<i>THSD1</i>preserves vascular integrity and protects against intraplaque haemorrhaging in ApoE<sup>−/−</sup>mice

Background and Purpose A ruptured intracranial aneurysm (IA) is the leading cause of a subarachnoid hemorrhage (SAH). 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 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 (thrombospondin type-1 domain-containing protein 1) was identified that segregated with the 9 affected (3 suffered SAH; 6 had unruptured IA) and 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 SAH (1.6% [95% CI, 0.8%–3.1%]). These THSD1 mutations/rare variants were highly enriched in our IA patient cohort relative to 89,040 chromosomes in 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 two animal models. This finding provides new insight into IA and SAH pathogenesis and provides new understanding of THSD1 function, which includes endothelial cell to extracellular matrix adhesion.

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“…Recent work from Haasdijk and colleagues with a distinct thsd1 morpholino has independently confirmed our zebrafish results. 29 …”

Section: Discussionmentioning

confidence: 99%

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

Santiago‐Sim

Fang

Hennessy

et al. 2016

Stroke

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“…Mouse ortholog (TMTSP) shares 78.6% homology with the human protein (Dc et al, ). The first functional study of the gene identified THSD‐1 protein as an regulator factor of endothelial barrier function that promote stability of advanced lesions with intraplaque haemorrhaging by retaining the vascular integrity of the intimal neovascualture (Haasdijk et al, ).…”

Section: Discussionmentioning

confidence: 99%

A recessive truncating variant in thrombospondin‐1 domain containing protein 1 gene THSD1 is the underlying cause of nonimmune hydrops fetalis, congenital cardiac defects, and haemangiomas in four patients from a consanguineous family

Abdelrahman

Al‐Shamsi

John

et al. 2018

American J of Med Genetics Pt A

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Non-immune hydrops fetalis (NIHF) is the abnormal accumulation of serous fluid in more than two fetal or neonatal interstitial spaces due to nonimmune causes. It is a serious condition that requires extensive medical care as it indicates severe fetal compromise. We clinically evaluated four patients from two branches of a highly consanguineous family from the UAE with NIHF using whole exome sequencing and in silico analysis. Fetal onset pleural and peritoneal effusions were detected in all four patients and were born with moderate to severe hydrops fetalis that resolved with age. Follow up showed relatively normal growth and development apart from mild ascites and haemangiomas in all affected children, recurrent hydrocele in all affected males, intestinal malabsorption in two patients, dysmorphic features in two patients, and congenital cardiac defects in three out of four patients. Molecular testing identified a homozygous eight nucleotide deletion in THSD1 gene (NM_199263:c.1163_1170delGGCCAGCC, p.Arg388Glnfs*66) as the underlying cause of this phenotype in the affected children. The novel variant cosegregates with the described phenotype in an autosomal recessive mode of inheritance and is predicted to be pathogenic as it leads to a truncated protein that lost important structural and functional domains. Thrombospondin-1 domain containing protein 1 gene THSD1 has been recently associated with of NIHF and embryonic lethality. Here, we report the novel truncating THSD1 variant, and describe new clinical features that have not been reported previously thus expanding the phenotype associate with loss-of-function mutations in THSD1 causing NIHF.

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“…Plaque inflammation also triggers smooth muscle cell loss and the production of matrix metalloproteinases (MMP) that weaken the fibrous cap, predisposing it to plaque rupture [ 2 , 5 ]. The thick necrotic acellular lipid core becomes increasingly hypoxic, stimulating angiogenesis, with the formation of immature microvessels prone to intra-plaque haemorrhage (IPH) [ 6 – 8 ].…”

Section: Introductionmentioning

confidence: 99%

New methods to image unstable atherosclerotic plaques

2018

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Atherosclerotic plaque rupture is the primary mechanism responsible for myocardial infarction and stroke, the top two killers worldwide. Despite being potentially fatal, the ubiquitous prevalence of atherosclerosis amongst the middle aged and elderly renders individual events relatively rare. This makes the accurate prediction of MI and stroke challenging. Advances in imaging techniques now allow detailed assessments of plaque morphology and disease activity. Both CT and MR can identify certain unstable plaque characteristics thought to be associated with an increased risk of rupture and events. PET imaging allows the activity of distinct pathological processes associated with atherosclerosis to be measured, differentiating patients with inactive and active disease states. Hybrid integration of PET with CT or MR now allows for an accurate assessment of not only plaque burden and morphology but plaque biology too. In this review, we discuss how these advanced imaging techniques hold promise in redefining our understanding of stable and unstable coronary artery disease beyond symptomatic status, and how they may refine patient risk-prediction and the rationing of expensive novel therapies.

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THSD1preserves vascular integrity and protects against intraplaque haemorrhaging in ApoE^−/−mice

Abstract: THSD1 is a new regulator of endothelial barrier function during vascular development and protects intraplaque microvessels against haemorrhaging in advanced atherosclerotic lesions.

Cited by 27 publications

References 29 publications

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

A recessive truncating variant in thrombospondin‐1 domain containing protein 1 gene THSD1 is the underlying cause of nonimmune hydrops fetalis, congenital cardiac defects, and haemangiomas in four patients from a consanguineous family

New methods to image unstable atherosclerotic plaques

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THSD1preserves vascular integrity and protects against intraplaque haemorrhaging in ApoE−/−mice

Abstract: THSD1 is a new regulator of endothelial barrier function during vascular development and protects intraplaque microvessels against haemorrhaging in advanced atherosclerotic lesions.

Cited by 27 publications

References 29 publications

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

A recessive truncating variant in thrombospondin‐1 domain containing protein 1 gene THSD1 is the underlying cause of nonimmune hydrops fetalis, congenital cardiac defects, and haemangiomas in four patients from a consanguineous family

New methods to image unstable atherosclerotic plaques

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THSD1preserves vascular integrity and protects against intraplaque haemorrhaging in ApoE^−/−mice