A human importin-ß-related disorder: Syndromic thoracic aortic aneurysm caused by bi-allelic loss-of-function variants in IPO8.

Importin 8, encoded by IPO8, is a ubiquitously expressed member of the importin-ß protein family that translocates cargo molecules such as proteins, RNAs, and ribonucleoprotein complexes into the nucleus in a RanGTP-dependent manner. Current knowledge of the cargoes of importin 8 is limited, but TGF-ß signaling components such as SMAD1-4 have been suggested to be among them. Here, we report that bi-allelic loss-of-function variants in IPO8 cause a syndromic form of thoracic aortic aneurysm (TAA) with clinical overlap with Loeys-Dietz and Shprintzen-Goldberg syndromes. Seven individuals from six unrelated families showed a consistent phenotype with early-onset TAA, motor developmental delay, connective tissue findings, and craniofacial dysmorphic features. A C57BL/6N Ipo8 knockout mouse model recapitulates TAA development from 8-12 weeks onward in both sexes but most prominently shows ascending aorta dilatation with a propensity for dissection in males. Compliance assays suggest augmented passive stiffness of the ascending aorta in male Ipo8-/- mice throughout life. Immunohistological investigation of mutant aortic walls reveals elastic fiber disorganization and fragmentation along with a signature of increased TGF-ß signaling, as evidenced by nuclear pSmad2 accumulation. RT-qPCR assays of the aortic wall in male Ipo8-/- mice demonstrate decreased Smad6/7 and increased Mmp2 and Ccn2 (Ctgf) expression, reinforcing a role for dysregulation of the TGF-ß signaling pathway in TAA development. Because importin 8 is the most downstream TGF-ß-related effector implicated in TAA pathogenesis so far, it offers opportunities for future mechanistic studies and represents a candidate drug target for TAA.

IPSC reprogramming of two patients with spondyloepiphyseal dysplasia congenita (SEDC).

Spondyloepiphyseal dysplasia congenita (SEDC) is a severe non-lethal type 2 collagenopathy caused by pathogenic variants in the COL2A1 gene, which encodes the alpha-1 chain of type II collagen. SEDC is clinically characterized by severe short stature, degenerative joint disease, hearing impairment, orofacial anomalies and ocular manifestations. To study and therapeutically target the underlying disease mechanisms, human iPSC-chondrocytes are considered highly suitable as they have been shown to exhibit several key features of skeletal dysplasias. Prior to creating iPSC-chondrocytes, peripheral blood mononuclear cells of two male SEDC patients, carrying the p.Gly1107Arg and p.Gly408Asp pathogenic variants, respectively, were successfully reprogrammed into iPSCs using the CytoTune™-iPS 2.0 Sendai Kit (Invitrogen).

Variable clinical expression of a Belgian TGFB3 founder variant suggests the presence of a genetic modifier.

Background: TGFB3 variants cause Loeys-Dietz syndrome type 5, a syndromic form of thoracic aortic aneurysm and dissection. The exact disease phenotype is hard to delineate because of few identified cases and highly variable clinical representation. Methodology: We provide the results of a haplotype analysis and a medical record review of clinical features of 27 individuals from 5 different families, originating from the Campine region in Flanders, carrying the NM_003239.5(TGFB3):c.787G>C p.(Asp263His) likely pathogenic variant, dbSNP:rs796051886, ClinVar:203492. The Asp263 residue is essential for integrin binding to the Arg-Gly-Asp (RGD) motif of the TGFß3-cytokine. Results: The haplotype analysis revealed a shared haplotype of minimum 1.92 Mb and maximum 4.14 Mb, suggesting a common founder originating >400 years ago. Variable clinical features included connective tissue manifestations, non-aneurysmal cardiovascular problems such as hypertrophic cardiomyopathy, bicuspid aortic valve, mitral valve disease, and septal defects. Remarkably, only in 4 out of the 27 variant-harboring individuals, significant aortic involvement was observed. In one family, a 31-year-old male presented with type A dissection. In another family, the male proband (65 years) underwent a Bentall procedure because of bicuspid aortic valve insufficiency combined with sinus of Valsalva of 50 mm, while an 80-year-old male relative had an aortic diameter of 43 mm. In a third family, the father of the proband (75 years) presented with ascending aortic aneurysm (44 mm). Conclusion: The low penetrance (15%) of aortic aneurysm/dissection suggests that haploinsufficiency alone by the TGFB3 variant may not result in aneurysm development but that additional factors are required to provoke the aneurysm phenotype.

Current progress in clinical, molecular, and genetic aspects of adult fibromuscular dysplasia.

Fibromuscular dysplasia (FMD) is a non-atherosclerotic vascular disease that may involve medium-sized muscular arteries throughout the body. The majority of FMD patients are women. Although a variety of genetic, mechanical, and hormonal factors play a role in the pathogenesis of FMD, overall, its cause remains poorly understood. It is probable that the pathogenesis of FMD is linked to a combination of genetic and environmental factors. Extensive studies have correlated the arterial lesions of FMD to histopathological findings of arterial fibrosis, cellular hyperplasia, and distortion of the abnormal architecture of the arterial wall. More recently, the vascular phenotype of lesions associated with FMD has been expanded to include arterial aneurysms, dissections, and tortuosity. However, in the absence of a string-of-beads or focal stenosis, these lesions do not suffice to establish the diagnosis. While FMD most commonly involves renal and cerebrovascular arteries, involvement of most arteries throughout the body has been reported. Increasing evidence highlights that FMD is a systemic arterial disease and that subclinical alterations can be found in non-affected arterial segments. Recent significant progress in FMD-related research has led to improve our understanding of the disease's clinical manifestations, natural history, epidemiology, and genetics. Ongoing work continues to focus on FMD genetics and proteomics, physiological effects of FMD on cardiovascular structure and function, and novel imaging modalities and blood-based biomarkers that can be used to identify subclinical FMD. It is also hoped that the next decade will bring the development of multi-centred and potentially international clinical trials to provide comparative effectiveness data to inform the optimal management of patients with FMD.