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Published on: July 3, 2014
COL4A1 mutations in patients with sporadic late-onset intracerebral hemorrhage
Yi-Chinn Weng1, Akshata Sonni, Cassandre Labelle-Dumais
1Department of Ophthalmology, Institute for Human Genetics, UCSF School of Medicine, San Francisco, CA, USA.
Insights
Mutations in the type IV collagen alpha 1 gene (COL4A1) contribute to sporadic intracerebral hemorrhages (ICHs). Two novel COL4A1 variants impair protein secretion, suggesting a role in nonfamilial ICH.
Area of Science:
- Genetics
- Neurology
- Molecular Biology
Background:
- Mutations in the type IV collagen alpha 1 gene (COL4A1) are known to cause inherited cerebrovascular diseases.
- The role of COL4A1 mutations in sporadic, nonfamilial intracerebral hemorrhages (ICHs) remains largely undetermined.
Observation:
- Sequencing of COL4A1 in 96 patients with sporadic ICH identified two rare nonsynonymous variants not found in 145 ICH-free controls.
- These identified variants (COL4A1(P352L) and COL4A1(R538G)) alter conserved amino acids and impair COL4A1 secretion.
Findings:
- The identified COL4A1 variants in sporadic ICH patients functionally mimic previously validated mutations causing familial cerebrovascular disease.
- These mutations significantly inhibit the secretion of COL4A1, impacting its extracellular presence.
Implications:
- The study suggests that COL4A1 mutations contribute to the etiology of sporadic ICH, extending beyond rare familial cases.
- Impaired COL4A1 secretion and altered intracellular/extracellular collagen accumulation may be key mechanisms in sporadic cerebrovascular disease.
Objective:
Mutations in the type IV collagen alpha 1 gene (COL4A1) cause dominantly inherited cerebrovascular disease. We seek to determine the extent to which COL4A1 mutations contribute to sporadic, nonfamilial, intracerebral hemorrhages (ICHs).
Methods:
We sequenced COL4A1 in 96 patients with sporadic ICH. The presence of putative mutations was tested in 145 ICH-free controls. The effects of rare coding variants on COL4A1 biosynthesis were compared to previously validated mutations that cause porencephaly, small vessel disease, and hereditary angiopathy, nephropathy, aneurysms, and cramps (HANAC) syndrome.
Results:
We identified 2 rare nonsynonymous variants in ICH patients that were not detected in controls, 2 rare nonsynonymous variants in controls that were not detected in patients, and 2 common nonsynonymous variants that were detected in patients and controls. No variant found in controls affected COL4A1 biosynthesis. Both variants (COL4A1(P352L) and COL4A1(R538G)) found only in patients changed conserved amino acids and impaired COL4A1 secretion much like mutations that cause familial cerebrovascular disease.
Interpretation:
This is the first assessment of the broader role for COL4A1 mutations in the etiology of ICH beyond a contribution to rare and severe familial cases and the first functional evaluation of the biosynthetic consequences of an allelic series of COL4A1 mutations that cause cerebrovascular disease. We identified 2 putative mutations in 96 patients with sporadic ICH and showed that these and other previously validated mutations inhibit secretion of COL4A1. Our data support the hypothesis that increased intracellular accumulation of COL4A1, decreased extracellular COL4A1, or both, contribute to sporadic cerebrovascular disease and ICH.
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