Splicing Aberrations in Congenital Myasthenic Syndromes

Abstract

The fidelity of splicing is indispensable for assuring rapidly changing cellular processes and physiological integrity of the cells. The precise biogenesis of ribo nucleoprotein complexes (RNPs) is therefore essential, which is ensured by proper complementation of RNA and RNA-binding proteins in a specific cellular context. Genetic mutations disrupting cis-acting splicing elements or compromising catalytic functions of trans-acting RNA-binding protein scan impair the biogenesis of functional RNPs and provoke pathological consequences. Analyses of splicing aberrations in human diseases not only allow us to understand the underlying maladies in pathological conditions, but also pave the way to gain insight into splicing regulation under physiological conditions. Dissection of the patho mechanisms of splicing defects in neuromuscular junction (NMJ) disorders has disclosed unprecedented roles of RNA-binding proteins in the neuromuscular signal transmission at the NMJ. This review focuses on splicing defects in congenital myasthenia syndromes (CMS), hereditary disorders caused by germ line mutations in molecules expressed at the NMJ. Splicing mis-regulations of the NMJ molecules that have been uncovered in the course of analyses of splicing mutations causing CMS can be extrapolated to other diseases caused by germ line or somatic mutations.