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COL4A1 mutations in patients with sporadic late-onset intracerebral hemorrhage.

ABSTRACT: 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).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.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.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.

SUBMITTER: Weng YC

PROVIDER: S-EPMC3335762 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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COL4A1 mutations in patients with sporadic late-onset intracerebral hemorrhage.

Weng Yi-Chinn YC Sonni Akshata A Labelle-Dumais Cassandre C de Leau Michelle M Kauffman W Berkeley WB Jeanne Marion M Biffi Alessandro A Greenberg Steven M SM Rosand Jonathan J Gould Douglas B DB

Annals of neurology 20120401 4

<h4>Objective</h4>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).<h4>Methods</h4>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 mutatio ...[more]

PMID: 22522439

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Project description:Background and purposeSeizures commonly occur in patients with intracerebral hemorrhage (ICH). Anticonvulsants are commonly used for preventing seizures in patients with ICH. Thus, patients with ICH at high risk of seizures must be identified. The study aims to elucidate whether double the score of cortex involvement in ICH patients can increase accuracy of CAVE score for predicting late seizures.MethodThis retrospective analysis of the medical records of surviving patients admitted between June 1, 2013, and December 31, 2019. Validated the CAVE score and modified it (CAVE2). The main outcome of patients with ICH was seizures. The first seizures occurring within 7 days after a stroke were defined as early seizures. Seizures occurring after 1 week of stroke onset, including patients who had experienced early seizures or patients who had not, were defined as late seizures. CAVE and CAVE2 scores were validated using the cohort. The accuracy and discrimination of those two scores were accessed by the area under the operating characteristic curve. Akaike information criterion, integrated discrimination improvement, and continuous net reclassification improvement were used to assess the performance of the CAVE and CAVE2 scores.ResultsIn the cohort showed that late seizures occurred in 12.7% (52/408) of patients with ICH. Male sex, age > 65 years, cortex involvement, and early seizures were associated with the occurrence of late seizures, with odds ratios of 2.09, 2.04, 4.12, and 3.78, respectively. The risk rate of late seizures was 6.66% (17/255), 14.8% (17/115), and 47.4% (18/38) for CAVE scores ≤ 1, 2, and ≥ 3, and 4.6% (12/258), 18.3% (13/71), and 54.4 (20/37) for CAVE2 scores ≤ 1, 2, and ≥ 3 respectively. The C-statistics for the CAVE and CAVE2 scores were 0.73 and 0.74 respectively.ConclusionThe CAVE score can identify patients with ICH and high risk for late seizures. The CAVE can be modified by changing the score of cortex involvement to 2 points to improve accuracy in predicting late seizures in patients with ICH.

Dataset Information

COL4A1 mutations in patients with sporadic late-onset intracerebral hemorrhage.

Publications

COL4A1 mutations in patients with sporadic late-onset intracerebral hemorrhage.

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