Impaired Synaptic Development, Maintenance, and Neuromuscular Transmission in LRP4-Related Myasthenia

Abstract

IMPORTANCE Congenital myasthenic syndromes (CMS) are heterogeneous disorders. Defining the phenotypic features, genetic basis, and pathomechanisms of a CMS is relevant to prognosis, genetic counseling, and therapy.OBJECTIVES To characterize clinical, structural, electrophysiologic, and genetic features of a CMS and to search for optimal therapy. DESIGN, SETTINGS, AND PARTICIPANTS Two sisters with CMS affecting the limb-girdle muscles were investigated between 2012 and 2014 at an academic medical center by clinical observation, in vitro analysis of neuromuscular transmission, cytochemical and electron microscopy studies of the neuromuscular junction, exome sequencing, expression studies in HEK293 and COS7 cells, and for response to therapy, and they were compared with 15 historical control participants. MAIN OUTCOMES AND MEASURESWe identified the disease gene and mutation, confirmed pathogenicity of the mutation by expression studies, and instituted optimal pharmacotherapy. RESULTS Quantitative analysis of single EP regions was done for all 15 control participants and microelectrode studies of neuromuscular transmission and α-bgt binding sites per EP was conducted for 13 control participants. Examination of the older sister's intercostal muscle end plates (EPs) showed them to be abnormally small, with attenuated reactivities for the acetylcholine receptor and acetylcholinesterase. 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 low-density lipoprotein receptor-related protein 4 (LRP4), a coreceptor for agrin to activate muscle-specific tyrosine kinase (MuSK), which is required for EP development and maintenance. Expression studies indicate that the mutation compromises the ability of LRP4 to bind to, phosphorylate, and activate MuSK. Treatment with albuterol sulfate improved the patients' symptoms. A previously identified patient harboring 2 heterozygous mutations in LRP4 had structurally abnormal intercostal EPs but no identifiable defect of neuromuscular transmission at these EPs. CONCLUSIONS AND RELEVANCEWe identified a second CMS kinship harboring mutations in LRP4, identified the mechanisms that impair neuromuscular transmission, and mitigated the disease by appropriate therapy.

R-spondin 2 promotes acetylcholine receptor clustering at the neuromuscular junction via Lgr5

“…2D). As previously reported3940, agrin activated ATF2-luc in MuSK/LRP4-cotransfected HEK293 cells. Addition of Rspo2-conditioned medium (CM) activated ATF2-luc in MuSK-transfected HEK293 cells, and more prominent activation was observed in MuSK/LRP4-cotransfected HEK293 cells.…”

A Novel Missense Variant in the AGRN Gene; Congenital Myasthenic Syndrome Presenting With Head Drop

“…4 Together with the low-density lipoprotein receptor–related protein 4 (LRP4) and MuSK, agrin forms agrin–MuSK–LRP4 signaling system, which is crucial for the development and maintenance of NMJ. 5 Secreted by the nerve terminal into the synaptic space, agrin plays the trigger role in activation of MuSK and clustering of MuSK and LRP4. 5 …”

ApoE, ApoE Receptors, and the Synapse in Alzheimer's Disease

“…Lrp4 is more commonly known as the gene defective in Cenani-Lenz syndrome [83–86], and for its role in neuromuscular junction (NMJ) development and in the maintenance of the adult NMJ, which is highlighted clinically by the role of anti-Lrp4 and anti-MuSK antibodies in myasthenia gravis [87]. Briefly, at the NMJ, Lrp4, APP and muscle-specific kinase (MuSK) form a complex to prepattern the muscle [88–90].…”