ClinVar Genomic variation as it relates to human health

Hughes et al. (2006) identified an 84-kb deletion that occurred between 2 virtually identical 29-kb segments of duplication and was located downstream of the CFH gene and upstream of the CFHR4 gene. By sequence analysis in 3 individuals who were homozygous for the deletion, Zipfel et al. (2007) showed that the deletion resulted from nonallelic homologous recombination. Hughes et al. (2006) found that a haplotype carrying a deletion of the CFHR1 and CFHR3 (605336) genes was associated with decreased risk of age-related macular degeneration (ARMD; see 603075), being present on 20% of chromosomes of controls and 8% of chromosomes of individuals with ARMD. The proteins encoded by these genes were absent in serum of homozygotes. The protective effect of the deletion haplotype could not be attributed to linkage disequilibrium with the Y402H variant of complement factor H (134370.0008) and was replicated in an independent sample. Extending their previous work (see Hughes et al., 2006), Zipfel et al. (2007) found that the CFHR1/CFHR3 deletion was associated with an increased risk of atypical hemolytic-uremic syndrome (aHUS; 235400) in 2 independent European cohorts. In the first group, 19 (16%) of 121 aHUS patients had the deletion compared to 2 of 100 control individuals. Three of the patients had a homozygous deletion. All patients had normal serum factor H levels. In the second group comprising 66 patients, 28% had the deletion compared to 6% of controls. Ten percent and 2% of patients and controls, respectively, were homozygous for the deletion. In vitro functional expression studies showed that CFHR1/CFHR3-deficient plasma had decreased protective activity against erythrocyte lysis, suggesting a defective regulation of complement activation. Zipfel et al. (2007) noted that the present study showed an opposite effect for the variant from that of Hughes et al. (2006), which may be due to a disease-modifying action of the deletion or linkage disequilibrium between the deletion and other susceptibility alleles. Of 147 patients with aHUS, 121 of whom had previously been reported by Zipfel et al. (2007), Jozsi et al. (2008) identified serum anti-CFH autoantibodies in 16 (11%); 14 lacked CFHR1/CFHR3 completely and 2 showed extremely low CFHR1/CFHR3 plasma levels. The findings illustrated a new combination of 2 susceptibility factors for the development of aHUS. The CFHR1/CFHR3 deletion exclusively occurs on one of the 2 protective CFH haplotypes, both of which are tagged by the protective allele of single-nucleotide polymorphism rs2274700 (A473A). In a German cohort of 530 ARMD patients, Fritsche et al. (2010) showed that protection against ARMD conferred by delta-CFHR3/CFHR1 was independent of the effects of CFH polymorphisms rs2274700 and rs1061170 (Y402H; 134370.0008). This suggested a functional role of CFHR1 and/or CFHR3 in disease pathogenesis. Fritsche et al. (2010) determined that CFHR3 is a novel human complement regulator that inhibits C3 (120700) convertase activity. CFHR3 displayed antiinflammatory effects by blocking C5A (see 120900) generation and C5A-mediated chemoattraction of neutrophils. In addition, CFHR3 and CFHR1 competed with factor H for binding to the central complement component C3. Thus, deficiency of CFHR3 and CFHR1 resulted in a loss of complement control but enhanced local regulation by factor H. Fritsche et al. (2010) hypothesized that dysregulation of complement may play a central role in ARMD pathology. (less)

Hughes et al. (2006) identified an 84-kb deletion that occurred between 2 virtually identical 29-kb segments of duplication and was located downstream of the CFH gene and upstream of the CFHR4 gene. By sequence analysis in 3 individuals who were homozygous for the deletion, Zipfel et al. (2007) showed that the deletion resulted from nonallelic homologous recombination. Hughes et al. (2006) found that a haplotype carrying a deletion of the CFHR1 and CFHR3 (605336) genes was associated with decreased risk of age-related macular degeneration (ARMD; see 603075), being present on 20% of chromosomes of controls and 8% of chromosomes of individuals with ARMD. The proteins encoded by these genes were absent in serum of homozygotes. The protective effect of the deletion haplotype could not be attributed to linkage disequilibrium with the Y402H variant of complement factor H (134370.0008) and was replicated in an independent sample. Extending their previous work (see Hughes et al., 2006), Zipfel et al. (2007) found that the CFHR1/CFHR3 deletion was associated with an increased risk of atypical hemolytic-uremic syndrome (aHUS; 235400) in 2 independent European cohorts. In the first group, 19 (16%) of 121 aHUS patients had the deletion compared to 2 of 100 control individuals. Three of the patients had a homozygous deletion. All patients had normal serum factor H levels. In the second group comprising 66 patients, 28% had the deletion compared to 6% of controls. Ten percent and 2% of patients and controls, respectively, were homozygous for the deletion. In vitro functional expression studies showed that CFHR1/CFHR3-deficient plasma had decreased protective activity against erythrocyte lysis, suggesting a defective regulation of complement activation. Zipfel et al. (2007) noted that the present study showed an opposite effect for the variant from that of Hughes et al. (2006), which may be due to a disease-modifying action of the deletion or linkage disequilibrium between the deletion and other susceptibility alleles. Of 147 patients with aHUS, 121 of whom had previously been reported by Zipfel et al. (2007), Jozsi et al. (2008) identified serum anti-CFH autoantibodies in 16 (11%); 14 lacked CFHR1/CFHR3 completely and 2 showed extremely low CFHR1/CFHR3 plasma levels. The findings illustrated a new combination of 2 susceptibility factors for the development of aHUS. The CFHR1/CFHR3 deletion exclusively occurs on one of the 2 protective CFH haplotypes, both of which are tagged by the protective allele of single-nucleotide polymorphism rs2274700 (A473A). In a German cohort of 530 ARMD patients, Fritsche et al. (2010) showed that protection against ARMD conferred by delta-CFHR3/CFHR1 was independent of the effects of CFH polymorphisms rs2274700 and rs1061170 (Y402H; 134370.0008). This suggested a functional role of CFHR1 and/or CFHR3 in disease pathogenesis. Fritsche et al. (2010) determined that CFHR3 is a novel human complement regulator that inhibits C3 (120700) convertase activity. CFHR3 displayed antiinflammatory effects by blocking C5A (see 120900) generation and C5A-mediated chemoattraction of neutrophils. In addition, CFHR3 and CFHR1 competed with factor H for binding to the central complement component C3. Thus, deficiency of CFHR3 and CFHR1 resulted in a loss of complement control but enhanced local regulation by factor H. Fritsche et al. (2010) hypothesized that dysregulation of complement may play a central role in ARMD pathology. (less)