Title: LRP4 myasthenia: Investigation of a second kinship reveals impaired development and maintenance of the neuromuscular junction
Abstract: Congenital myasthenic syndromes (CMS) are heterogeneous disorders. Defining the phenotypic features, the genetic basis, and the pathomechanisms of a CMS is relevant to prognosis, genetic counseling, and therapy. Two sisters, 34 and 20 years of age, suffering from a CMS affecting the limb-girdle muscles were evaluated clinically and by in vitro analysis of neuromuscular transmission, cytochemical and electron microscopy studies of the neuromuscular junction, exome sequencing, expression studies in HEK293 and COS-7 cells, and for response to therapy. Intercostal muscle endplates (EPs) were abnormally small with attenuated reactivities for the acetylcholine receptor and acetylcholine esterase. Most EPs had poorly differentiated or degenerate junctional folds and some appeared denuded of nerve terminals. The amplitude of the EP potential (EPP), the miniature EPP, and the quantal content of the EPP were all markedly reduced. Exome sequencing identified a novel homozygous p.Glu1233Ala mutation in LRP4, a co-receptor for agrin to activate MuSK, required for EP development and maintenance. Expression studies indicate that mutation compromises the ability of LRP4 to bind to, phosphorylate, and activate MuSK. Cholinergic agonists worsened and albuterol improved the patients' symptoms. In conclusion, we identified a CMS kinship with LRP4 myasthenia, defined the mechanisms that impair neuromuscular transmission, and mitigated the disease by appropriate therapy.
Publication Year: 2015
Publication Date: 2015-09-10
Language: en
Type: article
Indexed In: ['crossref']
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