Collagen IV in Gould syndrome and Alport syndrome.

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.