| Summary: | <p>Rapsyn is essential for clustering acetylcholine receptors (AChR) at the neuromuscular junction (NMJ). Congenital myasthenic syndrome (CMS) due to <em>RAPSN</em> mutations compromises neuromuscular transmission through a deficiency of AChR at the NMJ. <em>RAPSN</em>-CMS is autosomal recessive, and most patients harbour a common mutation p.Asn88Lys. A definitive genetic diagnosis for patients who do not carry the p.Asn88Lys allele can be challenging. In this thesis 10 novel variants in <em>RAPSN</em> are shown to impair AChR clustering <em>in vitro</em>, and are thus defined as pathogenic.</p> <p>The properties of <em>RAPSN</em> mutations p.Val45M, p.Asn88Lys, p.Arg91Leu and p.Ala153Thr were studied and were found to be diverse, though common mechanisms were found to underlie the AChR deficiency. The mutations reduce the stability of rapsyn and the stability of AChR-rapsyn clusters formed on cultured myotubes. A unique missense mutation in the AChR δ-subunit encoding gene, p.Glu381Lys, phenotypically mimics <em>RAPSN</em>-CMS, and investigations revealed that this mutation also causes instability of the AChR clusters.</p> <p>Salbutamol, a medication that is believed to stabilise NMJ, has recently been found to benefit AChR deficiency patients when used in combination with pyridostigmine. However, the mode of action of salbutamol at the NMJ is undefined. A pilot study was performed to evaluate the efficacy and mechanism of salbutamol therapy in a mouse model of AChR deficiency. Methodologies were established for the analysis of the effects of salbutamol and will provide the basis for a more detailed study of its beneficial action in disorders of neuromuscular transmission. </p>
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