ATP1A1-linked diseases require a malfunctioning protein product from one allele.

Heterozygous germline variants in ATP1A1, the gene encoding the α1 subunit of the Na+/K+-ATPase (NKA), have been linked to diseases including primary hyperaldosteronism and the peripheral neuropathy Charcot-Marie-Tooth disease (CMT). ATP1A1 variants that cause CMT induce loss-of-function of NKA. This heterodimeric (αβ) enzyme hydrolyzes ATP to establish transmembrane electrochemical gradients of Na+ and K+ that are essential for electrical signaling and cell survival. Of the 4 catalytic subunit isoforms, α1 is ubiquitously expressed and is the predominant paralog in peripheral axons. Human population sequencing datasets indicate strong negative selection against both missense and protein-null ATP1A1 variants. To test whether haploinsufficiency generated by heterozygous protein-null alleles are sufficient to cause disease, we tested the neuromuscular characteristics of heterozygous Atp1a1+/- knockout mice and their wildtype littermates, while also evaluating if exercise increased CMT penetrance. We found that Atp1a1+/- mice were phenotypically normal up to 18 months of age. Consistent with the observations in mice, we report clinical phenotyping of a healthy adult human who lacks any clinical features of known ATP1A1-related diseases despite carrying a plasma-membrane protein-null early truncation variant, p.Y148*. Taken together, these results suggest that a malfunctioning gene product is required for disease induction by ATP1A1 variants and that if any pathology is associated with protein-null variants, they may display low penetrance or high age of onset. Copyright © 2023. Published by Elsevier B.V.

Citation

Kerri Spontarelli, Victoria C Young, Ryan Sweazey, Alexandria Padro, Jeannie Lee, Tulio Bueso, Roberto M Hernandez, Jongyeol Kim, Alexander Katz, Francis Rossignol, Clesson Turner, Caralynn M Wilczewski, George L Maxwell, Miguel Holmgren, Jeremy D Bailoo, Sho T Yano, Pablo Artigas. ATP1A1-linked diseases require a malfunctioning protein product from one allele. Biochimica et biophysica acta. Molecular cell research. 2023 Sep 01;1871(1):119572

PMID: 37659504

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