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<p>Alport syndrome is a hereditary progressive nephropathy caused primarily by variants in genes encoding type IV collagen, the major structural component of the basement membrane in the kidneys, inner ear and eyes. Pathogenic variants in <i>COL4A3</i>,<i> COL4A4</i>, and <i>COL4A5</i> encode the α3, α4 and α5 chains of type IV collagen which disrupt network formation and stability of the α3α4α5(IV) collagen network. This causes structural and functional defects of GBM, which finally leads to chronic renal injury.About 80% of the cases are X-linked Alport syndrome caused by variants in <i>COL4A5</i> and resulting in a severe phenotype in males. The remaining cases are due to autosomal recessive or rarely, autosomal dominant mutations, predominantly in <i>COL4A3</i> or <i>COL4A4</i>. A broad range of pathogenic variants, including missense, nonsense, splicing, and frameshift variants, disrupt collagen biosynthesis and assembly. The dysfunctional collagen network alters GBM structure, affects cell interactions, and induces subsequent pathogenic cascades, such as tubulointerstitial fibrosis, mesangial matrix expansion, and progressive nephron destruction. The acceleration of oxidative stress and the induction of pro fibrotic mediators including TGF-β, facilitate chronic renal damage. With recent advances in genotype phenotype correlation, it is now possible to make meaningful predictions for disease severity, age at onset, and risk of extrarenal involvement. These discoveries have provided the foundation for candidate therapies, such as gene based treatments and exon skipping approaches aimed at restoring collagen function or preventing downstream injury. Ongoing studies to identify potential molecular targets and genetic modifiers will be critical for improving outcomes and guiding precision based therapy in Alport syndrome.</p>

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Decoding Alport Syndrome: From COL4A3-COL4A5 Molecular Pathogenesis to Precision Therapeutics

  • 期刊论文

  • 发表日期：

    2026年7月3日

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  • Nanak Singh Toor,
  • Mohd Haneef,
  • Sourabh Kosey,
  • Jashan Jindal

摘要

Alport syndrome is a hereditary progressive nephropathy caused primarily by variants in genes encoding type IV collagen, the major structural component of the basement membrane in the kidneys, inner ear and eyes. Pathogenic variants in COL4A3, COL4A4, and COL4A5 encode the α3, α4 and α5 chains of type IV collagen which disrupt network formation and stability of the α3α4α5(IV) collagen network. This causes structural and functional defects of GBM, which finally leads to chronic renal injury.About 80% of the cases are X-linked Alport syndrome caused by variants in COL4A5 and resulting in a severe phenotype in males. The remaining cases are due to autosomal recessive or rarely, autosomal dominant mutations, predominantly in COL4A3 or COL4A4. A broad range of pathogenic variants, including missense, nonsense, splicing, and frameshift variants, disrupt collagen biosynthesis and assembly. The dysfunctional collagen network alters GBM structure, affects cell interactions, and induces subsequent pathogenic cascades, such as tubulointerstitial fibrosis, mesangial matrix expansion, and progressive nephron destruction. The acceleration of oxidative stress and the induction of pro fibrotic mediators including TGF-β, facilitate chronic renal damage. With recent advances in genotype phenotype correlation, it is now possible to make meaningful predictions for disease severity, age at onset, and risk of extrarenal involvement. These discoveries have provided the foundation for candidate therapies, such as gene based treatments and exon skipping approaches aimed at restoring collagen function or preventing downstream injury. Ongoing studies to identify potential molecular targets and genetic modifiers will be critical for improving outcomes and guiding precision based therapy in Alport syndrome.