biostudies-literatureParadisi GTelethon FoundationMinistry of Health63-82https://www.ebi.ac.uk/biostudies/studies/S-EPMC12835968biostudies-literatureUnknown143Pathogenic variants in COL4A1 and COL4A2, encoding type IV collagen α1 and α2 chains-core components of all basement membranes-cause a multisystem disorder with variable expressivity. Affected individuals commonly present with cerebral small vessel disease (cSVD), unmanageable intracerebral haemorrhage (ICH), drug-resistant epilepsy, microphthalmia, and congenital cataract. Severe phenotypes are often linked to glycine substitutions that disrupt α1/α2 heterotrimer assembly, though insertions, deletions, and haploinsufficiency seem to also be pathogenic. Limited insight into collagen IV α1 and α2 biology and how specific variants affect their functions-coupled with a lack of rapid in vivo assays for functional variants classification-hampers patient stratification and therapy development. HMatrix biology : journal of the International Society for Matrix BiologyZebrafish col4a1 loss-of-function models mirror key neurovascular and ocular features of COL4A1/A2 syndrome and enable human variants assessment in vivo.PMC12835968RF-2021-123749635\u00D71000Venditti MBonavolonta VParadisi GFasano GPedalino CLauri ATartaglia MDel Bene FfalseZebrafish col4a1 loss-of-function models mirror key neurovascular and ocular features of COL4A1/A2 syndrome and enable human variants assessment in vivo.Pathogenic variants in COL4A1 and COL4A2, encoding type IV collagen α1 and α2 chains-core components of all basement membranes-cause a multisystem disorder with variable expressivity. Affected individuals commonly present with cerebral small vessel disease (cSVD), unmanageable intracerebral haemorrhage (ICH), drug-resistant epilepsy, microphthalmia, and congenital cataract. Severe phenotypes are often linked to glycine substitutions that disrupt α1/α2 heterotrimer assembly, though insertions, deletions, and haploinsufficiency seem to also be pathogenic. Limited insight into collagen IV α1 and α2 biology and how specific variants affect their functions-coupled with a lack of rapid in vivo assays for functional variants classification-hampers patient stratification and therapy development. H2026-01-01T00:00:00Z2026 Feb2026-06-17T06:58:47.246Z2026-06-17T03:10:45.004ZS-EPMC128359684124883610.1016/j.matbio.2025.11.004