{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T10:01:33Z","timestamp":1753869693996,"version":"3.41.2"},"reference-count":12,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2023,10,5]],"date-time":"2023-10-05T00:00:00Z","timestamp":1696464000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp;amp; Gen Med"],"published-print":{"date-parts":[[2024,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Introduction<\/jats:title><jats:p>Atypical hemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy. Personal genome analyses have revealed numerous aHUS\u2010causing variants, mainly complement\u2010related genes. However, not all aHUS\u2010causing variants have been functionally validated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>An exome sequence analysis of a Japanese multiplex family composed of three patients diagnosed with aHUS in infancy and showing frequent relapses clustered in a dominant transmission mode was performed. Protein interaction between the C3d and C\u2010terminal domains of factor H was analyzed using a quartz crystal microbalance.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Following filtering by heterozygous variants, amino acid substitutions, and allele frequency, the analysis revealed eight rare variants shared by the affected individuals. Variant prioritization listed <jats:italic>C3<\/jats:italic> p.W1034R as the most likely candidate gene mutation in the affected individuals, despite being classified as a variant of uncertain significance. Binding of recombinant C3d harboring 1034R to recombinant short consensus repeats 15 to 20 of factor H was significantly suppressed compared with that of C3 with 1034W.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p><jats:italic>C3<\/jats:italic> p.W1034R results in an inherited form of aHUS that often presents with recurrent episodes, possibly because of impaired interactions between the C3d and C\u2010terminal domains of factor H. Following comprehensive genomic analysis, functional validation of C3 p.W1034R strengthens the molecular basis for aHUS pathophysiology.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.2288","type":"journal-article","created":{"date-parts":[[2023,10,5]],"date-time":"2023-10-05T10:06:12Z","timestamp":1696500372000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Defective C3d caused by <i>C3<\/i> p.<scp>W1034R<\/scp> in inherited atypical hemolytic uremic syndrome"],"prefix":"10.1002","volume":"12","author":[{"given":"Masafumi","family":"Tsuchida","sequence":"first","affiliation":[{"name":"Division of Clinical Nephrology and Rheumatology, Kidney Research Center Niigata University Graduate School of Medical and Dental Sciences  Niigata Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6167-555X","authenticated-orcid":false,"given":"Shin","family":"Goto","sequence":"additional","affiliation":[{"name":"Division of Clinical Nephrology and Rheumatology, Kidney Research Center Niigata University Graduate School of Medical and Dental Sciences  Niigata Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hirofumi","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Division of Clinical Nephrology and Rheumatology, Kidney Research Center Niigata University Graduate School of Medical and Dental Sciences  Niigata Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sawako","family":"Goto","sequence":"additional","affiliation":[{"name":"Department of Applied Molecular Medicine, Kidney Research Center Niigata University Graduate School of Medical and Dental Sciences  Niigata Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroki","family":"Yamaguchi","sequence":"additional","affiliation":[{"name":"Division of Clinical Nephrology and Rheumatology, Kidney Research Center Niigata University Graduate School of Medical and Dental Sciences  Niigata Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ichiei","family":"Narita","sequence":"additional","affiliation":[{"name":"Division of Clinical Nephrology and Rheumatology, Kidney Research Center Niigata University Graduate School of Medical and Dental Sciences  Niigata Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,10,5]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2013050453"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2018070759"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102008\u201001\u2010133702"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10157\u2010018\u20101549\u20103"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2016060606"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1017087108"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2017.01.004"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra0902814"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/pro.3943"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102014\u201010\u2010609073"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkq603"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/nargab\/lqaa032"}],"container-title":["Molecular Genetics &amp; Genomic Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mgg3.2288","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,29]],"date-time":"2024-01-29T12:24:31Z","timestamp":1706531071000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/mgg3.2288"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,5]]},"references-count":12,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2024,1]]}},"alternative-id":["10.1002\/mgg3.2288"],"URL":"https:\/\/doi.org\/10.1002\/mgg3.2288","archive":["Portico"],"relation":{},"ISSN":["2324-9269","2324-9269"],"issn-type":[{"type":"print","value":"2324-9269"},{"type":"electronic","value":"2324-9269"}],"subject":[],"published":{"date-parts":[[2023,10,5]]},"assertion":[{"value":"2023-04-27","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-09-19","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-10-05","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2288"}}