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J Am Soc Nephrol 15:787-795, 2004
© 2004 American Society of Nephrology

CLINICAL SCIENCE

Heterozygous and Homozygous Factor H Deficiencies Associated with Hemolytic Uremic Syndrome or Membranoproliferative Glomerulonephritis: Report and Genetic Analysis of 16 Cases

Marie-Agnès Dragon-Durey*, Véronique Frémeaux-Bacchi*,{dagger}, Chantal Loirat{ddagger}, Jacques Blouin{dagger}, Patrick Niaudet§, Georges Deschenes, Paul Coppo#, Wolf Herman Fridman{dagger} and Laurence Weiss*

*INSERM U430, Institut des Cordeliers, Paris, France; {dagger}Service d’Immunologie Biologique, Hôpital Européen Georges Pompidou, Paris, France; {ddagger}On behalf of the "Société de Néphrologie Pédiatrique," Service de Néphrologie Pédiatrique, Hôpital Robert Debré, Paris, France; §Service de Néphrologie Pédiatrique, Hôpital Necker-Enfants Malades, Paris, France; Service de Néphrologie Pédiatrique, Hôpital Armand Trousseau, Paris, France; #On behalf of the "Réseau national des Microangiopathies Thrombotiques de l’adulte," Service d’Hématologie, Hôpital Necker-Enfants Malades, Paris, France.

Correspondence to Dr. Marie-Agnès Dragon-Durey, Service d’Immunologie Biologique, Hôpital Européen Georges Pompidou, 20 rue Leblanc, 75 015 Paris, France. Phone: 33-1-56-09-39-41; Fax: 33-1-56-09-20-80; E-mail: marie-agnes.durey{at}egp.ap-hop-paris.fr

ABSTRACT. Factor H (FH) is the major regulatory protein of the complement alternative pathway, with a structure consisting of a tandem array of 20 homologous units, called short consensus repeats (SCR). Reported are 16 FH-deficient patients. Among six patients with homozygous deficiency, four presented with membranoproliferative glomerulonephritis, and two with atypical hemolytic uremic syndrome (HUS). The ten other patients had heterozygous FH deficiency and developed atypical HUS. HUS onset occurred from birth to midadulthood, and disease progression was variable. Four children with homozygous or heterozygous FH deficiency and HUS underwent renal transplantation, which was successful in three but failed as a result of recurrence of HUS in one patient. All but one patient exhibited alternative pathway-mediated complement consumption, with no detectable FH antigenic levels or with 50% immunochemical or functional FH levels in the case of complete or partial deficiency, respectively. The molecular mechanisms of the deficiency were documented in all cases by exon-specific sequencing analysis. These mechanisms included nucleotide substitutions, insertion, or deletion located in SCR 2, 7, 11, 13, 15, and 20, leading to an amino acid substitution or to a stop codon. This report emphasizes the variability in the clinical progression of kidney diseases associated with FH deficiencies. Genetic analysis reveals the molecular abnormalities associated with FH deficiencies to be polymorphous.




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