NEFH

NEFH stands for neurofilament heavy polypeptide, the gene that encodes the neurofilament heavy chain (NF-H). NF-H is one of the core subunits of neuronal neurofilaments, a type IV intermediate filament system that also includes the light (NEFL) and medium (NEFM) chains. Together, these proteins form the neurofilament triplet that contributes to the structure of axons and helps determine axonal diameter.

NF-H has a distinctive long C-terminal tail domain rich in lysine-serine-proline (KSP) repeats. This tail is heavily phosphorylated by multiple kinases, and the phosphorylation state regulates filament assembly and spacing between filaments, influencing the overall organization of the neurofilament network. Phosphorylation also affects interactions with motor proteins and other cytoskeletal elements, thereby impacting axonal caliber and conduction velocity.

Expression of NEFH is highest in neurons of the central and peripheral nervous systems, particularly in long-projecting axons. Functionally, NF-H works with NEFL and NEFM to form neurofilaments that provide structural support, contribute to axonal integrity, and participate in axonal transport and stability over long distances.

Clinical and research relevance includes the observation that abnormal NF-H phosphorylation, fragmentation, or mislocalization is associated with several neurodegenerative conditions, and phosphorylated NF-H is used as a biomarker in some studies. Rare inherited variants in NEFH have been reported in neuropathies, though their pathogenic role varies and remains an area of ongoing investigation.