Diagnostic and pathophysiological relevance of tubular collagen IV α345 in Alport Syndrome
Wissenschaftliches Arbeitsprogramm:
Alport Syndrome (AS) is one of the most prevalent genetic kidney disorders caused by mutations in COL4A3, COL4A4 or COL4A5. The encoded collagen IV α345 network is crucial for basement membrane integrity in the kidney glomeruli, but equally strong expressed in distal kidney tubules. Disruption of tubular collagen IV α345 network might drive inflammation and fibrosis, but research has largely focused on glomeruli so far.
We have collected data from kidney biopsies from AS patients indicating that tubulointerstitial fibrosis and inflammation starts in the vicinity of the distal renal tubule (Loderbauer et al., 2025). Furthermore, tubular basement membrane from AS patients shows higher thickness variability. To further validate this data, we have exchanged kidney tissues from wildtype and homozygous Col4A3 knockout mice. We will perform Immunohistochemistry and electron microscopy to assess tubular phenotype and tubular thickness variability in these tissues.
Cultivation of patient-derived human urinary tubular cells (huPTCs) is established in our laboratory. These cells express collagen IV α345 protein and offer a platform for genetic analyses and functional assays to elucidate AS pathophysiology. We applied huPTCs in genetic diagnostics for a family with a phenotype indicative of AS, in which a putatively causative deep intronic variant in COL4A5 was identified. We plan to apply huPTCs for further validation of the pathogenecity of this variant on RNA- and protein level.