Sequence variants in human neurofilament proteins: Absence of linkage to familial amyotrophic lateral sclerosis

Neurofilaments, assembled from NF-L (68 kd), NF-M (95 kd), and NF-H (115 kd), are the most abundant structural components in large myelinated axons, particularly those of motor neurons. Aberrant neurofilament accumulation in cell bodies and axons of motor neurons is a prominent pathological feature of several motor neuron diseases, including sporadic and familial amyotrophic lateral sclerosis (ALS). Transgenic methods have proved in mice that mutation in or increased expression of neurofilament subunits can be primary causes of motor neuron disease that mimics the neurofilamentous pathology often reported in human disease. To examine whether mutation in neurofilament subunits causes or predisposes to ALS, we used single-strand conformation polymorphism coupled with DNA sequencing to search for mutations in the entirety of the human NF-L, NF-M, and NF-H genes from 100 familial ALS patients known not to carry mutations in superoxide dismutase 1 (SOD1), as well as from 75 sporadic ALS patients. Six polypeptide sequence variants were identified in rod and tail domains of NF-L, NF-M, or NF-H. However, all were found at comparable frequency in DNAs from normal individuals and no variant cosegregated with familial disease. Two deletions found previously in NF-H genes of sporadic ALS patients were not seen in this group of familial or sporadic ALS patients.