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.

Generation and validation of an iPSC line (BBANTWi008-A) from a Loeys-Dietz Syndrome type 3 patient.

Loeys-Dietz Syndrome (LDS) is an autosomal dominant connective tissue disorder. The major hallmark of LDS is thoracic aortic aneurysm and dissection (TAAD). We generated an induced pluripotent stem cell (iPSC) line of a severely affected LDS patient carrying a pathogenic SMAD3 p.Arg287Gln variant. Peripheral blood mononuclear cells were reprogrammed using non-integrating Sendai viral vectors. The autonomous pluripotency state of the resulting iPSC model was proven by the presence of pluripotency markers, trilineage differentiation potential and absence of the Sendai vector backbone. This iPSC line can be used to study and/or therapeutically target the cellular pathomechanisms of SMAD3-related LDS.

Hide and seek: Somatic SMAD3 mutations in melorheostosis.

In the current issue of JEM, Kang et al. (https://doi.org/10.1084/jem.20191499) describe somatic mutations in the SMAD3 gene causing endosteal melorheostosis. Using osteoblast models, the identified mutations are demonstrated to exert a gain-of-function mechanism, augmenting transforming growth factor (TGF) ß signaling. These findings provide further insights into the genetic etiology of melorheostosis and consolidate the importance of the TGFß pathway in skeletal disorders.