Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Apr;105(4):406-414.
doi: 10.1111/cge.14471. Epub 2024 Jan 12.

Is there a dominant-negative effect in individuals with heterozygous disease-causing variants in COL4A3/COL4A4?

Korbinian M Riedhammer  1   2 , Hannes Simmendinger  1 , Velibor Tasic  3 , Jovana Putnik  4 , Nora Abazi-Emini  3 , Natasa Stajic  4 , Riccardo Berutti  1 , Marc Weidenbusch  5 , Ludwig Patzer  6 , Adrian Lungu  7 , Gordana Milosevski-Lomic  4 , Roman Günthner  2 , Matthias C Braunisch  2 , Jasmina Ćomić  1   2 , Julia Hoefele  1
Affiliations

Is there a dominant-negative effect in individuals with heterozygous disease-causing variants in COL4A3/COL4A4?

Korbinian M Riedhammer et al. Clin Genet. 2024 Apr.

Abstract

Alport syndrome (AS) shows a broad phenotypic spectrum ranging from isolated microscopic hematuria (MH) to end-stage kidney disease (ESKD). Monoallelic disease-causing variants in COL4A3/COL4A4 have been associated with autosomal dominant AS (ADAS) and biallelic variants with autosomal recessive AS (ARAS). The aim of this study was to analyze clinical and genetic data regarding a possible genotype-phenotype correlation in individuals with disease-causing variants in COL4A3/COL4A4. Eighty-nine individuals carrying at least one COL4A3/COL4A4 variant classified as (likely) pathogenic according to the American College of Medical Genetics guidelines and current amendments were recruited. Clinical data concerning the prevalence and age of first reported manifestation of MH, proteinuria, ESKD, and extrarenal manifestations were collected. Individuals with monoallelic non-truncating variants reported a significantly higher prevalence and earlier diagnosis of MH and proteinuria than individuals with monoallelic truncating variants. Individuals with biallelic variants were more severely affected than those with monoallelic variants. Those with biallelic truncating variants were more severely affected than those with compound heterozygous non-truncating/truncating variants or individuals with biallelic non-truncating variants. In this study an association of heterozygous non-truncating COL4A3/COL4A4 variants with a more severe phenotype in comparison to truncating variants could be shown indicating a potential dominant-negative effect as an explanation for this observation. The results for individuals with ARAS support the, still scarce, data in the literature.

Keywords: Alport syndrome; COL4A3; COL4A4; dominant-negative effect; genotype-phenotype correlation.

PubMed Disclaimer

References

REFERENCES

    1. Funk SD, Lin MH, Miner JH. Alport syndrome and Pierson syndrome: diseases of the glomerular basement membrane. Matrix Biol. 2018;71-72:250-261.
    1. Weber S, Strasser K, Rath S, et al. Identification of 47 novel mutations in patients with Alport syndrome and thin basement membrane nephropathy. Pediatr Nephrol. 2016;31(6):941-955.
    1. Abou Tayoun AN, Pesaran T, DiStefano MT, et al. Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterion. Hum Mutat. 2018;39(11):1517-1524.
    1. Kearney HM, Thorland EC, Brown KK, Quintero-Rivera F, South ST. Working Group of the American College of Medical Genetics Laboratory Quality Assurance C. American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants. Genet Med. 2011;13(7):680-685.
    1. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-424.

Publication types

LinkOut - more resources