Work

Association of the Recurrent ATP1 A1 Variant p.Gly549Arg With Intermediate CMT and Loss of Na,K-ATPase Function

Year: 2025

Type: article

Abstract: Background and Objectives: variant causing dominant intermediate CMT disease and the functional characterization of the variant in the heterologous expression system. Methods: oocytes or HEK293 cells, respectively. Localization of the variants was evaluated by fluorescence microscopy of HEK293 cells expressing fluorescently tagged sodium pumps. Results: . The reduced plasma membrane density was also observed in HEK293 cells simultaneously expressing wildtype and Gly549Arg variants, marked with fluorescent proteins of different colors, suggesting that the mutant may be partially retained in intracellular membranes. No clear dominant-negative effects were identified in these experimental systems. Discussion: Our results demonstrate that the pathogenic nature of this variant causes considerable loss of function due to diminished plasma membrane localization and kinetic impairments on the enzyme, without obvious dominant-negative effects. Our findings are similar to those previously reported for other CMT disease-causing ATP1A1 variants.

Source: Neurology Genetics

DOI: 10.1212/nxg.0000000000200309