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Mario Negri Institute for Pharmacological Research, Clinical Research
Center for Rare Diseases, Aldo e Cele Daccò,
Villa Camozzi—Ranica, Italy
Hans-Knöll-Institute for Natural Products
Research, Jena, Germany
PE Applied Biosystems, Monza, Italy
§
Unit of Nephrology and Dialysis, Azienda Ospedaliera, Ospedali Riuniti di
Bergamo, Italy.
Correspondence to Dr. Jessica Caprioli, Clinical Research Center for Rare Diseases, Aldo e Cele Daccò, Mario Negri Institute for Pharmacological Research, Via Gavazzeni, 11, 24125 Bergamo, Italy. Phone: 390 35 319888; Fax: 390 35 319331; E-mail: caprioli{at}marionegri.it
Abstract. The aim of the present study was to clarify whether factor H mutations were involved in genetic predisposition to hemolytic uremic syndrome, by performing linkage and mutation studies in a large number of patients from those referred to the Italian Registry for Recurrent and Familial HUS/TTP. PCR and Western blot analyses were conducted to characterize the biochemical consequences of the mutations. Five mutations in the factor H gene were identified. Three, identified in two families and in a sporadic case, are heterozygous point mutations within the most C-terminal short consensus repeat 20 (SCR20) of factor H, resulting in single amino acid substitutions. The other two mutations introduce premature stop codons that interrupt the translation of factor H. A heterozygous nonsense mutation was identified in SCR8 in one family, and a homozygous 24-bp deletion within SCR20 was identified in a Bedouin family with a recessive mode of inheritance. Reverse transcription-PCR analysis of cDNA from peripheral blood leukocytes from the Bedouin family showed that the deletion lowered factor H mRNA levels. Although heterozygous mutations were associated with normal factor H levels and incomplete penetrance of the disease, the homozygous mutation in the Bedouin family resulted in severe reduction of factor H levels accompanied by very early disease onset. These data provide compelling molecular evidence that genetically determined deficiencies in factor H are involved in both autosomal-dominant and autosomal-recessive hemolytic uremic syndrome and identify SCR20 as a hot spot for mutations in the disease. The mutations identified here give an important hint to the relevance of the C-terminus of factor H in the control of the alternative complement activation pathway.
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