ATP1A1 mutations cause intermediate Charcot-Marie-Tooth disease

Hum Mutat. 2019 Dec;40(12):2334-2343. doi: 10.1002/humu.23886. Epub 2019 Aug 23.

Abstract

Intermediate Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of inherited neuropathies characterized by progressive muscle weakness and atrophy of the distal extremities, distal sensory loss. There were still a large proportion of causative genes for intermediate CMT failed to be identified. Here, using whole-exome sequencing technique, we identified two novel missense mutations in ATP1A1 gene, c.620C>T (p.S207F) and c.2629G>A (p.G877S), in two Chinese CMT families. Further functional analysis revealed that these mutations led to the loss function of the ATP1A1 protein. The two mutations did not affect the levels of messenger RNA but possessed a damaging effect on ATP1A1 protein expression and they downregulated the protein levels of ATP1A1 by promoting its proteasome degradation. Taken together, we confirmed ATP1A1 as a novel causative gene for intermediate CMT.

Keywords: ATP1A1; intermediate Charcot-Marie-Tooth; mosaicism; whole-exome sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age of Onset
  • Aged
  • Cell Line
  • Charcot-Marie-Tooth Disease / genetics*
  • Charcot-Marie-Tooth Disease / metabolism
  • China
  • Down-Regulation
  • Exome Sequencing / methods*
  • Female
  • HeLa Cells
  • Humans
  • Male
  • Middle Aged
  • Mutation, Missense*
  • Pedigree
  • Proteasome Endopeptidase Complex / metabolism
  • Proteolysis
  • Sodium-Potassium-Exchanging ATPase / chemistry
  • Sodium-Potassium-Exchanging ATPase / genetics*
  • Sodium-Potassium-Exchanging ATPase / metabolism*
  • Young Adult

Substances

  • Proteasome Endopeptidase Complex
  • ATP1A1 protein, human
  • Sodium-Potassium-Exchanging ATPase