A Genetic Variant in GPR126 Causing a Decreased Inclusion of Exon 6 Is Associated with Cartilage Development in Adolescent Idiopathic Scoliosis Population

Xu, Enjie; Shao, Wang; Jiang, Heng; Lin, Tao; Gao, Rui; Zhou, Xuhui

doi:10.1155/2019/4678969

Cited by 19 publications

(28 citation statements)

References 51 publications

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“…The role of Adgrg6 in myelination and remyelination suggests that it could be a promising therapeutic target for peripheral demyelinating diseases and possibly other diseases linked to Adgrg6 malfunction, such as adolescent idiopathic scoliosis [ 13 ]. We therefore set out to explore the therapeutic potential of stimulating Adgrg6-dependent promyelinating pathways using its natural ligand PrP.…”

Section: Introductionmentioning

confidence: 99%

Soluble dimeric prion protein ligand activates Adgrg6 receptor but does not rescue early signs of demyelination in PrP-deficient mice

et al. 2020

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The adhesion G-protein coupled receptor Adgrg6 (formerly Gpr126) is instrumental in the development, maintenance and repair of peripheral nervous system myelin. The prion protein (PrP) is a potent activator of Adgrg6 and could be used as a potential therapeutic agent in treating peripheral demyelinating and dysmyelinating diseases. We designed a dimeric Fc-fusion protein comprising the myelinotrophic domain of PrP (FT2Fc), which activated Adgrg6 in vitro and exhibited favorable pharmacokinetic properties for in vivo treatment of peripheral neuropathies. While chronic FT2Fc treatment elicited specific transcriptomic changes in the sciatic nerves of PrP knockout mice, no amelioration of the early molecular signs demyelination was detected. Instead, RNA sequencing of sciatic nerves revealed downregulation of cytoskeletal and sarcomere genes, akin to the gene expression changes seen in myopathic skeletal muscle of PrP overexpressing mice. These results call for caution when devising myelinotrophic therapies based on PrP-derived Adgrg6 ligands. While our treatment approach was not successful, Adgrg6 remains an attractive therapeutic target to be addressed in other disease models or by using different biologically active Adgrg6 ligands.

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Section: Introductionmentioning

confidence: 99%

Soluble dimeric prion protein ligand activates Adgrg6 receptor but does not rescue early signs of demyelination in PrP-deficient mice

et al. 2020

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“…The role of Adgrg6 in myelination and remyelination suggests that it could be a promising therapeutic target for peripheral demyelinating diseases and possibly other diseases linked to Adgrg6 malfunction, such as adolescent idiopathic scoliosis (Xu et al, 2019). We therefore set out to explore the therapeutic potential of stimulating Adgrg6-dependent promyelinating pathways using its natural ligand PrP.…”

Section: Introductionmentioning

confidence: 99%

Dimeric prion protein ligand activates Adgrg6 but does not rescue myelinopathy of PrP-deficient mice

Henzi

Senatore

Lakkaraju

et al. 2020

Preprint

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AbstractThe adhesion G-protein coupled receptor Adgrg6 (formerly Gpr126) is instrumental in the development, maintenance and repair of peripheral nervous system myelin. The prion protein (PrP) is a potent activator of Adgrg6 and could be used as a potential therapeutic agent in treating peripheral demyelinating and dysmyelinating diseases. We designed a dimeric Fc-fusion protein comprising the myelinotrophic domain of PrP (FT2Fc), which activated Adgrg6 in vitro and exhibited favorable pharmacokinetic properties for in vivo treatment of peripheral neuropathies. While chronic FT2Fc treatment elicited specific transcriptomic changes in the sciatic nerves of PrP knockout mice, no amelioration of the peripheral demyelinating neuropathy was detected. Instead, RNA sequencing of sciatic nerves revealed downregulation of cytoskeletal and sarcomere genes, akin to the gene expression changes seen in myopathic skeletal muscle of PrP overexpressing mice. These results call for caution when devising myelinotrophic therapies based on PrP-derived Adgrg6 ligands. While our treatment approach was not successful, Adgrg6 remains an attractive therapeutic target to be addressed in other disease models or by using different biologically active Adgrg6 ligands.Summary blurbA dimeric prion protein ligand activates Adgrg6 but fails to induce pro-myelination signaling upon chronic treatment in a mouse model of peripheral demyelination.

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“…Alternative splicing of exon 6 was observed in human and zebrafish 30,51 , producing isoforms that either include (S1 isoform, henceforth referred to as +ss) or exclude (S2 isoform, henceforth referred to as −ss) a 23 aa segment found within the unknown region between PTX and HormR. A genetic variant in GPR126 leading to decreased inclusion of exon 6 was recently found to be associated with adolescent idiopathic scoliosis 54 . Thus, determining the ECR structure, conformation, and other possible unexplored features will be instrumental in understanding Gpr126 function.…”

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confidence: 99%

Structural basis for adhesion G protein-coupled receptor Gpr126 function

et al. 2020

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Many drugs target the extracellular regions (ECRs) of cell-surface receptors. The large and alternatively-spliced ECRs of adhesion G protein-coupled receptors (aGPCRs) have key functions in diverse biological processes including neurodevelopment, embryogenesis, and tumorigenesis. However, their structures and mechanisms of action remain unclear, hampering drug development. The aGPCR Gpr126/Adgrg6 regulates Schwann cell myelination, ear canal formation, and heart development; and GPR126 mutations cause myelination defects in human. Here, we determine the structure of the complete zebrafish Gpr126 ECR and reveal five domains including a previously unknown domain. Strikingly, the Gpr126 ECR adopts a closed conformation that is stabilized by an alternatively spliced linker and a conserved calcium-binding site. Alternative splicing regulates ECR conformation and receptor signaling, while mutagenesis of the calcium-binding site abolishes Gpr126 function in vivo. These results demonstrate that Gpr126 ECR utilizes a multi-faceted dynamic approach to regulate receptor function and provide relevant insights for ECR-targeted drug design.

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A Genetic Variant in GPR126 Causing a Decreased Inclusion of Exon 6 Is Associated with Cartilage Development in Adolescent Idiopathic Scoliosis Population

Cited by 19 publications

References 51 publications

Soluble dimeric prion protein ligand activates Adgrg6 receptor but does not rescue early signs of demyelination in PrP-deficient mice

Soluble dimeric prion protein ligand activates Adgrg6 receptor but does not rescue early signs of demyelination in PrP-deficient mice

Dimeric prion protein ligand activates Adgrg6 but does not rescue myelinopathy of PrP-deficient mice

Structural basis for adhesion G protein-coupled receptor Gpr126 function

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