{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T14:27:57Z","timestamp":1790692077326,"version":"4.1.0"},"reference-count":29,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JASN"],"published-print":{"date-parts":[[2018,1]]},"abstract":"\n Atypical hemolytic uremic syndrome (aHUS), a rare form of thrombotic microangiopathy caused by complement pathogenic variants, mainly affects the kidney microvasculature. A retrospective genetic analysis in our aHUS cohort (\n n<\/jats:italic>\n =513) using multiple ligation probe amplification uncovered nine unrelated patients carrying a genetic abnormality in the complement factor H related 1 gene (\n CFHR1<\/jats:italic>\n ) that originates by recurrent gene conversion events between the\n CFH<\/jats:italic>\n and\n CFHR1<\/jats:italic>\n genes. The novel\n CFHR1<\/jats:italic>\n mutants encode an FHR-1 protein with two amino acid substitutions, L290S and A296V, converting the FHR-1 C terminus into that of factor H (FH). Next-generation massive-parallel DNA sequencing (NGS) analysis did not detect these genetic abnormalities. In addition to the\n CFHR1<\/jats:italic>\n mutant, six patients carried the previously uncharacterized\n CFH-411T<\/jats:italic>\n variant. In functional analyses, the mutant FHR-1 protein strongly competed the binding of FH to cell surfaces, impairing complement regulation, whereas the\n CFH-411T<\/jats:italic>\n polymorphism lacked functional consequences. Carriers of the\n CFHR1<\/jats:italic>\n mutation presented with severe aHUS during adulthood; 57% of affected women in this cohort presented during the postpartum period. Analyses in patients and unaffected carriers showed that FH plasma levels determined by the nonmutated chromosome modulate disease penetrance. Crucially, in the activated endothelial (HMEC-1) cell assay, reduced FH plasma levels produced by the nonmutated chromosome correlated inversely with impairment of complement regulation, measured as C5b-9 deposition. Our data advance understanding of the genetic complexities underlying aHUS, illustrate the importance of performing functional analysis, and support the use of complementary assays to disclose genetic abnormalities not revealed by current NGS analysis.\n <\/jats:p>","DOI":"10.1681\/asn.2017050518","type":"journal-article","created":{"date-parts":[[2017,10,9]],"date-time":"2017-10-09T21:10:32Z","timestamp":1507583432000},"page":"240-249","source":"Crossref","is-referenced-by-count":38,"title":["Factor H Competitor Generated by Gene Conversion Events Associates with Atypical Hemolytic Uremic Syndrome"],"prefix":"10.1681","volume":"29","author":[{"given":"Elena","family":"Goicoechea de Jorge","sequence":"first","affiliation":[{"name":"Department of Immunology, Complutense University and Research Institute Hospital 12 de Octubre (imas12), Madrid, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agust\u00edn","family":"Tortajada","sequence":"additional","affiliation":[{"name":"Department of Immunology, Complutense University and Research Institute Hospital 12 de Octubre (imas12), Madrid, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheila Pinto","family":"Garc\u00eda","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Biol\u00f3gicas and Ciber de Enfermedades Raras, Madrid, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Gastoldi","sequence":"additional","affiliation":[{"name":"IRCCS, Istituto di Ricerche Farmacologiche \u201cMario Negri,\u201d Clinical Research Center for Rare Diseases \u201cAldo e Cele Dacc\u00f2,\u201d Ranica, Bergamo, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e9ctor Mart\u00edn","family":"Merinero","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Biol\u00f3gicas and Ciber de Enfermedades Raras, Madrid, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jes\u00fas","family":"Garc\u00eda-Fern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Biol\u00f3gicas and Ciber de Enfermedades Raras, Madrid, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilia","family":"Arjona","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Biol\u00f3gicas and Ciber de Enfermedades Raras, Madrid, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mercedes","family":"Cao","sequence":"additional","affiliation":[{"name":"Servicio de Nefrologia, Hospital Universitario A Coru\u00f1a, A Coru\u00f1a, Spain; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Remuzzi","sequence":"additional","affiliation":[{"name":"IRCCS, Istituto di Ricerche Farmacologiche \u201cMario Negri,\u201d Clinical Research Center for Rare Diseases \u201cAldo e Cele Dacc\u00f2,\u201d Ranica, Bergamo, Italy;"},{"name":"Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Noris","sequence":"additional","affiliation":[{"name":"IRCCS, Istituto di Ricerche Farmacologiche \u201cMario Negri,\u201d Clinical Research Center for Rare Diseases \u201cAldo e Cele Dacc\u00f2,\u201d Ranica, Bergamo, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santiago","family":"Rodr\u00edguez de C\u00f3rdoba","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Biol\u00f3gicas and Ciber de Enfermedades Raras, Madrid, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2017,10,9]]},"reference":[{"key":"B1-20230819","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1056\/NEJMra020528","article-title":"Thrombotic microangiopathies.","volume":"347","author":"Moake","year":"2002","journal-title":"N Engl J Med"},{"key":"B2-20230819","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/j.kint.2016.10.005","article-title":"Atypical hemolytic uremic syndrome and C3 glomerulopathy: Conclusions from a \u201cKidney Disease: Improving Global Outcomes\u201d (KDIGO) Controversies Conference.","volume":"91","author":"Goodship","year":"2017","journal-title":"Kidney Int"},{"key":"B3-20230819","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1016\/j.imbio.2015.05.015","article-title":"Complement genetics and susceptibility to inflammatory disease. 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