Sheep erythrocyte potassium locus highlights MYADM family regulation of electroneutral potassium chloride cotransporters (KCC)

Authors: GONZALEZ, MICHAEL - Washington State University; Mousel, Michelle; Herndon, David; MASSA, ALISHA - Washington State University; DURFEE, CODIE - Former ARS Employee; KNOWLES, DONALD - Retired ARS Employee; Taylor, Joshua; NEIBERGS, HOLLY - Washington State University; SEABURY, CHRISTOPHER - Texas A&M University; WHITE, STEPHEN - Former ARS Employee

Submitted to: BMC Genomics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/3/2026
Publication Date: 6/16/2026
Citation: Gonzalez, M.V., Mousel, M.R., Herndon, D.R., Massa, A.T., Durfee, C.J., Knowles, D.P., Taylor, J.B., Neibergs, H.L., Seabury, C.M., White, S.N. 2026. Sheep erythrocyte potassium locus highlights MYADM family regulation of electroneutral potassium chloride cotransporters (KCC). BMC Genomics. https://doi.org/10.1186/s12864-026-13029-7.
DOI: https://doi.org/10.1186/s12864-026-13029-7

Interpretive Summary: Transmembrane cation transport is very important for maintaining cell homeostasis but there can be a wide range of acceptable cation levels. High or low potassium within red blood cells has been known to occur within domestic sheep, but the genetic mutation(s) contributing to this variation is unknown. Previous research identified a genomic region, myeloid associated differentiation marker-like (MYADMF) genes, that associated with red blood cell morphology. A genome wide association study was conducted and found red blood cell potassium level is associated with the MYADMF genes. The MYADMF genomic region is complicated and is made up of 37 genes or pseudogenes in domestic sheep. Comparing the MYADMF region in goats, cattle, and domestic pigs found, 33, 53, and 15 genes or pseudo genes, respectively but none in horses or rhinoceros. In humans, MYADM has been associated with high blood pressure, suggesting MYADM may have a role in blood pressure regulation by controlling potassium level in cells.

Technical Abstract: Domestic sheep have distinct low (LK) or high intracellular potassium (HK) erythrocytes that serve to transport potassium chloride. Potassium levels within erythrocytes is inherited as a single gene trait, although the responsible genetic variant(s) have not been identified. A genome-wide association identified an artiodactyl-specific tandem duplication locus of MYADMF genes as highly associated (P=1.1x10-63) with erythrocyte intracellular potassium concentration. Fine mapping of potential causal variants in an expanded sheep population showed maximal association with erythrocyte potassium for 47 variants (P<10-99) in a cluster of closely related haplotypes that accounted for all of the association signal in this region. Together with prior results, these data implicate a haplotype cluster in the MYADMF expanded locus comprising MYADMF15A1, MYADMF1G1, MYADMF1H1, MYADMF3A2, MYADMF1B4, and MYADMF13C1 that are associated with potassium chloride co-transport in sheep. To our knowledge this is the first report of a MYADMF gene regulating potassium transport. In humans, MYADM has been identified in multiple genome-wide association studies as associated with hypertension, but the role of MYADM in hypertension is unclear. Since another MARVEL domain protein, MAL, has been observed to stabilize ion transporters at the cell membrane, these data also suggest MYADM may function in blood pressure homeostasis by regulating potassium co-transport.