Therapy for Congenital Myasthenia, a destructive neuromuscular disorder

Shrestha Dutta, Amity University Kolkata

Congenital myasthenia is a group of disorders brought about by transformations in genes that are significant for the arrangement, function, and maintenance of neuromuscular synapses. Generally, mutations in genes are recessive and decrease gene action, thereby causing synaptic shortfalls that lead to early-stage structural and functional deficiencies in the neuromuscular neurotransmitter, which are liable for muscle weakness all through life.

The arrangement and maintenance of neuromuscular neurotransmitters require the aggregation of exceptionally specialized presynaptic and postsynaptic membranes, which includes the regulated activity of a few key molecules. AGRIN, which is delivered from motor nerve terminals, attaches to the lipoprotein receptor-related protein 4 (LRP4) in muscle, stimulating the development of a complex among LRP4 and muscle-specific kinase (MUSK), a receptor tyrosine kinase that acts as an expert controller of synaptic differentiation. LRP4, once aggregated in the postsynaptic layer because of MUSK initiation, also stimulates signals directly back to the motor axons to stimulate the presynaptic differentiation. Transformations in AGRIN, LRP4 and MUSK, also in the genes that encode subunits of acetylcholine receptors (AChRs), likewise cause CM.

Initiation of MUSK likewise relies upon the connector protein DOK7. Transformations in Dok7 are liable for 10–20% of all cases of Congenital Myasthenia. The disorder is incapacitating—causing weakness in appendage, neck, and facial muscles—and one-fourth of patients with DOK7 CM require non-obtrusive ventilation eventually during their lifetime. Few medications lessen the clinical symptoms. The N-terminal area of DOK7 contains a pleckstrin homology (PH) and phosphotyrosine-restricting (PTB) area, whose function is to dimerize DOK7 and attach to a phosphorylated tyrosine structure in the MUSK juxtamembrane (JM) region. A deterioration of DOK7 to attach MUSK leads to failure of AGRIN to stimulate MUSK phosphorylation, exhibiting that DOK7 is fundamental to balance out phosphorylation of MUSK, most likely by promoting its dimerization. Also, AGRIN-stimulated MUSK phosphorylation prompts phosphorylation of two tyrosine deposits in the C-terminal region of DOK7, which triggers the enlistment of CRK and CRK-L—proteins that take part in the aggregation of AChRs. The most widely recognized reason for Dok7 CM is a four-base-pair duplication (deposits 1124–1127, TGCC), that leads to a frameshift and early termination of DOK7. Some people with Dok7 CM are homozygous for this mutant allele, while others transport this mutant allele in blend with an alternate mutant allele of Dok7. The truncated type of DOK7 holds the PH and PTB spaces and attaches to the tyrosine-phosphorylated JM area of MUSK, yet does not have the two tyrosine deposits that are phosphorylated and select CRK proteins, proposing that the deficiency of these tyrosine residues accounts for the synaptic deficiency in this normal type of Dok7 CM.

The most well-known infection-causing transformation (DOK71124_1127 dup) shortens DOK7 and leads to the deficiency of two tyrosine deposits that are phosphorylated and select CRK proteins, which are significant for securing acetylcholine receptors at neural connections. This study portrays a mouse model of this normal type of CM (Dok7CM mice) and a mouse with point transformations in the two tyrosine residues (Dok72YF). The research shows that Dok7CM mice had serious deficiencies in neuromuscular neurotransmitter development that caused neonatal lethality. Out of the blue, these deficiencies were because of a serious inadequacy in phosphorylation and stimulation of muscle-explicit kinase (MUSK) instead of insufficiency in DOK7 tyrosine phosphorylation. The scientists created agonist antibodies against MUSK and showed that these antibodies re-established neuromuscular neurotransmitter development and prevented neonatal lethality and late-beginning disorders in Dok7CM mice. These discoveries distinguish a startling reason for sickness and a possible treatment for both DOK7 CM and different types of Congenital Myasthenia brought about by transformations in AGRIN, LRP4, or MUSK, and represent the capability of potential treatment to save inborn lethality.

Also read: Analysis of the interaction sites of SARS-CoV-2
Source:: Oury, J., Zhang, W., Leloup, N. et al. Mechanism of disease and therapeutic rescue of Dok7 congenital myasthenia. Nature (2021). https://doi.org/10.1038/s41586-021-03672-3

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About the Author: Shrestha Dutta is a 4th-year Biotechnology Engineering Student with a great interest in Genetics, Recombinant DNA Technology, and Immunology. She is a creative scientific writer at Bioxone with an inclination towards gaining knowledge regarding various sections of Biotechnology and engaging himself in various wet lab skills. She also has a review paper published in the journal IJSER.