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Congenital Disorders of Glycosylation and TMEM165 : A new player in proteoglycan synthesis

Abstract : Congenital Disorders of Glycosylation (CDG) is a group of human genetic disorders with defects in biosynthesis (glycosylation) of glycoproteins. Recent studies have discovered TMEM 165 as a novel protein deficient in CDG patients presenting bone abnormalities, suggesting a role of TMEM 165 in chondrogenesis and skeletal development. Proteoglycans (PGs) play a key role in several biological processes including chondrocytes maturation, growth plate development and intracellular signaling. Alterations in the synthesis of PGs may contribute to skeletal defects observed in TMEM 165-deficient CDG patients. To determine the link, if any, between TMEM165 deficiency and the synthesis of PGs, and to study the molecular mechanisms involved, we generated TMEM165 knock-out pre-chondrogenic ATDC5 cells using CRISPR/Cas9 technique. Interestingly, we showed that the knockdown of TMEM165 in ATDC5 cells resulted in profound defects in the synthesis of PGs and mainly impaired polymerization of both heparin-sulfate and chondroitin-sulfate glycosaminoglycan chains. Furthermore, we found that these defects can be overcome by supplying the cells with Mn2+. Similar results were observed in fibroblast cells from TMEM165-deficient CDG patient. These data suggest that TMEM165 is involved in the regulation of the homeostasis of Mn2+ which is used as a co-factor of Golgi glycosyltransferases and required for full enzyme activity. On the other hand, PGs play a key role in the regulation of TGFβ and BMP signaling. Given that these pathways regulate chondrogenesis and skeletal development their integrity was evaluated in TMEM 165-deficient ATDC5 cells and fibroblast from CDG patients. We demonstrated that TMEM165-deficiency functionally impairs TGFβ and BMP signaling pathways in both ATDC5 cells and human fibroblasts, suggesting a role in skeletal abnormalities observed in TMEM165-deficeint CDG patients. In addition, in vitro differentiation study of ATDC5 cells revealed that loss of TMEM165 expression promotes differentiation of ATDC5 cells towards hypertrophy, a process which may lead to premature chondrocyte maturation and to dwarfism observed in TMEM165-deficient CDG patients.
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Submitted on : Tuesday, January 11, 2022 - 4:11:30 PM
Last modification on : Tuesday, January 11, 2022 - 4:12:44 PM
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Sajida Khan. Congenital Disorders of Glycosylation and TMEM165 : A new player in proteoglycan synthesis. Biochemistry, Molecular Biology. Université de Lorraine, 2020. English. ⟨NNT : 2020LORR0155⟩. ⟨tel-03132575⟩



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