Dok-7 Mutations Underlie a Neuromuscular Junction Synaptopathy

Abstract

Congenital myasthenic syndromes (CMSs) are a group of inherited disorders of neuromuscular transmission characterized by fatigable muscle weakness. One major subgroup of patients shows a characteristic "limb girdle" pattern of muscle weakness, in which the muscles have small, simplified neuromuscular junctions but normal acetylcholine receptor and acetylcholinesterase function. We showed that recessive inheritance of mutations in Dok-7, which result in a defective structure of the neuromuscular junction, is a cause of CMS with proximal muscle weakness.

Genetic heterogeneity and pathophysiological mechanisms in congenital myasthenic syndromes

“…During the same year, Beeson et al identified DOK7 mutations in 21 patients with a clinical diagnosis of CMS exhibiting a limb girdle phenotype. [13][14] Since then DOK7 mutations have been confirmed in a significant number of other series. 53-54-55-56-57 The pathophysiological repercussions of DOK7 mutations appear to arise from abnormal activation of MuSK signalling leading to an abnormally unstable and simplified neuromuscular junction affecting both pre and postsynaptic structures.…”

“…The kinetic mutations fall into two categories according to whether they induce slow or fast channel syndromes [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] .…”

“…[4][5] To date 13 genes have been found to cause CMS when mutated. These are the pre-synaptic acetyltransferase CHAT 6 , the gene COLQ 7-8-9 encoding the triple stranded collagenic tail of the synaptic acetylcholinesterase (AChE), the genes encoding the different subunits of the postsynaptic acetylcholine receptors (AChR) CHRNA1, CHRNB1, CHRND, CHRNE and CHRNG, the RAPSN gene encoding the postsynaptic protein rapsyn 10 , the postsynaptic muscle specific kinase (MUSK) gene 11 , the postsynaptic sodium channel (SCN4) 12 , the DOK7 gene encoding the postsynaptic Dok-7 protein [13][14] , the LAMB2 encoding the synaptic Laminin B2 protein 15 , the AGRN gene encoding the postsynaptic agrin protein 16 and the PLEC1 gene encoding the postsynaptic protein plectin. 17-18-19 Genetic classification of the different CMS cohorts reveals that the majority of CMS patients have mutations in genes expressing postsynaptic endplate proteins [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] (table 1).…”

Therapeutic Strategies in Congenital Myasthenic Syndromes

“…3,4,13,15,[17][18][19][20][21] Although there are no double-blind, placebo-controlled clinical trials for CMS, several drugs have shown convincingly positive clinical effects.…”

Identity, developmental restriction and reactivity of extralaminar cells capping mammalian neuromuscular junctions

“…In adult mammals and most other vertebrates, each motor endplate is normally innervated by a single motor axon terminal and in most muscle fibres this NMJ is constrained to less than 0.1% of the muscle fibre cell surface (Sanes and Lichtman, 1999;Beeson et al, 2006). The strength of synaptic transmission at each NMJ in a motor unit virtually guarantees that all the muscle fibres supplied by a motor neuron contract in response to every action potential conducted into its motor nerve terminals (Wood and Slater, 2001).…”