E. Goicoechea de Jorge

Translational Mini-Review Series on Complement Factor H: Genetics and disease associations of human complement factor H

Factor H is an abundant plasma glycoprotein that plays a critical role in the regulation of the complement system in plasma and in the protection of host cells and tissues from damage by complement activation. Several recent studies have described the association of genetic variations of the complement factor H gene (CFH) with atypical haemolytic uraemic syndrome (aHUS), age‐related macular degeneration (AMD) and membranoproliferative glomerulonephritis (MPGN). This review summarizes our current knowledge of CFH genetics and examines the CFH genotype–phenotype correlations that are helping to understand the molecular basis underlying these renal and ocular pathologies.

Dimerization of complement factor H-related proteins modulates complement activation in vivo

The complement system is a key component regulation influences susceptibility to age-related macular degeneration, meningitis, and kidney disease. Variation includes genomic rearrangements within the complement factor H-related (CFHR) locus. Elucidating the mechanism underlying these associations has been hindered by the lack of understanding of the biological role of CFHR proteins. Here we present unique structural data demonstrating that three of the CFHR proteins contain a shared dimerization motif and that this hitherto unrecognized structural property enables formation of both homodimers and heterodimers. Dimerization confers avidity for tissue-bound complement fragments and enables these proteins to efficiently compete with the physiological complement inhibitor, complement factor H (CFH), for ligand binding. Our data demonstrate that these CFHR proteins function as competitive antagonists of CFH to modulate complement activation in vivo and explain why variation in the CFHRs predisposes to disease.

Recurrence of complement factor H-related protein 5 nephropathy in a renal transplant.

Complement factor H‐related protein 5 (CFHR5) nephropathy is a familial renal disease endemic in Cyprus. It is characterized by persistent microscopic hematuria, synpharyngitic macroscopic hematuria and progressive renal impairment. Isolated glomerular accumulation of complement component 3 (C3) is typical with variable degrees of glomerular inflammation. Affected individuals have a heterozygous internal duplication in the CFHR5 gene, although the mechanism through which this mutation results in renal disease is not understood. Notably, the risk of progressive renal failure in this condition is higher in males than females. We report the first documented case of recurrence of CFHR5 nephropathy in a renal transplant in a 53‐year‐old Cypriot male. Strikingly, histological changes of CFHR5 nephropathy were evident in the donor kidney 46 days post‐transplantation. This unique case demonstrates that renal‐derived CFHR5 protein cannot prevent the development of CFHR5 nephropathy.

Alkaptonuria in the Dominican Republic: identification of the founder AKU mutation and further evidence of mutation hot spots in the HGO gene

Alkaptonuria (AKU, MIM 203500), the first human disease to be recognised as a recessive trait and Archibald Garrods prototype “inborn error of metabolism”,1,2 is a rare disorder of the phenylalanine and tyrosine catabolic pathway caused by the deficiency of homogentisate dioxygenase (HGO, EC 1.13.11.5) activity.3 AKU patients are homozygous, or compound heterozygous, for loss of function mutations in HGO .4 As a consequence of this defect, AKU patients cannot convert homogentisate to maleylacetoacetate, which results in homogentisic aciduria, ochronosis, and arthritis.5 AKU shows remarkable allelic heterogeneity. More than 40 different AKU mutations have been identified in a total of fewer than 100 unrelated patients from many different countries. In addition to the AKU mutations, 19 polymorphisms have been encountered within the human HGO gene (for a complete description of the HGO mutations and polymorphisms see the AKU database (http://www.cib.csic.es/~akudb/index.htm)). The analysis of the haplotype association of polymorphisms in the AKU chromosomes has been very useful for the identification of the different AKU alleles and for tracing their migration during recent human history. In this regard, it has been shown that the three most widespread AKU mutation in Europe, M368V, V300G, and P230S (representing 20%, 5%, and 5% of European AKU chromosomes, respectively) are not recurrent mutations. Instead they are probably old mutations that were introduced into Europe with the founder populations and have spread throughout western Europe with the different migrations.6 Analysis of the HGO mutations and polymorphisms has also shown that the GGG sequence motif (or its reverse complement CCC) is a mutational hot spot in the HGO gene.7 AKU has a very low prevalence (1:100 000-250 000) in most populations. However, in certain areas, such as the Dominican Republic and Slovakia, the incidence of alkaptonuria is unusually high.8,9 In …

Molecular analyses of the HGO gene mutations in Turkish alkaptonuria patients suggest that the R58fs mutation originated from Central Asia and was spread throughout Europe and Anatolia by human migrations

Summary: Alkaptonuria (AKU) is a rare metabolic disorder of phenylalanine catabolism that is inherited as an autosomal recessive trait. AKU is caused by loss-of-function mutations in the homogentisate 1,2-dioxygenase (HGO) gene. The deficiency of homogentisate 1,2-dioxygenase activity causes homogentisic aciduria, ochronosis and arthritis. We present the first molecular study of the HGO gene in Turkish AKU patients. Seven unrelated AKU families from different regions in Turkey were analysed. Patients in three families were homozygous for the R58fs mutation; another three families were homozygous for the R225H mutation; and one family was homozygous for the G270R mutation. Analysis of nine intragenic HGO polymorphisms showed that the R58fs, R225H and G270R Turkish AKU mutations are associated with specific HGO haplotypes. The comparison with previously reported haplotypes associated with these mutations from other populations revealed that the R225H is a recurrent mutation in Turkey, whereas G270R most likely has a Slovak origin. Most interestingly, these analyses showed that the Turkish R58fs mutation shares an HGO haplotype with the R58fs mutation found in Finland, Slovakia and India, suggesting that R58fs is an old AKU mutation that probably originated in central Asia and spread throughout Europe and Anatolia during human migrations.

Lack of association between polymorphisms in C4b-binding protein and atypical haemolytic uraemic syndrome in the Spanish population.

Dysregulation of the alternative pathway of complement activation, caused by mutations or polymorphisms in the genes encoding factor H, membrane co‐factor protein, factor I or factor B, is associated strongly with predisposition to atypical haemolytic uraemic syndrome (aHUS). C4b‐binding protein (C4BP), a major regulator of the classical pathway of complement activation, also has capacity to regulate the alternative pathway. Interestingly, the C4BP polymorphism p.Arg240His has been associated recently with predisposition to aHUS and the risk allele His240 showed decreased capacity to regulate the alternative pathway. Identification of novel aHUS predisposition factors has important implications for diagnosis and treatment in a significant number of aHUS patients; thus, we sought to replicate these association studies in an independent cohort of aHUS patients. In this study we show that the C4BP His240 allele corresponds to the C4BP*2 allele identified previously by isoelectric focusing in heterozygosis in 1·9–3·7% of unrelated Caucasians. Crucially, we found no differences between 102 unrelated Spanish aHUS patients and 128 healthy age‐matched Spanish controls for the frequency of carriers of the His240 C4BP allele. This did not support an association between the p.Arg240His C4BP polymorphism and predisposition to aHUS in the Spanish population. In a similar study, we also failed to sustain an association between C4BP polymorphisms and predisposition to age‐related macular degeneration, another disorder which is associated strongly with polymorphisms in factor H, and is thought to involve alternative pathway dysregulation.

Atypical hemolytic uremic syndrome: telling the difference between H and Y

Mutations in the complement factor H (CFH) gene are frequently associated with atypical hemolytic uremic syndrome (aHUS). Hakobyan et al. have developed novel reagents that can rapidly determine the contribution of each CFH allele to the total plasma CFH pool, showing that low-expression CFH alleles are important risk factors for the development of aHUS. These reagents represent a significant contribution to the techniques used to determine susceptibility factors among individuals with aHUS.