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  • Severe clinical phenotype in Alport syndrome due to two COL4A4 exon skipping events [Elektronski vir]
    Pleško, Jerica ...
    Alport syndrome (AS) is a genetically heterogeneous disorder caused by mutations in COL4A3, COL4A4, or COL4A5, leading to progressive renal dysfunction. While genetic screening has advanced, many ... cases remain undiagnosed due to deep intronic splice site variants. We report a male patient diagnosed with autosomal recessive AS, characterized by hematuria, proteinuria, and chronic kidney disease progression. Initial kidney biopsy at age 10 revealed glomerular basement membrane thinning and focal sclerosis, while targeted DNA sequencing failed to detect pathogenic variants. Over 15 years, renal function declined, and a second biopsy showed severe GBM abnormalities with multilamellated structures. Whole-transcriptome sequencing revealed two events of exon skipping, specifically at exons 27 and 38 of the COL4A4 gene, which were verified by exon-specific PCR and Sanger sequencing. Intronic regions analysis revealed two heterozygous variants positioned 78 bp downstream of exon 27 and 8 bp upstream of exon 38, though their role in aberrant splicing remains uncertain. Immunofluorescence analysis confirmed disrupted α3α4α5(IV) heterotrimer assembly. This is the first documented case of dual exon-skipping events in COL4A4, highlighting their contribution to disease severity. Our findings emphasize the need for RNA-based diagnostics and raise questions about potential benefit of exon-skipping therapy in autosomal recessive AS.
    Vir: Kidney medicine. - ISSN 2590-0595 (Vol. 7, issue 10, 2025, str. 1-5)
    Vrsta gradiva - e-članek ; neleposlovje za odrasle
    Leto - 2025
    Jezik - angleški
    COBISS.SI-ID - 245836291

    Povezava(-e):

    https://www.sciencedirect.com/science/article/pii/S259005952500113X
    DiRROS - Digitalni repozitorij raziskovalnih organizacij Slovenije
    DOI

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