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Dok-7 is required for formation of the Neuromuscular JunctionEdit
During development, the growing end of motor neuron axons secrete a protein called agrin. This protein binds to several receptors on the surface of skeletal muscle. The receptor which seems to be required for formation of the neuromuscular junction (NMJ) is called MuSK (Muscle specific kinase). MuSK is a receptor tyrosine kinase - meaning that it induces cellular signaling by causing the addition of phosphate molecules to particular tyrosines on itself, and on proteins which bind the cytoplasmic domain of the receptor.
The requirement for MuSK in the formation of the NMJ was primarily demonstrated by mouse "knockout" studies. In mice which are deficient for either agrin or MuSK, the neuromuscular junction does not form.
Upon activation by its ligand agrin, MuSK signals via the proteins called Dok-7 and rapsyn, to induce "clustering" of acetylcholine receptors (AChR). Cell signaling downstream of MuSK requires Dok-7. Mice which lack this protein fail to develop endplates. Further, forced expression of Dok-7 induces the tyrosine phosphorylation, and thus the activation of MuSK. Dok-7 interacts with MuSK by way of protein "domain" called a "PTB domain."
In addition to the AChR, MuSK, and Dok-7 other proteins are then gathered, to form the endplate to the neuromuscular junction. The nerve terminates onto the endplate, forming the neuromuscular junction - a structure which is required to transmit nerve impulses to the muscle, and thus initiating muscle contraction.
Congenital Myasthenia SyndromeEdit
Homozygous mutation of Dok-7 is responsible for a form of congenital myasthenic syndrome (CMS) that is unique among disorders in this category because it affects muscles in the limbs and trunk but mostly spares the face, eyes, and functions of the mouth and pharnyx (chewing, swallowing and speech). Salbutamol can be effective in relieving CMS symptoms attributable to Dok-7 mutations.
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- Palace J, Lashley D, Newsom-Davis J, et al. (Jun 2007). Clinical features of the DOK7 neuromuscular junction synaptopathy. Brain 130 (Pt 6): 1507–15.
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