Bi-allelic variants in IPO۸ cause human importin- β -related disorders
- سال انتشار: 1400
- محل انتشار: کنفرانس بین المللی ژنتیک و ژنومیکس انسانی
- کد COI اختصاصی: CHGGE01_133
- زبان مقاله: انگلیسی
- تعداد مشاهده: 216
نویسندگان
Department of Medical Genetics, Next Generation Genetic Polyclinic, Mashhad, Iran
Department of Medical Genetics, Next Generation Genetic Polyclinic, Mashhad, Iran
Department of Medical Genetics, Next Generation Genetic Polyclinic, Mashhad, Iran
Department of Pediatric Neurology, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
Department of Medical Genetics, Next Generation Genetic Polyclinic, Mashhad, Iran
Hassan Mottaghi Moghaddam Shahri
Pediatric Department, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
چکیده
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 ۸اطلاعات بیشتر در مورد COI
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