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. 2021 Feb;9(2):e1576.
doi: 10.1002/mgg3.1576. Epub 2020 Dec 24.

Deciphering the pathogenesis of the COL4-related hematuric nephritis: A genotype/phenotype study

Vera Uliana  1 , Paola Sebastio  1 , Matteo Riva  2 , Diana Carli  3 , Claudio Ruberto  4 , Laura Bianchi  4 , Claudio Graziano  5 , Irene Capelli  6 , Flavio Faletra  7 , Roberto Pillon  8 , Teresa Mattina  9 , Alberto Sensi  10 , Francesco Bonatti  2 , Antonio Percesepe  1   2
Affiliations

Deciphering the pathogenesis of the COL4-related hematuric nephritis: A genotype/phenotype study

Vera Uliana et al. Mol Genet Genomic Med. 2021 Feb.

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.

Keywords: COL4A3; COL4A5; Alport syndrome; COL4A4 gene mutations; genotype/phenotype.

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Conflict of interest statement

The authors have declared no conflicts of interest for this article.

Figures

FIGURE 1
FIGURE 1
Probability of end‐stage renal disease for the heterozygous COL4A3/COL4A4 ATS patients compared to the recessive and X‐linked counterparts (Panel a) and for the heterozygous COL4A3/COL4A4 heterozygous carriers of truncating variants vs. those with missense substitutions in the glycine domains (Panel b)
See this image and copyright information in PMC

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