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Factors driving immune-dysregulatory disease in individual mutation carriers have remained ill-understood. In addition to its role as a negative regulator of the complement system, CD46 modifies T cell-intrinsic metabolic adaptation and cytokine production. Comparative immunologic analysis of diseased vs\n                    <jats:italic>.<\/jats:italic>\n                    healthy CD46 mutation carriers has not been performed in detail yet. In this study, we comprehensively analyzed clinical, molecular, immune-phenotypic, cytokine secretion, immune-metabolic, and genetic profiles in healthy vs\n                    <jats:italic>.<\/jats:italic>\n                    diseased individuals carrying a rare, heterozygous\n                    <jats:italic>CD46<\/jats:italic>\n                    mutation identified within a large single family. Five out of six studied individuals carried a\n                    <jats:italic>CD46<\/jats:italic>\n                    gene splice-site mutation causing an in-frame deletion of 21 base pairs. One child suffered from aHUS and his paternal uncle manifested with adult-onset systemic lupus erythematosus (SLE). Three mutation carriers had no clinical evidence of CD46-related disease to date. CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cell-intrinsic CD46 expression was uniformly 50%-reduced but was comparable in diseased vs\n                    <jats:italic>.<\/jats:italic>\n                    healthy mutation carriers. Reconstitution experiments defined the 21-base pair-deleted\n                    <jats:italic>CD46<\/jats:italic>\n                    variant as intracellularly\u2014but not surface-expressed and haploinsufficient. Both healthy and diseased mutation carriers displayed reduced CD46-dependent T cell mitochondrial adaptation. Diseased mutation carriers had lower peripheral regulatory T cell (Treg) frequencies and carried potentially epistatic, private rare variants in other inborn errors of immunity (IEI)-associated proinflammatory genes, not found in healthy mutation carriers. In conclusion, low Treg and rare non-\n                    <jats:italic>CD46<\/jats:italic>\n                    immune-gene variants may contribute to clinically manifest\n                    <jats:italic>CD46<\/jats:italic>\n                    haploinsufficiency-associated immune-dysregulation.\n                  <\/jats:p>","DOI":"10.1007\/s10875-023-01547-y","type":"journal-article","created":{"date-parts":[[2023,7,21]],"date-time":"2023-07-21T11:02:05Z","timestamp":1689937325000},"page":"1840-1856","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Immunologic and Genetic Contributors to CD46-Dependent Immune Dysregulation"],"prefix":"10.1007","volume":"43","author":[{"given":"Benedikt J","family":"Meyer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Kunz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sayuri","family":"Seki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Higgins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adhideb","family":"Ghosh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin","family":"Hupfer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian","family":"Baldrich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia R","family":"Hirsiger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna\u00efse J","family":"Jauch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Val\u00e9rie","family":"Burgener","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonas","family":"L\u00f6tscher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Aschwanden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Dickenmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mihaela","family":"Stegert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph T","family":"Berger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Daikeler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingmar","family":"Heijnen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander A","family":"Navarini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Rudin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Yamamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Kemper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Hess","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9121-6936","authenticated-orcid":false,"given":"Mike","family":"Recher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,7,21]]},"reference":[{"issue":"12","key":"1547_CR1","doi-asserted-by":"crossref","first-page":"2808","DOI":"10.1016\/j.biocel.2013.09.016","volume":"45","author":"H Yamamoto","year":"2013","unstructured":"Yamamoto H, Fara AF, Dasgupta P, Kemper C. 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