{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T17:45:23Z","timestamp":1776015923602,"version":"3.50.1"},"posted":{"date-parts":[[2024,10,23]]},"group-title":"Genetics","reference-count":74,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,10,23]],"date-time":"2024-10-23T00:00:00Z","timestamp":1729641600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,10,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Primary aldosteronism is characterized by renin-independent hyperaldosteronism that originates from aldosterone-producing lesions in the adrenal glands. Under physiological conditions, aldosterone synthase (\n                  <jats:italic>CYP11B2<\/jats:italic>\n                  ) expression is confined to the adrenal zona glomerulosa where it catalyzes the final reaction yielding aldosterone. The regulation of\n                  <jats:italic>CYP11B2<\/jats:italic>\n                  transcription depends on the control of cellular membrane potential and cytosolic calcium activity. In primary aldosteronism, aldosterone-producing adenomas (APAs) are characterized by disrupted regulation of CYP11B2 expression resulting in autonomous biosynthesis of aldosterone. These lesions often harbor aldosterone-driver somatic mutations in genes encoding ion transporters\/channels\/pumps that increase cytosolic calcium activity causing increased\n                  <jats:italic>CYP11B2<\/jats:italic>\n                  expression and aldosterone biosynthesis. We investigated APAs devoid of known somatic mutations and detected a missense mutation and a deletion-insertion variant in\n                  <jats:italic>MCOLN3<\/jats:italic>\n                  which encodes for mucolipin-3 (TRPML3) \u2014 a highly conserved inwardly-rectifying, cation-permeable channel. These\n                  <jats:italic>MCOLN3<\/jats:italic>\n                  mutations were identified in three APAs derived from male patients with primary aldosteronism: p. Y391D and p.N411_V412delinsI. Both mutations are located near the ion pore and selectivity filter of TRPML3. This is the first report of disease-causing\n                  <jats:italic>MCOLN3<\/jats:italic>\n                  mutations in humans. Functional studies suggest\n                  <jats:italic>\n                    MCOLN3\n                    <jats:sup>Y391D<\/jats:sup>\n                  <\/jats:italic>\n                  might directly or indirectly via membrane depolarization alter calcium influx of transfected adrenocortical cells, resulting in increased\n                  <jats:italic>CYP11B2<\/jats:italic>\n                  transcription and aldosterone production. This study implicates mutated\n                  <jats:italic>MCOLN3<\/jats:italic>\n                  as a driver of aldosterone excess in primary aldosteronism.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance Statement<\/jats:title>\n                  <jats:p>\n                    Primary aldosteronism is a common but under-diagnosed endocrine disease that contributes to global hypertension burden and cardiovascular mortality and morbidity. Hyperaldosteronism in primary aldosteronism is mainly caused by adrenal lesions harboring somatic mutations that disrupt intracellular calcium levels and consequently aldosterone synthase expression and aldosterone production. Majority of these mutations have been identified in genes encoding ion transporters\/channels\/pumps. Herein, we report the first disease-causing somatic mutations in human\n                    <jats:italic>MCOLN3<\/jats:italic>\n                    in aldosterone-producing adenomas (APAs) devoid of known mutations.\n                    <jats:italic>In vitro<\/jats:italic>\n                    investigations showed the\n                    <jats:italic>MCOLN3<\/jats:italic>\n                    variant (p.Y391D) caused an influx of cytosolic calcium in adrenocortical cells and the subsequent increase in aldosterone synthase and aldosterone biosynthesis.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.10.20.619295","type":"posted-content","created":{"date-parts":[[2024,10,23]],"date-time":"2024-10-23T13:40:33Z","timestamp":1729690833000},"source":"Crossref","is-referenced-by-count":2,"title":["Somatic Mutations in\n                  <i>MCOLN3<\/i>\n                  in Aldosterone-Producing Adenomas cause Primary Aldosteronism"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2969-1127","authenticated-orcid":false,"given":"Desmar\u00e9","family":"van Rooyen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7955-7220","authenticated-orcid":false,"given":"Sascha","family":"Bandulik","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Grace","family":"Coon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6151-1573","authenticated-orcid":false,"given":"Miriam","family":"Laukemper","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8696-3400","authenticated-orcid":false,"given":"Chandan","family":"Kumar-Sinha","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8254-5404","authenticated-orcid":false,"given":"Aaron M.","family":"Udager","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0490-2437","authenticated-orcid":false,"given":"Chaelin","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3786-3638","authenticated-orcid":false,"given":"Heather","family":"Wachtel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1325-315X","authenticated-orcid":false,"given":"Debbie L.","family":"Cohen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7225-2897","authenticated-orcid":false,"given":"James M.","family":"Luther","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0641-8873","authenticated-orcid":false,"given":"Thomas","family":"Giordano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9831-6190","authenticated-orcid":false,"given":"Adina","family":"Turcu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6084-0659","authenticated-orcid":false,"given":"Richard","family":"Warth","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5557-8406","authenticated-orcid":false,"given":"William E.","family":"Rainey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2593-5008","authenticated-orcid":false,"given":"Juilee","family":"Rege","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024102600101596000_2024.10.20.619295v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2006.07.059"},{"key":"2024102600101596000_2024.10.20.619295v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(20)32540-7"},{"key":"2024102600101596000_2024.10.20.619295v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2017.01.052"},{"key":"2024102600101596000_2024.10.20.619295v1.4","doi-asserted-by":"publisher","DOI":"10.1001\/jamasurg.2018.5842"},{"key":"2024102600101596000_2024.10.20.619295v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(08)60834-X"},{"key":"2024102600101596000_2024.10.20.619295v1.6","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgaa484"},{"key":"2024102600101596000_2024.10.20.619295v1.7","doi-asserted-by":"publisher","DOI":"10.1126\/science.1198785"},{"key":"2024102600101596000_2024.10.20.619295v1.8","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.118.12070"},{"key":"2024102600101596000_2024.10.20.619295v1.9","doi-asserted-by":"crossref","unstructured":"C. E. Gomez-Sanchez et al., Primary aldosteronism caused by a pI157S somatic KCNJ5 mutation in a black adolescent female with aldosterone-producing adenoma. Front Endocrinol 13, 921449 (2022).","DOI":"10.3389\/fendo.2022.921449"},{"key":"2024102600101596000_2024.10.20.619295v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2716"},{"key":"2024102600101596000_2024.10.20.619295v1.11","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2550"},{"key":"2024102600101596000_2024.10.20.619295v1.12","doi-asserted-by":"crossref","unstructured":"C. B. Xie et al., Regulation of aldosterone secretion by Cav1.3. Sci Rep 6, 24697 (2016).","DOI":"10.1038\/srep24697"},{"key":"2024102600101596000_2024.10.20.619295v1.13","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2695"},{"key":"2024102600101596000_2024.10.20.619295v1.14","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.119.14349"},{"key":"2024102600101596000_2024.10.20.619295v1.15","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.111.186478"},{"key":"2024102600101596000_2024.10.20.619295v1.16","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2015-2149"},{"key":"2024102600101596000_2024.10.20.619295v1.17","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-023-01498-5"},{"key":"2024102600101596000_2024.10.20.619295v1.18","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-023-01403-0"},{"key":"2024102600101596000_2024.10.20.619295v1.19","doi-asserted-by":"crossref","unstructured":"T. \u00c5kerstr\u00f6m et al., Activating mutations in CTNNB1 in aldosterone producing adenomas. Sci Rep 6, 19546 (2016).","DOI":"10.1038\/srep19546"},{"key":"2024102600101596000_2024.10.20.619295v1.20","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2016-1700"},{"key":"2024102600101596000_2024.10.20.619295v1.21","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00906-y"},{"key":"2024102600101596000_2024.10.20.619295v1.22","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2018-01004"},{"key":"2024102600101596000_2024.10.20.619295v1.23","doi-asserted-by":"publisher","DOI":"10.1038\/s41581-023-00753-6"},{"key":"2024102600101596000_2024.10.20.619295v1.24","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2018.1518671"},{"key":"2024102600101596000_2024.10.20.619295v1.25","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2022.2148808"},{"key":"2024102600101596000_2024.10.20.619295v1.26","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0854.2009.00935.x"},{"key":"2024102600101596000_2024.10.20.619295v1.27","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2023.2300922"},{"key":"2024102600101596000_2024.10.20.619295v1.28","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0854.2009.00924.x"},{"key":"2024102600101596000_2024.10.20.619295v1.29","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.117.028201"},{"key":"2024102600101596000_2024.10.20.619295v1.30","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.222425399"},{"key":"2024102600101596000_2024.10.20.619295v1.31","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0709096104"},{"key":"2024102600101596000_2024.10.20.619295v1.32","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0709846104"},{"key":"2024102600101596000_2024.10.20.619295v1.33","doi-asserted-by":"crossref","unstructured":"F. C. Luft et al., Salt sensitivity and resistance of blood pressure. Age and race as factors in physiological responses. Hypertension 17, I102 (1991).","DOI":"10.1161\/01.HYP.17.1_Suppl.I102"},{"key":"2024102600101596000_2024.10.20.619295v1.34","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.27.3.481"},{"key":"2024102600101596000_2024.10.20.619295v1.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.cjca.2011.11.010"},{"key":"2024102600101596000_2024.10.20.619295v1.36","doi-asserted-by":"publisher","DOI":"10.1210\/me.2003-0005"},{"key":"2024102600101596000_2024.10.20.619295v1.37","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2011-2384"},{"key":"2024102600101596000_2024.10.20.619295v1.38","first-page":"873","article-title":"The unique steroidogenesis of the aldosteronoma in the differential diagnosis of primary aldosteronism","volume":"76","year":"1993","journal-title":"The Journal of Clinical Endocrinology & Metabolism"},{"key":"2024102600101596000_2024.10.20.619295v1.39","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-17-0563"},{"key":"2024102600101596000_2024.10.20.619295v1.40","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgaa367"},{"key":"2024102600101596000_2024.10.20.619295v1.41","doi-asserted-by":"publisher","DOI":"10.1210\/en.2015-2029"},{"key":"2024102600101596000_2024.10.20.619295v1.42","doi-asserted-by":"crossref","unstructured":"F. G\u00fcrtler et al., Cellular pathophysiology of mutant voltage-dependent Ca2+ channel CACNA1H in primary aldosteronism. Endocrinology 161 (2020).","DOI":"10.1210\/endocr\/bqaa135"},{"key":"2024102600101596000_2024.10.20.619295v1.43","doi-asserted-by":"publisher","DOI":"10.1080\/07435809609043735"},{"key":"2024102600101596000_2024.10.20.619295v1.44","doi-asserted-by":"publisher","DOI":"10.1210\/en.2014-1782"},{"key":"2024102600101596000_2024.10.20.619295v1.45","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-008-0523-4"},{"key":"2024102600101596000_2024.10.20.619295v1.46","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0707963105"},{"key":"2024102600101596000_2024.10.20.619295v1.47","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.169185"},{"key":"2024102600101596000_2024.10.20.619295v1.48","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2017.08.005"},{"key":"2024102600101596000_2024.10.20.619295v1.49","doi-asserted-by":"publisher","DOI":"10.4161\/auto.7.12.17909"},{"key":"2024102600101596000_2024.10.20.619295v1.50","doi-asserted-by":"publisher","DOI":"10.4161\/auto.25900"},{"key":"2024102600101596000_2024.10.20.619295v1.51","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21218323"},{"key":"2024102600101596000_2024.10.20.619295v1.52","doi-asserted-by":"publisher","DOI":"10.3390\/cells10082125"},{"key":"2024102600101596000_2024.10.20.619295v1.53","doi-asserted-by":"publisher","DOI":"10.1038\/nature07311"},{"key":"2024102600101596000_2024.10.20.619295v1.54","doi-asserted-by":"crossref","unstructured":"J. J. Jennings, Jr. , et al., Mitochondrial aberrations in mucolipidosis type IV J Biol Chem 281 , 39041\u201339050 (2006).","DOI":"10.1074\/jbc.M607982200"},{"key":"2024102600101596000_2024.10.20.619295v1.55","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2009.12.056"},{"key":"2024102600101596000_2024.10.20.619295v1.56","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.3502"},{"key":"2024102600101596000_2024.10.20.619295v1.57","doi-asserted-by":"crossref","unstructured":"K. Noben-Trauth , \"The TRPML3 channel: from gene to function\" in Advances in Experimental Medicine and Biology. (Springer, 2011), vol. 704, chap. 13, pp. 229-237.","DOI":"10.1007\/978-94-007-0265-3_13"},{"key":"2024102600101596000_2024.10.20.619295v1.58","doi-asserted-by":"publisher","DOI":"10.1210\/en.2016-1758"},{"key":"2024102600101596000_2024.10.20.619295v1.59","doi-asserted-by":"crossref","unstructured":"H. J. Kim et al., Gain-of-function mutation in TRPML3 causes the mouse varitint-waddler phenotype J Biol Chem 282 , 36138\u201336142 (2007).","DOI":"10.1074\/jbc.C700190200"},{"key":"2024102600101596000_2024.10.20.619295v1.60","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2008.156992"},{"key":"2024102600101596000_2024.10.20.619295v1.61","first-page":"e282","article-title":"Histological characterization of aldosterone-producing adrenocortical adenomas with different somatic mutations","volume":"105","year":"2019","journal-title":"The Journal of Clinical Endocrinology & Metabolism"},{"key":"2024102600101596000_2024.10.20.619295v1.62","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2010-2785"},{"key":"2024102600101596000_2024.10.20.619295v1.63","doi-asserted-by":"publisher","DOI":"10.1373\/clinchem.2015.251199"},{"key":"2024102600101596000_2024.10.20.619295v1.64","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.114.04453"},{"key":"2024102600101596000_2024.10.20.619295v1.65","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(17)30135-3"},{"key":"2024102600101596000_2024.10.20.619295v1.66","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.37.3.845"},{"key":"2024102600101596000_2024.10.20.619295v1.67","doi-asserted-by":"publisher","DOI":"10.1007\/s00467-012-2367-6"},{"key":"2024102600101596000_2024.10.20.619295v1.68","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.114.03311"},{"key":"2024102600101596000_2024.10.20.619295v1.69","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2015-3239"},{"key":"2024102600101596000_2024.10.20.619295v1.70","doi-asserted-by":"crossref","unstructured":"J. Rege et al., Identification of somatic mutations in CLCN2 in aldosterone-producing adenomas. Journal of the Endocrine Society 4 (2020).","DOI":"10.1210\/jendso\/bvaa123"},{"key":"2024102600101596000_2024.10.20.619295v1.71","doi-asserted-by":"publisher","DOI":"10.1016\/0039-128X(87)90097-3"},{"key":"2024102600101596000_2024.10.20.619295v1.72","doi-asserted-by":"publisher","DOI":"10.1210\/en.2005-0951"},{"key":"2024102600101596000_2024.10.20.619295v1.73","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsbmb.2003.07.006"},{"key":"2024102600101596000_2024.10.20.619295v1.74","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2005-0836"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2024.10.20.619295","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T07:19:01Z","timestamp":1768461541000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2024.10.20.619295"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,23]]},"references-count":74,"URL":"https:\/\/doi.org\/10.1101\/2024.10.20.619295","relation":{},"subject":[],"published":{"date-parts":[[2024,10,23]]},"subtype":"preprint"}}