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

Abstract

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.

Effects of Charcot-Marie-Tooth-linked mutations of the neurofilament light subunit on intermediate filament formation

“…A variant (D469N) in the tail domain of NFL has been described while searching for mutations in NFs in amyotrophic lateral sclerosis patients. This variant was not linked to disease (Vechio et al, 1996) and we used it as a control.…”

Variation of the neurofilament medium KSP repeat sub-domain across mammalian species: implications for altering axonal structure

“…Moreover, no amino acid variations were identified within exon 3 of any of the species, with the exception of published single nucleotide polymorphisms (SNPs) in mouse (NCBI SNPs rs31130946, rs30628515, rs30748232, rs31130043, rs52626242). No human SNPs were observed but previous studies have observed rare SNPs within human NF-M exon 3 (Garcia et al, 2006;Vechio et al, 1996).…”

Intermediate Filaments in Neurodegenerative Diseases

“…Indeed, codon deletions or insertions in the KSP repeat motifs of NFH have been identified in patients with sporadic ALS [10][11][12]. However, two others studies failed to identify such variants in the NF genes linked to sporadic and familial ALS [13,14], suggesting that mutations in the NF genes are not a systematic common cause of ALS but could be a risk factor for sporadic ALS. Peripherin mutations have also been identified in three sporadic ALS patients [15][16][17], including a frameshift mutation in the PRPH gene able to disrupt the NF network assembly in vitro, reinforcing the view that NF disorganization may contribute to pathogenesis.…”