Premium
COL4A1 mutations in patients with sporadic late‐onset intracerebral hemorrhage
Author(s) -
Weng YiChinn,
Sonni Akshata,
LabelleDumais Cassandre,
de Leau Michelle,
Kauffman W. Berkeley,
Jeanne Marion,
Biffi Alessandro,
Greenberg Steven M.,
Rosand Jonathan,
Gould Douglas B.
Publication year - 2012
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.22682
Subject(s) - nonsynonymous substitution , intracerebral hemorrhage , mutation , genetics , biology , disease , missense mutation , cerebral amyloid angiopathy , medicine , pathology , gene , dementia , genome , subarachnoid hemorrhage
Abstract 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. ANN NEUROL 2012;