Abstract
Collagen IV is a basement membrane component that is encoded by six genes in mammals (COL4Α1–COL4A6). The α-chains encoded by these genes assemble into three known heterotrimers — collagen α1α1α2(IV), α3α4α5(IV) and α5α5α6(IV) — that provide structure and act as multifunctional signalling platforms. The ancestral collagen superfamily members collagen alpha-1(IV) chain (COL4Α1) and collagen alpha-2(IV) chain (COL4Α2) are present throughout the animal kingdom and in all developing and most mature mammalian tissues. Consistent with this broad distribution, variants in COL4A1 and COL4A2 cause a congenital multisystem disorder called Gould syndrome (GS), which is characterized by cerebral, ocular, muscular and kidney defects. The main clinical consequences involve the cerebral vasculature (porencephaly, small-vessel disease, leukoencephalopathy and intracerebral haemorrhage). However, the full clinical spectrum, including the organs affected and acquired phenotypes such as vascular dementia, is still being defined. By contrast, variants in COL4A3, COL4A4 or COL4A5 cause Alport syndrome (AS), a disorder of variable severity that affects the kidney, ear and eye. AS nephropathies often progress from haematuria to proteinuria, renal impairment and kidney failure. The auditory features include sensorineural hearing loss, whereas the ocular features comprise corneal dystrophy, lenticonus, dot-and-fleck retinopathy and maculopathy. Although GS and AS have little clinical resemblance, the high conservation of the genes and proteins suggests common elements of underlying pathophysiology. Conventional therapies that modify haemodynamics have lengthened the time to kidney failure for patients living with AS. However, no curative or mechanism-based interventions exist for GS. Gene-editing approaches hold promise for both disorders.
Key points
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Collagen IV is component of basement membranes that is encoded by six α-chain genes (COL4Α1–COL4A6) that assemble into three known heterotrimers: collagen α1α1α2(IV), α3α4α5(IV) and α5α5α6(IV).
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COL4Α1 and COL4Α2 variants cause Gould syndrome (GS), which is characterized by cerebral, ocular, muscular and renal manifestations, whereas COL4Α3, COL4Α4 and COL4Α5 variants cause Alport syndrome (AS), which is characterized by a spectrum of pathologies affecting the kidney, ear and eye.
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GS nephropathies are variable, include haematuria, proteinuria and the presence of cysts and can progress to kidney failure; AS nephropathies are also variable, begin with haematuria and often progress to proteinuria, renal impairment and kidney failure.
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As no effective treatment options for GS exist, current interventions are aimed at managing the symptoms.
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Although no curative treatment for AS is available, interventions that target the renin–angiotensin–aldosterone system are efficient at slowing disease progression, delaying kidney failure and increasing life expectancy.
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Potential shared therapeutic avenues for GS and AS include promoting secretion of defective collagen IV and attenuating TGFβ signalling; gene therapies and gene-editing approaches are also promising treatment strategies.
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Acknowledgements
J.H.M. acknowledges funding from the NIH (R01DK128660, U54DK137332), the Alport Syndrome Foundation and Kidney Research UK under a contract from the University of Manchester. D.B.G. acknowledges funding from the NIH (R33NS115132, RF1NS128217, R21NS133610, R21DK140866). The UCSF Department of Ophthalmology is supported by a Core Grant from the National Eye Institute (P30EY002162) and an unrestricted grant from Research to Prevent Blindness.
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J.H.M. is a member of the Alport Syndrome Foundation’s Scientific Advisory Research Network, has ownership interest in Sintra Therapeutics and has consultancy relationships with Eloxx Pharmaceuticals, Sintra Therapeutics and Bayer AG. The other authors declare no competing interests.
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Glossary
- Porencephaly
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A cerebrovascular condition characterized by the presence of cystic cavities, which are caused by destructive vascular lesions in the germinal matrix.
- Schizencephaly
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A rare congenital cerebral condition characterized by unilateral or bilateral abnormal clefts or splits of the cerebral hemispheres.
- Stria vascularis
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A capillary loop within the cochlea that produces endolymph for the scala media, one of the three fluid-filled compartments of the cochlea.
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Massoudi, D., Miner, J.H. & Gould, D.B. Collagen IV in Gould syndrome and Alport syndrome. Nat Rev Nephrol (2025). https://doi.org/10.1038/s41581-025-00982-x
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DOI: https://doi.org/10.1038/s41581-025-00982-x
