Deciphering the pathogenesis of the COL4‐related hematuric nephritis: A genotype/phenotype study. Issue 2 (24th December 2020)

• Record Type: Journal Article
• Authors: Uliana, Vera; Sebastio, Paola; Riva, Matteo; Carli, Diana; Ruberto, Claudio; Bianchi, Laura; Graziano, Claudio; Capelli, Irene; Faletra, Flavio; Pillon, Roberto; Mattina, Teresa; Sensi, Alberto; Bonatti, Francesco; Percesepe, Antonio
• Is Part Of: Molecular genetics & genomic medicine. Volume 9:Issue 2(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-12-24
• Subjects: Alport syndrome -- COL4A3 -- COL4A4 gene mutations -- COL4A5 -- genotype/phenotype; Medical genetics -- Periodicals; Genomics -- Periodicals; 616.042
• DOI: 10.1002/mgg3.1576
• Languages: English
• ISSNs: 2324-9269

Abstract

Abstract: Background: Alport syndrome (ATS) is a hereditary progressive hematuric nephropathy associated with sensorineural deafness and ocular abnormalities, which is caused by mutations in the COL4A5 gene (X‐linked ATS) and in two autosomal genes, COL4A4 and COL4A3, responsible of both recessive ATS and, when present in heterozygosity, of a spectrum of phenotypes ranging from isolated hematuria to frank renal disease. Methods: Retrospective analysis of the clinical and genetic features of 76 patients from 34 unrelated ATS families (11 with mutations in COL4A5, 11 in COL4A3, and 12 in COL4A4 ) and genotype/phenotype correlation for the COL4A3 / COL4A4 heterozygotes (34 patients from 14 families). Results: Eight (24%) of the 34 heterozygous COL4A3 and COL4A4 carriers developed renal failure at a mean age of 57 years, with a significantly lower risk than hemizygous COL4A5 or double heterozygous COL4A3 / COL4A4 carriers ( p < 0.01), but not different from that of the heterozygous COL4A5 females ( p = 0.6). Heterozygous carriers of frameshift/splicing variants in COL4A3 / COL4A4 presented a higher risk of developing renal failure than those with missense variants in the glycine domains ( p = 0.015). Conclusion: The renal functional prognosis of patients with COL4A3 / COL4A4 ‐positive ATS recapitulates that of the X‐linked ATS forms, with differences between heterozygous vs. double heterozygous patients and between carriers of loss‐of‐function vs. missense variants. Abstract : Heterozygotes for COL4A3 and COL4A4 variants showed a significantly lower risk than hemizygous COL4A5 or double heterozygous COL4A3/COL4A4 carriers ( p < 0.01), but not different from that of the heterozygous COL4A5 females ( p = 0.6). Heterozygote carriers of frameshift/splicing variants in COL4A3/COL4A4 presented a higher risk of developing renal failure than those with missense variants in the glycine domains ( p = 0.015).