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

Korbinian M Riedhammer1,2, Hannes Simmendinger1, Velibor Tasic3

  • 1Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, TUM School of Medicine and Health, Munich, Germany.

Clinical Genetics
|January 12, 2024
PubMed

Insights

Alport syndrome (AS) genetic variants in COL4A3/COL4A4 show genotype-phenotype correlations. Non-truncating variants may cause more severe disease than truncating variants in autosomal dominant AS.

Area of Science:

  • Nephrology
  • Genetics
  • Molecular Biology

Background:

  • Alport syndrome (AS) presents a wide range of symptoms, from microscopic hematuria (MH) to end-stage kidney disease (ESKD).
  • Autosomal dominant AS (ADAS) and autosomal recessive AS (ARAS) are linked to COL4A3/COL4A4 gene variants.
  • Understanding genotype-phenotype correlations is crucial for predicting AS progression.

Purpose of the Study:

  • To investigate the relationship between specific COL4A3/COL4A4 genetic variants and clinical manifestations in Alport syndrome.
  • To analyze genotype-phenotype correlations in individuals with pathogenic COL4A3/COL4A4 variants.

Main Methods:

  • Recruitment of 89 individuals with pathogenic COL4A3/COL4A4 variants.
  • Collection of clinical data including microscopic hematuria, proteinuria, ESKD, and extrarenal manifestations.
  • Analysis of genetic variants (monoallelic vs. biallelic, truncating vs. non-truncating).

Main Results:

  • Individuals with monoallelic non-truncating variants showed earlier and more frequent microscopic hematuria and proteinuria compared to those with monoallelic truncating variants.
  • Biallelic variants led to more severe disease than monoallelic variants.
  • Biallelic truncating variants resulted in more severe phenotypes than compound heterozygous or biallelic non-truncating variants.

Conclusions:

  • Heterozygous non-truncating COL4A3/COL4A4 variants are associated with a more severe Alport syndrome phenotype, potentially due to a dominant-negative effect.
  • Findings for autosomal recessive AS support existing literature, highlighting the impact of biallelic variants.

Keywords:
Alport syndromeCOL4A3COL4A4dominant-negative effectgenotype-phenotype correlation

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