have been detected in a small percentage of individuals with amyotrophic lateral sclerosis. In some cases, unaffected family members of people with this disorder also have a NEFH mutation. Based on these observations, a mutation in the NEFH gene appears to increase the risk of developing amyotrophic lateral sclerosis but does not directly cause this disorder.

Researchers have identified several mutations that delete or insert DNA building blocks (base pairs) within the NEFH gene, which produces a KSP motif of abnormal length. The abnormal KSP motif may disrupt cross-linking between neurofilaments. One NEFH mutation changes one of the protein building blocks (amino acids) used to make the heavy subunit. Specifically, the amino acid alanine replaces the amino acid threonine at position 380 (written as Ala380Thr or A380T). The effect of this mutation is unknown, but it may impair the assembly of neurofilaments.

It is not known how NEFH mutations increase the risk of developing amyotrophic lateral sclerosis. Disrupted cross-linking or assembly of neurofilaments may lead to the accumulation of these filaments in motor neurons. Deposits of neurofilaments in deteriorating motor neurons appear to be an early feature of amyotrophic lateral sclerosis. It is unclear, however, whether these deposits play a role in causing this disorder or are a byproduct of dying motor neurons.