Bi-allelic variants in IPO۸ cause human importin- β -related disorders

Backgrounds: IPO۸ protein encodes Importin ۸ which translocates cargo molecules into thenucleus. One of them is TGF-β signaling components, dysregulated transforming growth factors,which cause connective tissue disorders. Bi-allelic loss-of-function variants in IPO۸ cause asyndromic form of thoracic aortic aneurysm (TAA) with clinical overlap with Loeys-Dietz andShprintzen-Goldberg syndromes. Here, we reported two patients (male and female) fromunrelated families with variants in IPO۸ with symptoms like cardio-vascular anomalies,connective tissue findings, craniofacial dysmorphic features, developmental delay, and immunedysregulation.Materials and Methods: We performed whole-exome sequencing and Sanger sequencing toidentify pathogenic variant(s) in the families. By using CRISPR/ Cas۹-mediated inactivation inzebrafish, the role of IPO۸ in nuclear translocation was identified. A mild to the severe defectingpattern in the early embryonic development level of zebrafish based on the IPO۸’S role in TGF-βsignaling was demonstrated as well as severe cardiovascular and skeletal defects. In addition, byusing the C۵۷BL/۶N IPO۸ knockout mouse model cardiovascular defects in both sexes areshown.Results: A homozygous variant, IPO۸: c.۷۲۸del (p.Pro۲۴۳LeufsTer۲۷) in the male proband andIPO۸: c.۲۳۴۷_۲۳۶۹del (p.Leu۷۸۳ValfsTer۵) in female patient is identified. It is demonstratedthat IPO۸ deficiency leads to TGF-β signalopathy which has functions in the development,patterning, and homeostasis of the affected tissues.Conclusion: Our work demonstrated that IPO۸ has an important role in TGF-β signaling andcauses connective tissue defect. we know importin ۸ is a TGF-β-related effector and involve inTAA pathogenesis so far, next future opportunities would be mechanistic studies andrepresenting candidate drug targets for TAA.

کلیدواژه ها:

Loeys-Dietz syndrome ، Shprintzen-Goldberg syndrome ، thoracic aortic aneurysm ، TGF-beta ، importin ۸