ATP1A1 – Charcot-Marie-Tooth disease

Charcot-Marie-Tooth disease (CMT) comprises a heterogeneous group of inherited peripheral neuropathies characterized by distal muscle weakness, atrophy, and sensory loss. Monoallelic variants in ATP1A1 (encoding the α1 subunit of the Na⁺/K⁺-ATPase) have been identified as a cause of autosomal-dominant CMT, expanding the genetic landscape of axonal and intermediate CMT subtypes (PMID:29499166).

Genetic studies have reported at least 10 unrelated CMT probands harboring de novo or segregating ATP1A1 missense variants across nine families, demonstrating autosomal-dominant inheritance with segregation of disease (PMID:29499166; PMID:31373411). Recurrent and novel variants include c.1798C>G (p.Pro600Ala), c.620C>T (p.Ser207Phe), and c.1799C>G (p.Pro600Arg), affecting conserved transmembrane and linker domains essential for pump function.

Functional assessments in patient-derived iPSC-derived neurons demonstrate defective neuronal differentiation and reduced ATP1A1 expression for p.Pro600Ala, correlating with impaired maturation and electrophysiological immaturity of post-mitotic neurons (PMID:31707753). Electrophysiological analyses in Xenopus oocytes and ouabain-resistant HEK cells confirm loss-of-function of p.Pro600Arg and related variants, with reduced pump activity and decreased cell viability under ouabain challenge (PMID:36738336).

Mechanistically, these dominant missense variants induce a dysfunctional Na⁺/K⁺-ATPase that cannot support axonal ionic homeostasis, leading to secondary neuronal degeneration. In contrast, haploinsufficient (null) alleles lack sufficient dominant-negative effect and display low penetrance, underscoring a dominant-negative or gain-of-function pathogenic mechanism.

Overall, multiple independent pedigrees, segregation data, and concordant in vitro and cellular model findings provide Strong clinical validity for ATP1A1 in CMT. Additional functional work in vivo and deeper phenotypic profiling may further refine prognostic and therapeutic approaches.

Key Take-home: Heterozygous ATP1A1 missense variants cause autosomal-dominant CMT via dominant-negative loss of Na⁺/K⁺-ATPase function, offering a target for molecular diagnosis and potential pump-stabilizing therapies.

References

• American journal of human genetics • 2018 • Mutations in ATP1A1 Cause Dominant Charcot-Marie-Tooth Type 2. PMID:29499166
• Human mutation • 2019 • ATP1A1 mutations cause intermediate Charcot-Marie-Tooth disease. PMID:31373411
• Journal of the peripheral nervous system • 2019 • Insights into the pathogenesis of ATP1A1-related CMT disease using patient-specific iPSCs. PMID:31707753
• Journal of neurology • 2023 • The phenotypic spectrum of pathogenic ATP1A1 variants expands: the novel p.P600R substitution causes demyelinating Charcot-Marie-Tooth disease. PMID:36738336

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