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Congenital myasthenic syndromes (CMS) are hereditary disorders of neuromuscular transmission characterized by fatigable muscle weakness. The number of cases recognized is increasing with improved diagnosis. To date we have identified over 300 different mutations present in over 350 unrelated kinships. The underlying genetic defects are diverse, involving a series of different genes with a variety of different phenotypes. The type of treatment and its effectiveness will depend on the underlying pathogenic mechanism. We aim to define the molecular mechanism for each mutation identified and feed this information back to the clinic as a basis to tailor patient treatment. Here, we describe some of the methods that can be used to define if a DNA sequence variant is pathogenic with reference to variants in DOK7. We highlight a new mechanism for disruption of AChR function, where a mutation in the AChR ɛ-subunit gene causes reduced ion channel conductance and discuss new methods for identifying gene mutations. The study of these disorders is proving highly informative for understanding the diverse molecular mechanisms that can underlie synaptic dysfunction.

Original publication

DOI

10.1111/nyas.12000

Type

Journal article

Journal

Ann N Y Acad Sci

Publication Date

12/2012

Volume

1275

Pages

63 - 69

Keywords

Agrin, Humans, Muscle Proteins, Mutation, Myasthenic Syndromes, Congenital, Receptor Protein-Tyrosine Kinases, Receptors, Cholinergic, Synapses