Variant-specific quantification of factor H in plasma identifies null alleles associated with atypical hemolytic uremic syndrome

被引:43
作者
Hakobyan, Svetlana [1 ]
Tortajada, Agustin [2 ]
Harris, Claire L. [1 ]
de Cordoba, Santiago R. [2 ]
Morgan, Bryan P. [1 ]
机构
[1] Cardiff Univ, Sch Med, Dept Infect Immun & Biochem, Cardiff CF14 4XN, Wales
[2] CSIC, Ctr Invest Biol, Madrid, Spain
关键词
complement; family history; hemolytic uremic syndrome; polymorphisms; MEMBRANE COFACTOR PROTEIN; HUMAN-COMPLEMENT; MONOCLONAL-ANTIBODIES; MUTATIONS; FHL-1/RECONECTIN; PREDISPOSE; DEFICIENCY; SECRETION; DOMAINS;
D O I
10.1038/ki.2010.275
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
Atypical hemolytic uremic syndrome (aHUS) is associated with complement alternative pathway defects in over half the cases. Point mutations that affect complement surface regulation are common in factor H (CFH); however, sometimes individuals have null mutations in heterozygosis. The latter are difficult to identify, although a consistently low plasma factor H (fH) concentration is suggestive; definitive proof requires demonstration that the mutant sequence is not expressed in vitro. Here, novel reagents and assays that distinguish and individually quantify the common factor H-Y402H polymorphic variants were used to identify alleles of the CFH gene, resulting in low or null expression of full-length fH and also normal or increased expression of the alternative splice product factor H-like-1 (FHL-1). Our assay identified three Y402H heterozygotes with low or absent fH-H402 but normal or increased FHL-1-H402 levels in a cohort of affected patients. Novel mutations explained the null phenotype in two cases, which was confirmed by family studies in one. In the third case, family studies showed that a known mutation was present on the Y allele. The cause of reduced expression of the H allele was not found, although the data suggested altered splicing. In each family, inheritance of low expression or null alleles for fH strongly associated with aHUS. Thus, our assays provide a rapid means to identify fH expression defects without resorting to gene sequencing or expression analysis. Kidney International (2010) 78, 782-788; doi: 10.1038/ki.2010.275; published online 11 August 2010
引用
收藏
页码:782 / 788
页数:7
相关论文
共 32 条
[1]   Human factor H deficiency - Mutations in framework cysteine residues and block in H protein secretion and intracellular catabolism [J].
Ault, BH ;
Schmidt, BZ ;
Fowler, NL ;
Kashtan, CE ;
Ahmed, AE ;
Vogt, BA ;
Colten, HR .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (40) :25168-25175
[2]   HIV-associated thrombotic microangiopathy in the era of highly active antiretroviral therapy: An observational study [J].
Becker, S ;
Fusco, G ;
Fusco, J ;
Balu, R ;
Gangjee, S ;
Brennan, C ;
Feinberg, J .
CLINICAL INFECTIOUS DISEASES, 2004, 39 :S267-S275
[3]   Non-enteropathic hemolytic uremic syndrome: Causes and short-term course [J].
Constantinescu, AR ;
Bitzan, M ;
Weiss, LS ;
Christen, E ;
Kaplan, BS ;
Cnaan, A ;
Trachtman, H .
AMERICAN JOURNAL OF KIDNEY DISEASES, 2004, 43 (06) :976-982
[4]   The human complement factor H:: functional roles, genetic variations and disease associations [J].
de Córdoba, SR ;
Esparza-Gordillo, J ;
de Jorge, EG ;
Lopez-Trascasa, M ;
Sánchez-Corral, P .
MOLECULAR IMMUNOLOGY, 2004, 41 (04) :355-367
[5]   Gain-of-function mutations in complement factor B are associated with atypical hemolytic uremic syndrome [J].
de Jorge, Elena Goicoechea ;
Harris, Claire L. ;
Esparza-Gordillo, Jorge ;
Carreras, Luis ;
Arranz, Elena Aller ;
Garrido, Cynthia Abarrategui ;
Lopez-Trascasa, Margarita ;
Sanchez-Corral, Pilar ;
Morgan, B. Paul ;
Rodriguez de Cordoba, Santiago .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (01) :240-245
[6]   Drug-induced thrombotic thrombocytopenic purpura/hemolytic uremic syndrome: A concise review [J].
Dlott, JS ;
Danielson, CF ;
Blue-Hnidy, DE ;
McCarthy, LJ .
THERAPEUTIC APHERESIS AND DIALYSIS, 2004, 8 (02) :102-111
[7]   Heterozygous and homozygous factor H deficiencies associated with hemolytic uremic syndrome or membranoproliferative glomerulonephritis:: Report and genetic analysis of 16 cases [J].
Dragon-Durey, MA ;
Frémeaux-Bacchi, V ;
Loirat, C ;
Blouin, J ;
Niaudet, P ;
Deschenes, G ;
Coppo, P ;
Fridman, WH ;
Weiss, L .
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2004, 15 (03) :787-795
[8]   Complement factor H polymorphism and age-related macular degeneration [J].
Edwards, AO ;
Ritter, R ;
Abel, KJ ;
Manning, A ;
Panhuysen, C ;
Farrer, LA .
SCIENCE, 2005, 308 (5720) :421-424
[9]   Insights into hemolytic uremic syndrome:: Segregation of three independent predisposition factors in a large, multiple affected pedigree [J].
Esparza-Gordillo, J ;
de Jorge, EG ;
Garrido, CA ;
Carreras, L ;
López-Trascasa, M ;
Sánchez-Corral, P ;
de Córdoba, SR .
MOLECULAR IMMUNOLOGY, 2006, 43 (11) :1769-1775
[10]   Genetic and environmental factors influencing the human factor H plasma levels [J].
Esparza-Gordillo, J ;
Soria, JM ;
Buil, A ;
Almasy, L ;
Blangero, J ;
Fontcuberta, J ;
de Córdoba, SR .
IMMUNOGENETICS, 2004, 56 (02) :77-82