| Autor: |
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 |
| Rok vydání: |
2023 |
| Předmět: |
|
| Zdroj: |
bioRxiv |
| Popis: |
Heterozygous germline variants inATP1A1, 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).ATP1A1variants 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-nullATP1A1variants. To test whether haploinsufficiency generated by heterozygous protein-null alleles are sufficient to cause disease, we tested the neuromuscular characteristics of heterozygousAtp1a1+/-knockout mice and their wildtype littermates, while also evaluating if exercise increased CMT penetrance. We found thatAtp1a1+/-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 knownATP1A1-related diseases despite carrying a protein-null early truncation variant, p.Y148*. Taken together, these results suggest that a malfunctioning gene product is required for disease induction byATP1A1variants and that if any pathology is associated with protein-null variants, they may display low penetrance or high age of onset. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
|
