Analysis of heavy neurofilament subunit gene polymorphism in Russian patients with sporadic motor neuron disease (MND)

Abstract

Motor neuron disease (MND) results in the selective degeneration of motor neurons in the cerebral cortex, brain stem and spinal cord. The most common form of MND is amyotrophic lateral sclerosis (ALS). MND is complex and many genetic systems may be involved in the pathogenesis of this disease. Pathological and animal studies implicate neurofilament involvement in MND. The heavy subunit (NEFH) tail domain contains a repeated motif. In humans, there are two common variants: the 45 motif repeats long allele (L) and 44 motif repeats short allele (S). Previous studies have shown that the NEFH tail may be involved in the pathogenesis of MND. To investigate whether the L/S genotypes of the NEFH gene are associated with MND, we studied the frequency of L and S alleles in sporadic MND patients and a control population from Moscow. We observed a difference in SS genotype frequency between the control population and sporadic MND patients from Moscow. It was established that the SS genotype is sufficiently higher in sporadic MND patients. Moreover, we determined that patients with the SS genotype have the highest value of loss of the total clinical score. In summary, we conclude that the NEFH gene is involved in the pathogenesis of sporadic MND. The SS genotype represents a risk factor for the development and progression of sporadic MND in the Moscow population.

Cryptic amyloidogenic elements in mutant NEFH causing Charcot-Marie-Tooth 2 trigger aggresome formation and neuronal death

“…Mouse models with overexpression of neurofilaments subunits have a motor neuropathy resembling ALS [20]. Rare mutations in the peripherin and in the KSP repeats motifs have been reported [1, 8], and a latter study showed that a short allele of the NEFH tail was associated with ALS [30]. Other studies found no mutations of NEFH in ALS [9, 28].…”

Epigenetic silencing of neurofilament genes promotes an aggressive phenotype in breast cancer

“…12 Neurofilaments are type IV intermediate filaments that are the main structural component of the cytoskeleton in mature neurons 13 determining axon caliber and conductivity for proper neuronal function. 14,15 Neurofilaments have been implicated in the pathology of neurological diseases, [16][17][18] but recent data also point to a role in the pathology of cancer. [19][20][21] For example, NEFL and NEFM are both located within the 8p21 chromosome region and LOH of this region has been described in several cancers including breast cancer.…”

Genetics of Amyotrophic Lateral Sclerosis

“…In humans there are two common polymorphic variants of 44 (short) or 45 (long) repeats. Homozygosity for the short repeat allele is associated with Russian sporadic motor neuron disease patients (Skvortsova et al, 2004). Deletions and insertions in the KSP repeats of NEFH were detected in ALS patients (Al-Chalabi et al, 1999;Figlewicz et al, 1994;Tomkins et al, 1998).…”