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

Biochim Biophys Acta Mol Cell Res. 2023 Aug 31:119572. doi: 10.1016/j.bbamcr.2023.119572. Online ahead of print.ABSTRACTHeterozygous 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 th...

Source: Biochimica et Biophysica Acta - September 2, 2023 Category: Biochemistry Authors: 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 Pab Source Type: research