on March 19, 2009
Published online before print March 19, 2009, doi: 10.1161/STROKEAHA.108.540245
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Submitted on October 18, 2008
From the Department of Genetics (T.S.S., S.M.J., J.G.S., C.E.S.), Harvard Medical School, Boston, Mass; the Department of Internal Medicine and Institute of Molecular Medicine (H.P., D.M.M.) and the Department of Neurosurgery (D.H.K.), The University of Texas Health Science Center at Houston; and the Department of Pathology (C.E.S.), Brigham and Women's Hospital, Boston, Mass. * To whom correspondence should be addressed. E-mail: Dong.H.Kim{at}uth.tmc.edu.
Background and Purpose—Familial aggregation of intracranial aneurysms (IA) strongly suggests a genetic contribution to pathogenesis. However, genetic risk factors have yet to be defined. For families affected by aortic aneurysms, specific gene variants have been identified, many affecting the receptors to transforming growth factor-beta (TGF- Methods—To identify genetic variants in TGF- Results—No mutations were found in TGFB1, TGFBR1, TGFBR2, or ACVR1. Novel variants identified in ENG (p.A60E) and TGFBR3 (p.W112R) were not detected in at least 892 reference chromosomes. ENG p.A60E showed significant association with familial IA in case-control studies (P=0.0080). No association with IA could be found for any of the known polymorphisms tested. Conclusions—Mutations in TGF-
Accepted on November 12, 2008
Sequencing of TGF-
Teresa Santiago-Sim PhD; 
Pathway Genes in Familial Cases of Intracranial Aneurysm
). In recent work, we found that aortic and intracranial aneurysms may share a common genetic basis in some families. We hypothesized, therefore, that mutations in TGF- receptors might also play a role in IA pathogenesis. and its receptors, TGFB1, TGFBR1, TGFBR2, ACVR1, TGFBR3, and ENG were directly sequenced in 44 unrelated patients with familial IA. Novel variants were confirmed by restriction digestion analyses, and allele frequencies were analyzed in cases versus individuals without known intracranial disease. Similarly, allele frequencies of a subset of known SNPs in each gene were also analyzed for association with IA. receptor genes are not a major cause of IA. However, we identified rare variants in ENG and TGFBR3 that may be important for IA pathogenesis in a subset of families.
Key words: aneurysm • endoglin • betaglycan • TGFBR1, TGFBR2