Heterozygous THBS2 pathogenic variant causes Ehlers-Danlos syndrome with prominent vascular features in humans and...

Ehlers-Danlos syndromes (EDS) are a group of connective tissue disorders caused by mutations in collagen and collagen-interacting genes. We delineate a novel form of EDS with vascular features through clinical and histopathological phenotyping and genetic studies of a three-generation pedigree, displaying an apparently autosomal dominant phenotype of joint hypermobility and frequent joint dislocations, atrophic scarring, prolonged bleeding time and age-related aortic dilatation and rupture. Coagulation tests as well as platelet counts and function were normal. Reticular dermis displayed highly disorganized collagen fibers and transmission electron microscopy (TEM) revealed abnormally shaped fibroblasts and endothelial cells, with high amount and irregular shape of extracellular matrix (ECM) substance, especially near blood vessels. Genetic analysis unraveled a heterozygous mutation in THBS2 (NM_003247.5:c.2686T>C, p.Cys896Arg). We generated CRISPR/Cas9 knock-in (KI) mice, bearing the heterozygous human mutation in the mouse ortholog. The KI mice demonstrated phenotypic traits correlating with those observed in the human subjects, as evidenced by morphologic, histologic, and TEM analyses, in conjunction with bleeding time assays. Our findings delineate a novel form of human EDS with classical-like elements combined with vascular features, caused by a heterozygous THBS2 missense mutation. We further demonstrate a similar phenotype in heterozygous THBS2^Cys896Arg KI mice, in line with previous studies in Thbs2 homozygous null-mutant mice. Notably, THBS2 encodes Thrombospondin-2, a secreted homotrimeric matricellular protein that directly binds the ECM-shaping Matrix Metalloproteinase 2 (MMP2), mediating its clearance. THBS2 loss-of-function attenuates MMP2 clearance, enhancing MMP2-mediated proteoglycan cleavage, causing ECM abnormalities similar to those seen in the human and mouse disease we describe.