CMT2DD

Genetic Context

HGNC-Approved Gene Symbol

ATP1A1

Gene Full Name

ATPase Na+/K+ transporting subunit alpha 1

HGNC Gene Alias(es)

ATPase, Na+/K+ Transporting, Alpha 1 Polypeptide

Chromosome

1p13.1

Zygosity of Responsible Variant

Heterozygous

Mitochondrial Involvement

No

Variant Mechanism

Toxic Gain of Function (GoF)

Details

Mechanistic basis:
Neomorphic

Confidence:
Medium

Prediction:
Functional evidence supports a neomorphic gain-of-function mechanism for CMT2DD: the dominant missense substitutions in the alpha1 subunit of the Na/K-ATPase yield a pump that is aberrant rather than absent, and functional dissection of these variants (Clausen et al. 2023) concluded that disease requires expression of the malfunctioning product from one allele and is not haploinsufficiency. An unregulated cation leak through the mutant pump, dissipating the electrochemical gradient that peripheral axons depend on, fits the reported biophysics.

Rationale:
A mutant alpha1 pump that leaks cations creates a defect the remaining wild-type copy cannot offset, because the lesion lies in the ion gradient itself rather than in how much transporter is present. That reading follows from the requirement for a malfunctioning product and the explicit exclusion of haploinsufficiency, though a single functional study is thin ground for deciding what the mutant pump actually does.

ClinVar Pathogenic Variants

View ATP1A1 ClinVar Variants

ClinGen Curation

View ATP1A1 ClinGen Curation

CMT2DD OMIM Entry

CMT2DD OMIM

ATP1A1 OMIM Entry

ATP1A1 OMIM