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Project

Identifying COL4A1 and COL4A2 mutations in sporadic cerebral white matter disease

Worldwide cerebral small vessel disease represents a major health problem. The clinical and radiological presentation of the disease is diverse: Intracerebral hemorrhage, lacunar infarcts and white matter disease. Most cases of small vessel disease are sporadic, but familial forms have been identified, with the commonest being CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy). Recently, other genes causing similar disorders have been discovered, one of which is COL4A1. Mutations in COL4A1 were reported in patients with (recurrent) hemorrhagic stroke as well as in patients with white matter disease. Recently a role for COL4A1 and COL4A2 mutations in the etiology of sporadic late-onset intracranial hemorrhage has been identified. Almost all mutations reported are missense mutations, and a dominant negative effect has seen suggested as pathogenic mechanism where the altered gene product acts antagonistically to the wild-type allele. We have recently identified two families with novel mutations in COL4A1 and the type of mutations suggested reduced expression of COL4A1 to cause disease. Potentially both mechanisms are involved but penetrance and clinical presentation might vary based on the type of mutation. In this project we aim to identify mutations in sporadic patients with a specific clinical phenotype of cerebral small vessel disease: White matter disease. The findings of this study can raise the possibility that COL4A1 and COL4A2 mutations underlie a significant proportion of patients with white matter disease. Furthermore the result of these mutations on the protein level, misexpression versus reduced expression, might gain new insights in the pathogenesis of COL4A1- and COL4A2-related disorders.

Date:1 Jan 2014 →  31 Dec 2014
Keywords:COL4A1 mutations, COL4A2 mutations, cerebral white matter disease
Disciplines:Laboratory medicine, Palliative care and end-of-life care, Regenerative medicine, Other basic sciences, Other health sciences, Nursing, Other paramedical sciences, Other translational sciences, Other medical and health sciences