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Exome sequencing identified the homozygous nonsense variant c.1832G&gt;A\/p.(Trp611*) in <jats:italic>TMCO3<\/jats:italic> in two sisters with isolated short stature. Radiological studies, biochemical measurements, assessment of the skeletal status, and three\u2010dimensional bone microarchitecture revealed no relevant skeletal and bone abnormalities in both sisters. The homozygous <jats:italic>TMCO3<\/jats:italic> variant segregated with short stature in the family. <jats:italic>TMCO3<\/jats:italic> transcript levels were reduced by ~50% in leukocyte\u2010derived RNA of both sisters compared with controls, likely due to nonsense\u2010mediated mRNA decay. In primary urinary cells of heterozygous family members, we detected significantly reduced TMCO3 protein levels. TMCO3 is functionally uncharacterized. We ectopically expressed wild\u2010type TMCO3 in HeLa and ATDC5 chondrogenic cells and detected TMCO3 predominantly at the Golgi apparatus, whereas the TMCO3<jats:sup>W611*<\/jats:sup> mutant did not reach the Golgi. Coordinated co\u2010expression of TMCO3<jats:sup>W611*<\/jats:sup>\u2010HA and EGFP in HeLa cells confirmed intrinsic instability and\/or degradation of the mutant. <jats:italic>Tmco3<\/jats:italic> is expressed in all relevant mouse skeletal cell types. Highest abundance of Tmco3 was found in chondrocytes of the prehypertrophic zone in mouse and minipig growth plates where it co\u2010localizes with a Golgi marker. Knockdown of <jats:italic>Tmco3<\/jats:italic> in differentiated ATDC5 cells caused reduced and increased expression of <jats:italic>Pthlh<\/jats:italic> and <jats:italic>Ihh<\/jats:italic>, respectively. Measurement of long bones in <jats:italic>Tmco3<\/jats:italic><jats:sup>tm1b(KOMP)Wtsi<\/jats:sup> knockout mice revealed significant shortening of forelimbs and hindlimbs. TMCO3 is a potential member of the monovalent cation:proton antiporter 2 (CPA2) family. By in silico tools and homology modeling, TMCO3 is predicted to have an N\u2010terminal secretory signal peptide, forms a dimer localized to the membrane, and is organized in a dimerization and a core domain. The core domain contains the CPA2 motif essential for K<jats:sup>+<\/jats:sup> binding and selectivity. Collectively, our data demonstrate that loss of TMCO3 causes growth defects in both humans and mice. \u00a9 2023 American Society for Bone and Mineral Research (ASBMR).<\/jats:p>","DOI":"10.1002\/jbmr.4827","type":"journal-article","created":{"date-parts":[[2023,8,9]],"date-time":"2023-08-09T07:01:45Z","timestamp":1691564505000},"page":"1334-1349","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["<scp>TMCO3<\/scp>, a Putative K<sup>+<\/sup>:Proton Antiporter at the Golgi Apparatus, Is Important for Longitudinal Growth in Mice and Humans"],"prefix":"10.1093","volume":"38","author":[{"given":"Tess","family":"Holling","sequence":"first","affiliation":[{"name":"Institute of Human Genetics University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Brylka","sequence":"additional","affiliation":[{"name":"Department of Osteology and 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