In vitro and Drosophila models of rare monogenic disorders
- سال انتشار: 1400
- محل انتشار: کنفرانس بین المللی ژنتیک و ژنومیکس انسانی
- کد COI اختصاصی: CHGGE01_213
- زبان مقاله: انگلیسی
- تعداد مشاهده: 43
نویسندگان
Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
چکیده
Backgrounds: Primary cilia (PC) are immotile sensory cellular organelles that transduce diverseextracellular cues to direct development and homeostasis. Ciliary dysfunction has beendetermined as a cause of inherited ciliopathies with skeletal, renal, nervous system and otherabnormalities. We investigated the molecular underpinnings of novel and known skeletaldysplasias, short-rib thoracic dysplasia ۱۶ (SRTD۱۶) and achondrogenesis type ۱A (ACG۱A)that are associated with IFT۵۲ and TRIP۱۱, respectively.Materials and Methods: We evaluated four affected foetuses, two each from two families, withACG۱A phenotype. Exome and genome sequencing were used to identify candidate variants inTRIP۱۱. Molecular analysis of TRIP۱۱ mRNA, protein and PC features were done todemonstrate pathogenicity in patient-derived fibroblast cells. In a separate study we investigatethe role of IFT۵۲ in PC dependent manner in osteogenic differentiation using lentiviral shRNAknockdown (KD) in C۳H۱۰T۱/۲ mesenchymal stem cells and explored the role of IFT۵۲ in vivousing Drosophila.Results: We demonstrated a pathogenic biallelic deep intronic variant c.۵۴۵۷+۸۱T> A in TRIP۱۱that causes ACG۱A. We observed severe impairment of primary ciliogenesis, not reported so farin patient cells with TRIP۱۱-related disorder. Further we show that silencing Ift۵۲ leads toimpaired primary ciliogenesis and abrogated osteogenic differentiation in vitro. In DrosophilaIFT۵۲ KD led to significant deficits in chordotonal structure and function, such as adultclimbing, larval mobility and hearing.Conclusion: Our studies have evaluated the molecular pathology of ACG۱A and SRTD۱۶. Ituncovered the essential role of primary cilia in these disorders underscoring its fundamentalfunction in skeletal development.کلیدواژه ها
Achondrogenesis ۱A, Short-rib thoracic dysplasia ۱۶, IFT۵۲, TRIP۱۱, Primary ciliaاطلاعات بیشتر در مورد COI
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