Update on the Genetics of Stroke and Cerebrovascular Disease 2006

Abstract

The last year has again seen several advances in the genetics of cerebrovascular disease covering a spectrum of disorders ranging from small vessel disease to intracranial aneurysms to ischemic stroke. A key discovery was the identification of collagen type IV α1 (COL4A1) mutations in families with cerebral small vessel disease.1,2 Col4a1 was initially identified as the causative gene in a mouse mutant with perinatal cerebral hemorrhage and porencephalopathy.1 Heterozygous ( Col4a1 +/Δ40) mice develop recurrent hemorrhages in the basal ganglia—the typical site of intracerebral hemorrhage in hypertensive patients. Subsequent analysis of affected family members with porencephalopathy and cerebral small vessel disease revealed several mutations in the human COL4A1 gene.1–3 Type IV collagens are an integral component of the vascular basement membrane. COL4A1 and COL4A2, the most abundant type IV collagens, form hetero-trimers. The triple helix domain contains repeated glycine-proline-X motifs, which are critical for helix formation during collagen assembly. Most identified mutations involve glycine residues within such motifs. It was therefore hypothesized that COL4A1 mutations interfere with triple helix formation or heterotrimer secretion; in fact, there is evidence from Col4a1 +/Δ40 embryonic tissue that mutations inhibit collagen secretion into the basement membrane. Ultrastructural abnormalities in capillaries from COL4A1 mutation carriers indicate disordered basement membrane assembly. The phenotypic spectrum associated with COL4A1 mutations is broad and strongly connected to small vessel disease. Key features include leukoencephalopathy, microhemorrhages, and clinically overt hemorrhage. The structural compromise of small blood vessels is illustrated by the fact that birth trauma, brain trauma, and oral anticoagulants may trigger intracerebral hemorrhage in COL4A1 mutation carriers.1,2 Furthermore, the precipitating role of these factors exemplifies gene-environment interactions. Genes encoding vascular basement membrane-associated proteins remain attractive candidates for intracerebral hemorrhage and leukoencephalopathy. Epidemiological studies demonstrate a strong genetic influence on the development of intracranial aneurysms …