A novel missense variant of SCN4A co‐segregates with congenital essential tremor in a consanguineous Kurdish family

Abstract

Essential tremor (ET) is a neurological disorder characterized by bilateral and symmetric postural, isometric, and kinetic tremors of forelimbs produced during voluntary movements. To date, only a single SCN4A variant has been suggested to cause ET. In continuation of the previous report on the association between SCN4A and ET in a family from Spain, we validated the pathogenicity of a novel SCN4A variant and its involvement in ET in a second family affected by this disease. We recruited a Kurdish family with four affected members manifesting congenital tremor. Using wholeexome sequencing, we identified a novel missense variant in SCN4A, NM_000334.4: c.4679C>T; p.(Pro1560Leu), thus corroborating SCN4A's role in ET. The residue is highly conserved across vertebrates and the substitution is predicted to be pathogenic by various in silico tools. Western blotting and immunocytochemistry performed in cells derived from one of the patients showed reduced immunoreactivity of SCN4A as compared to control cells. The study provides supportive evidence for the role of SCN4A in the etiology of ET and expands the phenotypic spectrum of channelopathies to this neurological disorder.

Targeting Circuit Abnormalities in Neurodegenerative Disease

“…At least in CTC circuits, some of this aberrant electrical activity has been attributed to T-type calcium channels, inhibitors of which are already being developed (Handforth et al, 2010;Scott et al, 2022). Genetic analyses of families with ET have also revealed that mutations in the SCN4A gene, which encodes a voltage-gated sodium channel, segregate with the disease (Bergareche et al, 2015;Asif et al, 2021). Records from mutant SCN4A channels show faster activation and inactivation, which likely contributes to oscillation firing.…”