Gould DB et al. (2006) Role of COL4A1 in small-vessel disease and hemorrhagic stroke. N Engl J Med 354: 1489–1496

Cerebral small-vessel disease is associated with intracerebral hemorrhage and ischemic stroke. Gould et al. have identified mutations in the gene encoding type 4 collagen α1, a basement membrane protein, that cause vascular disease in both humans and mice.

Mice carrying mutations in the Col4a1 gene were predisposed to stress-induced cerebral hemorrhage. All naturally born newborn mutant mice had hemorrhage due to birth trauma, and approximately 50% of these pups died on the day of birth. All adult mutant mice studied had intracerebral hemorrhage, and the death rate was higher in mutant mice than in wild-type mice. Some mutant mice were also affected by retinal vascular tortuosity, glomerular basement membrane defects and microalbuminuria.

Phenotypic similarities between mice with Col4a1 mutations and a French family with small-vessel disease led the researchers to screen the family for COL4A1 mutations. Family members were affected by retinal arteriolar tortuosity, MRI scans showed cerebral microbleeds and white-matter abnormalities, and two family members died of intracerebral hemorrhage. Sequence analysis revealed a point mutation in COL4A1 that caused a glycine residue in the triple-helix domain of the protein to be replaced by glutamic acid. Glycine residues are highly conserved in type 4 collagen α1, and mutations that affect these residues are known to be pathogenic in many species.

The authors conclude that COL4A1 mutations cause weakening of the vascular basement membrane and predispose affected individuals to hemorrhage, and suggest that mutations in other basement membrane proteins could also cause small-vessel disease.