Cation leak through the ATP1A3 pump causes spasticity and intellectual disability

Area of Science:

• Neurogenetics
• Molecular Biology
• Ion Transport

Background:

• ATP1A3 gene encodes a critical sodium-potassium ATPase subunit in neurons.
• Pathogenic variants in ATP1A3 cause diverse neurological disorders, but the basis for varied phenotypes is not fully understood.

Purpose of the Study:

• To investigate a novel ATP1A3 variant, p.(Pro775Leu), identified in individuals with spasticity and developmental delay.
• To elucidate the molecular mechanism underlying the observed mild neurological phenotypes associated with this ATP1A3 variant.

Main Methods:

• Clinical phenotyping of nine individuals with the ATP1A3:c.2324C>T; p.(Pro775Leu) variant.
• Electrophysiological studies to assess the functional impact of the p.(Pro775Leu) variant on sodium-potassium ATPase activity.
• Analysis of ion and proton leakage and sodium ion binding kinetics.

Main Results:

• The novel ATP1A3 variant p.(Pro775Leu) was identified in nine individuals presenting with spasticity and developmental delay/intellectual disability.
• This variant uniquely causes sodium and proton leakage into cells, with altered sodium binding kinetics.
• Phenotypes observed were milder than typical ATP1A3-associated disorders, resembling hereditary spastic paraplegia or cerebral palsy.

Conclusions:

• The ATP1A3:c.2324C>T; p.(Pro775Leu) variant results in mild neurological phenotypes due to cation leak, not just altered transport rate.
• This cation leak mechanism provides a molecular explanation for genotype-phenotype correlations in ATP1A3-related disorders.
• Highlights the importance of biophysical properties beyond transport rate in understanding ion channelopathies.