Cfhr5 Deficiency

A number sign (#) is used with this entry because CFHR5 deficiency is caused by heterozygous mutation in the CFHR5 gene (608593) on chromosome 1q32.

Clinical Features

Gale et al. (2010) reported 2 unrelated families with an autosomal dominant form of glomerulonephritis resulting in renal failure. Both families had ancestors from the Troodos mountains of Cyprus. Additional patients of Cypriot origin with a similar disorder were subsequently identified. In all, there were 26 patients from 11 families. All had microscopic hematuria, and many developed macroscopic hematuria following upper respiratory tract infections. Renal biopsies showed glomerulonephritis with C3 (120700) deposits in the subendothelium and mesangium. There was also mesangial matrix expansion, increased glomerular cellularity, and segmental capillary wall thickening. The initial pathologic diagnosis in these patients was membranoproliferative glomerulonephritis type I, which was later refined to C3 glomerulonephritis. The risk of progression appeared to be greater in men than in women with the disease. None of the patients had evidence of retinal disease.

In a comment on the report of Gale et al. (2010), Karumanchi and Thadhani (2010) noted the clinical similarity of this disorder, which they termed 'CFHR5 nephropathy,' to IgA nephropathy (161950).

Vernon et al. (2012) reported a girl who developed chronic glomerulonephritis with C3 deposits following a streptococcal infection. The patient presented at age 7 years with dark-colored proteinuria after a 10-day history of fever and sore throat. After treatment for the infection, she had persistent hematuria and proteinuria. Nine months later, kidney biopsy showed mesangial hypercellularity, segmental endocapillary hypercellularity, and segmental capillary wall double contours. There was mesangial and capillary deposition of C3, C9 (120940), and CFHR5. Electron microscopy showed thickening of the glomerular basement membranes, intramembranous electron-dense deposits, and subendothelial and subepithelial deposits. Twenty months after presentation, a second kidney biopsy showed persistent membranoproliferative glomerulonephritis with tubulointerstitial scarring. Serum CFHR5 was decreased to 37.3% of control values. Treatment with an angiotensin receptor (see 106165) blocker resulted in improved kidney function.

Inheritance

The transmission pattern of CFHR5 deficiency in the Cypriot families reported by Gale et al. (2010) was consistent with autosomal dominant inheritance.

Molecular Genetics

By linkage analysis followed by candidate gene analysis in 2 families with CFHR5 deficiency and glomerulonephritis with family origins in Cyprus, Gale et al. (2010) identified a heterozygous duplication of exons 2 and 3 of the CFHR5 gene (608593.0001). The internal duplication was not seen in a set of 102 controls, but was found in 1 of 1,015 Cypriot controls. Screening of this gene in additional patients of Cypriot origin identified several more with the same duplication. In total, 26 patients from 11 ostensibly unrelated families with renal disease carried the mutation. Haplotype analysis performed in 5 families indicated a founder effect. In vitro functional expression studies showed that the mutant protein bound less well to surface-bound complement compared to wildtype. However, the mutant protein circulated and showed enhanced cofactor activity with complement factor I (CFI; 217030) compared to wildtype CFHR5. Although the precise pathomechanism, was unclear, the findings of abnormal complement deposition in patient renal biopsies indicated a defect in the regulation of C3.

In a girl with CFHR5 deficiency resulting in glomerulonephritis and persistent renal disease following a streptococcal infection, Vernon et al. (2012) identified a heterozygous truncating mutation in the CFHR5 gene (608693.0005). The mutation was also present in her unaffected mother and sister, suggesting that presence of the mutation is not sufficient to cause disease, but likely acts as a susceptibility factor for the development of glomerulonephritis.