{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T02:44:17Z","timestamp":1774320257458,"version":"3.50.1"},"reference-count":53,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2021,8,4]],"date-time":"2021-08-04T00:00:00Z","timestamp":1628035200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000291","name":"Kidney Research UK","doi-asserted-by":"publisher","award":["RP_030_20180306"],"award-info":[{"award-number":["RP_030_20180306"]}],"id":[{"id":"10.13039\/501100000291","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp;amp; Gen Med"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Calcium kidney stones are common and recurrences are often not preventable by available empiric remedies. Their etiology is multifactorial and polygenic, and an increasing number of genes are implicated. Their identification will enable improved management.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>DNA from three stone\u2010formers in a Southampton family (UK) and two from an Italian family were analyzed independently by whole exome sequencing and selected variants were genotyped across all available members of both pedigrees. A disease variant of <jats:italic>SLC25A25<\/jats:italic> (OMIM 608745), encoding the mitochondrial ATP\u2010Mg\/Pi carrier 3 (APC3) was identified, and analyzed structurally and functionally with respect to its calcium\u2010regulated transport activity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>All five patients had a heterozygous dominant <jats:italic>SLC25A25<\/jats:italic> variant (rs140777921; GRCh37.p13: chr 9 130868670 G&gt;C; p.Gln349His; Reference Sequence NM_001006641.3). Non\u2010stone formers also carried the variant indicating incomplete penetrance. Modeling suggests that the variant lacks a conserved polar interaction, which may cause structural instability. Calcium\u2010regulated ATP transport was reduced to ~20% of the wild type, showing a large reduction in function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The transporter is important in regulating mitochondrial ATP production. This rare variant may increase urine lithogenicity through impaired provision of ATP for solute transport processes in the kidney, and\/or for purinergic signaling. Variants found in other genes may compound this abnormality.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.1749","type":"journal-article","created":{"date-parts":[[2021,8,4]],"date-time":"2021-08-04T08:37:15Z","timestamp":1628066235000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Exome sequencing identifies a disease variant of the mitochondrial ATP\u2010Mg\/Pi carrier SLC25A25 in two families with kidney stones"],"prefix":"10.1002","volume":"9","author":[{"given":"M. Reza","family":"Jabalameli","sequence":"first","affiliation":[{"name":"Department of Human Genetics and Genomic Medicine University of Southampton Southampton UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fiona M.","family":"Fitzpatrick","sequence":"additional","affiliation":[{"name":"Medical Research Council Mitochondrial Biology Unit University of Cambridge Cambridge UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roberto","family":"Colombo","sequence":"additional","affiliation":[{"name":"Faculty of Medicine \u2018Agostino Gemelli\u2019 Catholic University of the Sacred Heart Rome Italy"},{"name":"Center for the Study of Rare Inherited Diseases Niguarda Ca\u00b4Granda Metropolitan Hospital Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah A.","family":"Howles","sequence":"additional","affiliation":[{"name":"Nuffield Department of Surgical Sciences University of Oxford Oxford UK"},{"name":"Academic Endocrine Unit, Radcliffe Department of Medicine University of Oxford Oxford UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gary","family":"Leggatt","sequence":"additional","affiliation":[{"name":"Department of Human Genetics and Genomic Medicine University of Southampton Southampton UK"},{"name":"Wessex Kidney Centre Queen Alexandra Hospital Portsmouth UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valerie","family":"Walker","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry University Hospital Southampton Southampton UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akira","family":"Wiberg","sequence":"additional","affiliation":[{"name":"Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences University of Oxford Oxford UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edmund R. 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