PMID- 34163073 OWN - NLM STAT- MEDLINE DCOM- 20211007 LR - 20221027 IS - 1476-4687 (Electronic) IS - 0028-0836 (Print) IS - 0028-0836 (Linking) VI - 595 IP - 7867 DP - 2021 Jul TI - Mechanism of disease and therapeutic rescue of Dok7 congenital myasthenia. PG - 404-408 LID - 10.1038/s41586-021-03672-3 [doi] AB - Congenital myasthenia (CM) is a devastating neuromuscular disease, and mutations in DOK7, an adaptor protein that is crucial for forming and maintaining neuromuscular synapses, are a major cause of CM(1,2). The most common disease-causing mutation (DOK7(1124_1127 dup)) truncates DOK7 and leads to the loss of two tyrosine residues that are phosphorylated and recruit CRK proteins, which are important for anchoring acetylcholine receptors at synapses. Here we describe a mouse model of this common form of CM (Dok7(CM) mice) and a mouse with point mutations in the two tyrosine residues (Dok7(2YF)). We show that Dok7(CM) mice had severe deficits in neuromuscular synapse formation that caused neonatal lethality. Unexpectedly, these deficits were due to a severe deficiency in phosphorylation and activation of muscle-specific kinase (MUSK) rather than a deficiency in DOK7 tyrosine phosphorylation. We developed agonist antibodies against MUSK and show that these antibodies restored neuromuscular synapse formation and prevented neonatal lethality and late-onset disease in Dok7(CM) mice. These findings identify an unexpected cause for disease and a potential therapy for both DOK7 CM and other forms of CM caused by mutations in AGRIN, LRP4 or MUSK, and illustrate the potential of targeted therapy to rescue congenital lethality. CI - (c) 2021. The Author(s). FAU - Oury, Julien AU - Oury J AD - Helen L. and Martin S. Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, NYU Grossman School of Medicine, New York, NY, USA. FAU - Zhang, Wei AU - Zhang W AD - Helen L. and Martin S. Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, NYU Grossman School of Medicine, New York, NY, USA. FAU - Leloup, Nadia AU - Leloup N AD - Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA. FAU - Koide, Akiko AU - Koide A AD - Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA. AD - Department of Medicine, NYU Grossman School of Medicine, New York, NY, USA. FAU - Corrado, Alexis D AU - Corrado AD AD - Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA. FAU - Ketavarapu, Gayatri AU - Ketavarapu G AUID- ORCID: 0000-0001-5029-8595 AD - Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA. FAU - Hattori, Takamitsu AU - Hattori T AD - Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA. AD - Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA. FAU - Koide, Shohei AU - Koide S AUID- ORCID: 0000-0001-5473-4358 AD - Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA. shohei.koide@nyulangone.org. AD - Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA. shohei.koide@nyulangone.org. FAU - Burden, Steven J AU - Burden SJ AUID- ORCID: 0000-0002-3550-6891 AD - Helen L. and Martin S. Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, NYU Grossman School of Medicine, New York, NY, USA. steve.burden@med.nyu.edu. LA - eng GR - R01 NS075124/NS/NINDS NIH HHS/United States GR - R37 NS036193/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20210623 PL - England TA - Nature JT - Nature JID - 0410462 RN - 0 (Agrin) RN - 0 (Antibodies) RN - 0 (Crk protein, mouse) RN - 0 (Dok-7 protein, mouse) RN - 0 (LDL-Receptor Related Proteins) RN - 0 (Lrp4 protein, mouse) RN - 0 (Muscle Proteins) RN - 0 (Proto-Oncogene Proteins c-crk) RN - 21820-51-9 (Phosphotyrosine) RN - EC 2.7.10.1 (MuSK protein, mouse) RN - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases) SB - IM CIN - Nat Rev Drug Discov. 2021 Aug;20(8):587. PMID: 34239091 MH - Aging MH - Agrin/genetics/metabolism MH - Animals MH - Animals, Newborn MH - Antibodies/immunology MH - Disease Models, Animal MH - Female MH - LDL-Receptor Related Proteins/genetics/metabolism MH - Male MH - Mice MH - Molecular Targeted Therapy MH - Muscle Fibers, Skeletal/chemistry/metabolism MH - Muscle Proteins/chemistry/*genetics/metabolism MH - *Mutation MH - Myasthenic Syndromes, Congenital/*drug therapy/*genetics/immunology MH - Phosphorylation MH - Phosphotyrosine/genetics/metabolism MH - Proto-Oncogene Proteins c-crk/metabolism MH - Receptor Protein-Tyrosine Kinases/agonists/genetics/immunology/metabolism MH - Recurrence MH - Synapses/metabolism PMC - PMC8277574 COIS- S.J.B. is an inventor on a patent (no. 9,329,182) for 'Method of treating motor neuron disease with an antibody that agonizes MUSK'. S.J.B., S.K., J.O., A.K. and N.L. are inventors on a patent application (no. 1474662.02232) for 'Therapeutic MUSK Antibodies' filed by New York University. These patents have been licensed to Argenx BVBA. S.J.B. and S.K. received research funding from Argenx BVBA. S.K. is a scientific advisory board member and holds equity in and receives consulting fees from Black Diamond Therapeutics, and receives research funding from Puretech Health. EDAT- 2021/06/25 06:00 MHDA- 2021/10/08 06:00 PMCR- 2021/06/23 CRDT- 2021/06/24 06:28 PHST- 2021/01/15 00:00 [received] PHST- 2021/05/25 00:00 [accepted] PHST- 2021/06/25 06:00 [pubmed] PHST- 2021/10/08 06:00 [medline] PHST- 2021/06/24 06:28 [entrez] PHST- 2021/06/23 00:00 [pmc-release] AID - 10.1038/s41586-021-03672-3 [pii] AID - 3672 [pii] AID - 10.1038/s41586-021-03672-3 [doi] PST - ppublish SO - Nature. 2021 Jul;595(7867):404-408. doi: 10.1038/s41586-021-03672-3. Epub 2021 Jun 23.