The molecular basis of Familial hemolytic uremic syndrome : Mutation analysis of factor H gene reveals a hot spot in short consensus repeat 20

• Published in: Journal of the American Society of Nephrology Vol. 12; no. 2; pp. 297 - 307
• Main Authors: CAPRIOLI, Jessica, BETTINAGLIO, Paola, ZIPFEL, Peter F, AMADEI, Barbara, DAINA, Erica, GAMBA, Sara, SKERKA, Christine, MARZILIANO, Nicola, REMUZZI, Giuseppe, NORIS, Marina
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 01-02-2001
• Subjects: Amino Acid Sequence; Base Sequence; Biological and medical sciences; Complement Factor H - chemistry; Complement Factor H - genetics; Genetic Predisposition to Disease; Hemolytic-Uremic Syndrome - genetics; Humans; Medical sciences; Molecular Sequence Data; Mutation; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Pedigree; Polymorphism, Single-Stranded Conformational; Renal failure; Repetitive Sequences, Amino Acid; Chromosomal aberration; Kidney disease; Human; Urinary system disease; Hemolytic uremic syndrome; Reverse transcription; Hemopathy; Homozygosity; Heterozygosity; Hemolytic anemia; Gene; Autosomal character; Renal failure; Deletion; Abnormal chromosome; Recessive character; Genetics; Dominant character; Mutation
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/ASN.V122297

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.