LRP4 third β-propeller domain mutations cause novel congenital myasthenia by compromising agrin-mediated MuSK signaling in a position-specific manner
| العنوان: | LRP4 third β-propeller domain mutations cause novel congenital myasthenia by compromising agrin-mediated MuSK signaling in a position-specific manner |
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| المؤلفون: | Kenyu Ito, Bisei Ohkawara, Yasutomo Ito, Tomohiko Nakata, Akio Masuda, Macarena Cabrera-Serrano, Margherita Milone, Andrew G. Engel, Nobuyuki Asai, Kinji Ohno, Mikako Ito |
| المصدر: | Human Molecular Genetics. 23:1856-1868 |
| بيانات النشر: | Oxford University Press (OUP), 2013. |
| سنة النشر: | 2013 |
| مصطلحات موضوعية: | Neuromuscular transmission, Muscle Proteins, medicine.disease_cause, Edrophonium, Mice, Postsynaptic potential, Chlorocebus aethiops, Receptors, Cholinergic, Wnt Signaling Pathway, beta Catenin, Genetics (clinical), Mutation, Agrin, biology, Wnt signaling pathway, Articles, General Medicine, Cell biology, medicine.anatomical_structure, COS Cells, Female, Pyridostigmine Bromide, medicine.medical_specialty, animal structures, Beta-catenin, Adolescent, Neuromuscular Junction, Cholinergic Agonists, Neuromuscular junction, Cell Line, Internal medicine, Genetics, medicine, Animals, Humans, Molecular Biology, LDL-Receptor Related Proteins, Acetylcholine receptor, Myasthenic Syndromes, Congenital, Base Sequence, Receptor Protein-Tyrosine Kinases, Sequence Analysis, DNA, Protein Structure, Tertiary, Enzyme Activation, Wnt Proteins, HEK293 Cells, Endocrinology, biology.protein, Cholinesterase Inhibitors |
| الوصف: | Congenital myasthenic syndromes (CMS) are heterogeneous disorders in which the safety margin of neuromuscular transmission is compromised by one or more specific mechanisms. Using Sanger and exome sequencing in a CMS patient, we identified two heteroallelic mutations, p.Glu1233Lys and p.Arg1277His, in LRP4 coding for the postsynaptic low-density lipoprotein receptor-related protein 4. LRP4, expressed on the surface of the postsynaptic membrane of the neuromuscular junction, is a receptor for neurally secreted agrin, and LRP4 bound by agrin activates MuSK. Activated MuSK in concert with Dok-7 stimulates rapsyn to concentrate and anchor AChR on the postsynaptic membrane and interacts with other proteins implicated in the assembly and maintenance of the neuromuscular junction. LRP4 also functions as an inhibitor of Wnt/beta-catenin signaling. The identified mutations in LRP4 are located at the edge of its 3rd beta-propeller domain and decrease binding affinity of LRP4 for both MuSK and agrin. Mutations in the LRP4 3rd beta-propeller domain were previously reported to impair Wnt signaling and cause bone diseases including Cenani–Lenz syndactyly syndrome and sclerosteosis-2. By analyzing naturally occurring and artificially introduced mutations in the LRP4 3rd beta-propeller domain, we show that the edge of the domain regulates the MuSK signaling whereas its central cavity governs Wnt signaling. We conclude that LRP4 is a new CMS disease gene and that the 3rd beta propeller domain of LRP4 mediates the two signaling pathways in a position-specific manner. |
| تدمد: | 1460-2083 0964-6906 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::abe966b76fe11bb091a34a21ce213a36 https://doi.org/10.1093/hmg/ddt578 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....abe966b76fe11bb091a34a21ce213a36 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14602083 09646906 |
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