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Abstract: SA-PO592

Deleterious Impact of a Novel CFH Splice Site Mutation in Atypical Hemolytic Uremic Syndrome

Session Information

Category: Genetic Diseases of the Kidney

  • 802 Non-Cystic Mendelian Diseases


  • Seidel, Anna, University Clinic Leipzig, Leipzig, Germany
  • Schönauer, Ria, University Clinic Leipzig, Leipzig, Germany
  • Bergmann, Carsten, Bioscientia, Ingelheim, Germany
  • Grohmann, Maik, Bioscientia, Ingelheim, Germany
  • Lindner, Tom H., University Clinic Leipzig, Leipzig, Germany
  • Halbritter, Jan, University Clinic Leipzig, Leipzig, Germany

Atypical hemolytic uremic syndrome (aHUS) is a rare disease typically based upon uncontrolled activation of the alternative complement pathway (ACP). Clinical signs and symptoms comprise microangiopathic haemolytic anemia (MAHA), thrombocytopenia, and acute kidney failure (AKI). Mutations in ACP regulating genes such as C3, CFI, CFH, and MCP/CD46 are found in around 50% of patients.


A 27 year-old female without prior past medical history presented with nausea, confusion, petechial bleeding, and anuric AKI necessitating initiation of dialysis. Laboratory examination revealed MAHA with schistocytes but normal ADAMTS13-levels. Kidney biopsy showed glomerulary thrombotic microangiopathy (TMA), which was treated with steroids, plasmapheresis, and eculizumab (induction/maintenance), leading to complete hematological and clinical remission, as well as significant recovery of kidney function within 2 months. Targeted next generation sequencing for aHUS-associated genes identified a paternally transmitted novel heterozygous mutation in the CFH gene (c.3134-2A>G). CFH encodes complement factor H, a key inhibitory protein of the ACP. The mutation is located in the obligatory splice acceptor site of intron 19. Sanger sequencing of patient cDNA indicated that as a consequence of the mutation, alternative splicing results in a deletion of the first 27 base pairs of exon 20. On the protein level, CFH consists of 20 similar structural conserved Sushi domains, where each has four conserved cysteines forming two disulfide bonds. This in-frame deletion leads to a partial loss of the Sushi domain 18 (p.Asp1045_Thr1053del) including a cysteine (p.Cys1048). As this cysteine is thought to be essential for proper protein folding, its loss may consequently result in a defective protein structure, impairing binding to C3.


In summary, we detected a new CFH splice site mutation in a patient with aHUS, which probably leads to an incorrect protein structure impairing inhibitory control of C3 and thereby ACP activity. Incomplete penetrance demonstrated by the clinically asymptomatic father underlines the necessity of an additional disease trigger for aHUS manifestation.