2. Academic Validation
  3. THSD1 (Thrombospondin Type 1 Domain Containing Protein 1) Mutation in the Pathogenesis of Intracranial Aneurysm and Subarachnoid Hemorrhage

THSD1 (Thrombospondin Type 1 Domain Containing Protein 1) Mutation in the Pathogenesis of Intracranial Aneurysm and Subarachnoid Hemorrhage

  • Stroke. 2016 Dec;47(12):3005-3013. doi: 10.1161/STROKEAHA.116.014161.
Teresa Santiago-Sim 1,  Xiaoqian Fang 1,  Morgan L Hennessy 1,  Stephen V Nalbach 1,  Steven R DePalma 1,  Ming Sum Lee 1,  Steven C Greenway 1,  Barbara McDonough 1,  Georgene W Hergenroeder 1,  Kyla J Patek 1,  Sarah M Colosimo 1,  Krista J Qualmann 1,  John P Hagan 1,  Dianna M Milewicz 1,  Calum A MacRae 1,  Susan M Dymecki 1,  Christine E Seidman 1,  J G Seidman 1,  Dong H Kim 2
Affiliations

Affiliations

  • 1 From the Department of Neurosurgery (T.S.-S., X.F., G.W.H., K.J.P., S.M.C., K.J.Q., J.P.H., D.H.K.) and Division of Medical Genetics, Department of Internal Medicine (D.M.M.), The University of Texas Medical School at Houston; Department of Genetics, Harvard Medical School, Boston, MA (M.L.H., S.V.N., S.R.D., S.C.G., B.M., S.M.D., C.E.S., J.G.S.); Department of Neurosurgery (S.V.N.), Department of Medicine (M.S.L., C.A.M.), and Cardiovascular Division (C.E.S.), Brigham and Women's Hospital, Boston, MA; and Howard Hughes Medical Institute, Chevy Chase, MD (C.E.S.).
  • 2 From the Department of Neurosurgery (T.S.-S., X.F., G.W.H., K.J.P., S.M.C., K.J.Q., J.P.H., D.H.K.) and Division of Medical Genetics, Department of Internal Medicine (D.M.M.), The University of Texas Medical School at Houston; Department of Genetics, Harvard Medical School, Boston, MA (M.L.H., S.V.N., S.R.D., S.C.G., B.M., S.M.D., C.E.S., J.G.S.); Department of Neurosurgery (S.V.N.), Department of Medicine (M.S.L., C.A.M.), and Cardiovascular Division (C.E.S.), Brigham and Women's Hospital, Boston, MA; and Howard Hughes Medical Institute, Chevy Chase, MD (C.E.S.). Dong.H.Kim@uth.tmc.edu.
PMID: 27895300 DOI: 10.1161/STROKEAHA.116.014161
Abstract

Background and purpose: A ruptured intracranial aneurysm (IA) is the leading cause of a subarachnoid hemorrhage. This study seeks to define a specific gene whose mutation leads to disease.

Methods: More than 500 IA probands and 100 affected families were enrolled and clinically characterized. Whole exome Sequencing was performed on a large family, revealing a segregating THSD1 (thrombospondin type 1 domain containing protein 1) mutation. THSD1 was sequenced in other probands and controls. Thsd1 loss-of-function studies in zebrafish and mice were used for in vivo analyses and functional studies performed using an in vitro endothelial cell model.

Results: A nonsense mutation in THSD1 was identified that segregated with the 9 affected (3 suffered subarachnoid hemorrhage and 6 had unruptured IA) and was absent in 13 unaffected family members (LOD score 4.69). Targeted THSD1 Sequencing identified mutations in 8 of 507 unrelated IA probands, including 3 who had suffered subarachnoid hemorrhage (1.6% [95% confidence interval, 0.8%-3.1%]). These THSD1 mutations/rare variants were highly enriched in our IA patient cohort relative to 89 040 chromosomes in Exome Aggregation Consortium (ExAC) database (P<0.0001). In zebrafish and mice, Thsd1 loss-of-function caused cerebral bleeding (which localized to the subarachnoid space in mice) and increased mortality. Mechanistically, THSD1 loss impaired endothelial cell focal adhesion to the basement membrane. These adhesion defects could be rescued by expression of wild-type THSD1 but not THSD1 mutants identified in IA patients.

Conclusions: This report identifies THSD1 mutations in familial and sporadic IA patients and shows that THSD1 loss results in cerebral bleeding in 2 animal models. This finding provides new insight into IA and subarachnoid hemorrhage pathogenesis and provides new understanding of THSD1 function, which includes endothelial cell to extracellular matrix adhesion.

Keywords

animal disease models; cerebral hemorrhage; intracranial aneurysm; medical genetics; subarachnoid hemorrhage.

Figures