Abstract
BackgroundAlport syndrome and C3 glomerulonephritis (C3GN) are rare kidney diseases, frequently responsible for familial haematuria, proteinuria, and renal impairment. With the rapid development of molecular genetic testing, Alport syndrome causes have been restricted mostly to variants in the COL4A5 or COL4A3/COL4A4 genes. Moreover, a broad range of genetic contributors in the complement and complement-regulating proteins are definitely implicated in the pathogenesis of C3GN.MethodsWe sought a family with persistent microscopic haematuria associated with renal failure. Clinicopathologic and follow-up data were obtained, and molecular genetic testing was used to screen for pathogenic variants.ResultsWe describe a three-generation family with Alport syndrome showing a dominant maternal inheritance. Notably, renal biopsy showed the concurrent histological evidence of C3GN in the proband harbouring an uncommon heterozygous variation in CFHR5, c.508G > A. The alteration leads to replacement of a highly conserved residue at position 170 of the β-strand subunit of CFHR5 (p.Val170Met). In silico analysis showed that the variation was predicted to deregulate complement activation by altering the structural properties and enhancing C3b binding capacity to compete with Complement Factor H (CFH), which was in line with experimental data previously published.ConclusionsThe comorbidity findings between Alport syndrome and C3GN indicate an underlying overlap and require further study.
Highlights
Alport syndrome and C3 glomerulonephritis (C3GN) are rare kidney diseases, frequently responsible for familial haematuria, proteinuria, and renal impairment
Clinical presentation and follow‐up We investigated a three-generation Han Chinese family characterized by persistent microscopic haematuria associated with renal failure (Fig. 1a)
Our study reports a pedigree characterized by microscopic haematuria and variety in the speed of onset of renal failure
Summary
Alport syndrome and C3 glomerulonephritis (C3GN) are rare kidney diseases, frequently responsible for familial haematuria, proteinuria, and renal impairment. With the rapid development of molecular genetic testing, Alport syndrome causes have been restricted mostly to variants in the COL4A5 or COL4A3/COL4A4 genes. 80% of rare diseases have an identified genetic background with substantial geographic or ethnic variations in incidence [2]. We report a family with dominant maternal transmitted inheritance, in which five out of eight members (I:1, II:, II:4, III:, and III:2) exhibited microscopic haematuria and proteinuria and two out of the 5 patients (II: and III:1) developed end-stage renal disease (ESRD). Renal biopsy showed the comorbidity of Alport syndrome and C3GN in the proband carrying an uncommon heterozygous c.508G > A (p.Val170Met) variant in the CFHR5 gene. The functional effect of the p.Val170Met variation was exhaustively evaluated
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