Atypical haemolytic uraemic syndrome associated with a hybrid complement gene

PLoS Med. 2006 Oct;3(10):e431. doi: 10.1371/journal.pmed.0030431.

Abstract

Background: Sequence analysis of the regulators of complement activation (RCA) cluster of genes at chromosome position 1q32 shows evidence of several large genomic duplications. These duplications have resulted in a high degree of sequence identity between the gene for factor H (CFH) and the genes for the five factor H-related proteins (CFHL1-5; aliases CFHR1-5). CFH mutations have been described in association with atypical haemolytic uraemic syndrome (aHUS). The majority of the mutations are missense changes that cluster in the C-terminal region and impair the ability of factor H to regulate surface-bound C3b. Some have arisen as a result of gene conversion between CFH and CFHL1. In this study we tested the hypothesis that nonallelic homologous recombination between low-copy repeats in the RCA cluster could result in the formation of a hybrid CFH/CFHL1 gene that predisposes to the development of aHUS.

Methods and findings: In a family with many cases of aHUS that segregate with the RCA cluster we used cDNA analysis, gene sequencing, and Southern blotting to show that affected individuals carry a heterozygous CFH/CFHL1 hybrid gene in which exons 1-21 are derived from CFH and exons 22/23 from CFHL1. This hybrid encodes a protein product identical to a functionally significant CFH mutant (c.3572C>T, S1191L and c.3590T>C, V1197A) that has been previously described in association with aHUS.

Conclusions: CFH mutation screening is recommended in all aHUS patients prior to renal transplantation because of the high risk of disease recurrence post-transplant in those known to have a CFH mutation. Because of our finding it will be necessary to implement additional screening strategies that will detect a hybrid CFH/CFHL1 gene.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged, 80 and over
  • Blotting, Southern
  • Complement C3b Inactivator Proteins / genetics
  • Complement Factor H / genetics
  • Complement System Proteins / genetics
  • DNA Breaks
  • DNA Mutational Analysis
  • Female
  • Gene Dosage
  • Genetic Predisposition to Disease
  • Hemolytic-Uremic Syndrome / genetics*
  • Humans
  • Male
  • Middle Aged
  • Mutant Chimeric Proteins / genetics*
  • Nucleic Acid Amplification Techniques / methods
  • Polymerase Chain Reaction / methods
  • Sequence Analysis, DNA

Substances

  • CFH-CFHL1 protein, human
  • CFHR1 protein, human
  • Complement C3b Inactivator Proteins
  • Mutant Chimeric Proteins
  • complement factor H, human
  • Complement Factor H
  • Complement System Proteins

Associated data

  • OMIM/605337
  • OMIM/608593
  • RefSeq/NM_000249
  • RefSeq/NM_000251