Factor H Competitor Generated by Gene Conversion Events Associates with Atypical Hemolytic Uremic Syndrome.

Autor:	Goicoechea de Jorge E; Department of Immunology, Complutense University and Research Institute Hospital 12 de Octubre (imas12), Madrid, Spain., Tortajada A; Department of Immunology, Complutense University and Research Institute Hospital 12 de Octubre (imas12), Madrid, Spain., García SP; Centro de Investigaciones Biológicas and Ciber de Enfermedades Raras, Madrid, Spain., Gastoldi S; IRCCS, Istituto di Ricerche Farmacologiche 'Mario Negri,' Clinical Research Center for Rare Diseases 'Aldo e Cele Daccò,' Ranica, Bergamo, Italy., Merinero HM; Centro de Investigaciones Biológicas and Ciber de Enfermedades Raras, Madrid, Spain., García-Fernández J; Centro de Investigaciones Biológicas and Ciber de Enfermedades Raras, Madrid, Spain., Arjona E; Centro de Investigaciones Biológicas and Ciber de Enfermedades Raras, Madrid, Spain., Cao M; Servicio de Nefrologia, Hospital Universitario A Coruña, A Coruña, Spain; and., Remuzzi G; IRCCS, Istituto di Ricerche Farmacologiche 'Mario Negri,' Clinical Research Center for Rare Diseases 'Aldo e Cele Daccò,' Ranica, Bergamo, Italy.; Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy., Noris M; IRCCS, Istituto di Ricerche Farmacologiche 'Mario Negri,' Clinical Research Center for Rare Diseases 'Aldo e Cele Daccò,' Ranica, Bergamo, Italy., Rodríguez de Córdoba S; Centro de Investigaciones Biológicas and Ciber de Enfermedades Raras, Madrid, Spain; srdecordoba@cib.csic.es.
Jazyk:	angličtina
Zdroj:	Journal of the American Society of Nephrology : JASN [J Am Soc Nephrol] 2018 Jan; Vol. 29 (1), pp. 240-249. Date of Electronic Publication: 2017 Oct 09.
DOI:	10.1681/ASN.2017050518
Abstrakt:	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 =513) using multiple ligation probe amplification uncovered nine unrelated patients carrying a genetic abnormality in the complement factor H related 1 gene ( CFHR1 ) that originates by recurrent gene conversion events between the CFH and CFHR1 genes. The novel CFHR1 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 CFHR1 mutant, six patients carried the previously uncharacterized CFH-411T variant. In functional analyses, the mutant FHR-1 protein strongly competed the binding of FH to cell surfaces, impairing complement regulation, whereas the CFH-411T polymorphism lacked functional consequences. Carriers of the CFHR1 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. (Copyright © 2018 by the American Society of Nephrology.)
Databáze:	MEDLINE
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