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Kidney Research Fund","doi-asserted-by":"publisher","award":["NU-005589"],"award-info":[{"award-number":["NU-005589"]}],"id":[{"id":"10.13039\/501100004185","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004185","name":"Northern Counties Kidney Research Fund","doi-asserted-by":"publisher","award":["18.011"],"award-info":[{"award-number":["18.011"]}],"id":[{"id":"10.13039\/501100004185","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Apart from increased fluid intake, patients with kidney stone disease (KSD) due to renal phosphate wasting require specific metaphylaxis. NaPi2a, NaPi2c, and NHERF1 regulate plasma phosphate concentration by reabsorbing phosphate in proximal kidney tubules and have been found altered in monogenic hypophosphatemia with a risk of KSD. In this study, we aimed at assessing the combined genetic alterations impacting NaPi2a, NaPi2c, and NHERF1. Therefore, we screened our hereditary KSD registry for cases of oligo- and digenicity, conducted reverse phenotyping, and undertook functional studies. As a result, we identified three patients from two families with digenic alterations in NaPi2a, NaPi2c, and NHERF1. In family 1, the index patient, who presented with severe renal calcifications and a bone mineralization disorder, carried digenic alterations affecting both NaPi transporter 2a and 2c. Functional analysis confirmed an additive genetic effect. In family 2, the index patient presented with kidney function decline, distinct musculature-related symptoms, and intracellular ATP depletion. Genetically, this individual was found to harbor variants in both NaPi2c and NHERF1 pointing towards genetic interaction. In summary, digenicity and gene dosage are likely to impact the severity of renal phosphate wasting and should be taken into account in terms of metaphylaxis through phosphate substitution.<\/jats:p>","DOI":"10.3390\/nu15092081","type":"journal-article","created":{"date-parts":[[2023,4,26]],"date-time":"2023-04-26T01:16:25Z","timestamp":1682471785000},"page":"2081","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Clinical and Functional Assessment of Digenicity in Renal Phosphate Wasting"],"prefix":"10.3390","volume":"15","author":[{"given":"Friederike","family":"Petzold","sequence":"first","affiliation":[{"name":"Division of Nephrology, University of Leipzig Medical Center, 04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ria","family":"Sch\u00f6nauer","sequence":"additional","affiliation":[{"name":"Division of Nephrology, University of Leipzig Medical Center, 04103 Leipzig, Germany"},{"name":"Department of Nephrology, Charit\u00e9 Universit\u00e4tsmedizin Berlin, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2274-0662","authenticated-orcid":false,"given":"Andreas","family":"Werner","sequence":"additional","affiliation":[{"name":"Biosciences Institute, Newcastle University, Newcastle upon Tyne NE1 7RU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1377-9880","authenticated-orcid":false,"given":"Jan","family":"Halbritter","sequence":"additional","affiliation":[{"name":"Division of Nephrology, University of Leipzig Medical Center, 04103 Leipzig, Germany"},{"name":"Department of Nephrology, Charit\u00e9 Universit\u00e4tsmedizin Berlin, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.eururo.2012.03.052","article-title":"Prevalence of Kidney Stones in the United States","volume":"62","author":"Scales","year":"2012","journal-title":"Eur. 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