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KEY POINTS: The physiological significance of the developmental switch from fetal to adult acetylcholine receptors in muscle (AChRs) and the functional impact of AChR clustering by rapsyn are still not well studied. Performing patch clamp experiments we show that recovery from desensitisation is faster in the adult AChR isoform. Recovery from desensitisation is determined by the AChR isoform specific cytoplasmic M3-M4 domain. The co-expression of rapsyn in muscle cells induced AChR clustering and facilitated recovery from desensitisation in both fetal and adult AChRs. In fetal AChRs, facilitation of recovery kinetics by rapsyn was independent of AChR clustering. These effects could be crucial adaptations to motor neuron firing rates that in rodents have been shown to increase around the time of birth when AChRs cluster at the developing neuromuscular junctions. ABSTRACT: The neuromuscular junction (NMJ) is the site of a number of autoimmune and genetic disorders, many involving the muscle-type nicotinic acetylcholine receptor (AChR), but there are aspects of normal NMJ development and function that need to be better understood. In particular, there are still questions regarding the implications of the developmental switch from fetal to adult AChRs and how their functions might be modified by rapsyn that clusters the AChRs. Desensitisation of human muscle AChRs was studied using the patch clamp technique to measure whole-cell currents in muscle-type (TE671/CN21) and non-muscle (HEK293) cell lines expressing either fetal or adult AChRs. Desensitisation time constants were similar with both AChR isoforms but recovery time constants were shorter in cells expressing adult compared to fetal AChRs (p<0.0001). Chimeric experiments showed that recovery from desensitisation was determined by the M3-M4 cytoplasmic loops of the \u03b3- and \u03b5-subunits. Expression of rapsyn in TE671/CN21 cells induced AChR aggregation and also, surprisingly, shortened recovery time constants in both fetal and adult AChRs. However, this was not dependent on clustering as rapsyn also facilitated recovery from desensitisation in HEK293 cells expressing a \u03b4-R375H AChR mutant that in C2C12 myotubes did not form clusters. Thus, rapsyn interactions with AChRs lead not only to clustering but also to a clustering-independent faster recovery from desensitisation. Both effects of rapsyn could be a necessary adjustment to the motor neuron firing rates that increase around the time of birth. This article is protected by copyright. All rights reserved.
\n \n\n \n \nMutations in DPAGT1 are a newly recognised cause of congenital myasthenic syndrome. DPAGT1 encodes an early component of the N-linked glycosylation pathway. Initially mutations in DPAGT1 have been associated with the onset of the severe multisystem disorder - congenital disorder of glycosylation type 1J. However, recently it was established that certain mutations in this gene can cause symptoms restricted to muscle weakness resulting from defective neuromuscular transmission. We report four cases from a large Iranian pedigree with prominent limb-girdle weakness and minimal craniobulbar symptoms who harbour a novel mutation in DPAGT1, c.652C>T, p.Arg218Trp. This myasthenic syndrome may mimic myopathic disorders and is likely under-diagnosed. \u00a9 2013 Elsevier B.V.
\n \n\n \n \n\u00a9 Springer International Publishing AG, part of Springer Nature 2018. Congenital myasthenic syndromes (CMS) are a group of genetic disorders of neuromuscular transmission. Fetal manifestations (hydramnios and arthrogryposis) are sometimes present. The onset occurs usually during the neonatal period but sometimes also in childhood, adolescence, or even adulthood. CMS are characterized by muscle weakness affecting the axial and limb muscles (hypotonia), the ocular muscles (ptosis and ophthalmoplegia), and the facial and bulbar muscles (affecting sucking and swallowing, and leading to dysphonia). The symptoms fluctuate and worsen with physical effort. Severe forms are associated with respiratory disease. The diagnostic strategy involves two steps: (1) establishing the diagnosis of a CMS based on its familial occurrence and early onset and (2) identifying the physiopathological type of disease on the basis of the mode of transmission, by detecting a repetitive CMAP after single stimulation upon EMG (characteristic of acetylcholinesterase deficiency and slow-channel syndrome), the response to anticholinesterases, studies of endplate morphology, and molecular analysis. The most frequent forms are postsynaptic CMS, which are caused by mutations leading to reduced amount, or, more rarely, kinetic anomalies of the acetylcholine receptor (slow-channel syndrome and fast-channel syndrome), or by mutations in the RAPSN, MuSK, SCN4A sodium channel, and DOK7 genes (Table 45.1).
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