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Neurobeachin is essential for neuromuscular synaptic transmission.

ABSTRACT: We report a random disruption in the mouse genome that resulted in lethal paralysis in homozygous newborns. The disruption blocked expression of neurobeachin, a protein containing a BEACH (beige and Chediak-Higashi) domain implicated in synaptic vesicle trafficking and an AKAP (A-kinase anchor protein) domain linked to localization of cAMP-dependent protein kinase activity. nbea-null mice demonstrated a complete block of evoked synaptic transmission at neuromuscular junctions, whereas nerve conduction, synaptic structure, and spontaneous synaptic vesicle release were completely normal. These findings support an essential role for neurobeachin in evoked neurotransmitter release at neuromuscular junctions and suggest that it plays an important role in synaptic transmission.

SUBMITTER: Su Y

PROVIDER: S-EPMC6729756 | biostudies-literature | 2004 Apr

REPOSITORIES: biostudies-literature

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Neurobeachin is essential for neuromuscular synaptic transmission.

Su Yuhua Y Balice-Gordon Rita J RJ Hess Darren M DM Landsman Douglas S DS Minarcik Jeremy J Golden Jeffrey J Hurwitz Ivy I Liebhaber Stephen A SA Cooke Nancy E NE

The Journal of neuroscience : the official journal of the Society for Neuroscience 20040401 14

We report a random disruption in the mouse genome that resulted in lethal paralysis in homozygous newborns. The disruption blocked expression of neurobeachin, a protein containing a BEACH (beige and Chediak-Higashi) domain implicated in synaptic vesicle trafficking and an AKAP (A-kinase anchor protein) domain linked to localization of cAMP-dependent protein kinase activity. nbea-null mice demonstrated a complete block of evoked synaptic transmission at neuromuscular junctions, whereas nerve cond ...[more]

PMID: 15071111

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Project description:ImportanceCongenital 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.ObjectivesTo characterize clinical, structural, electrophysiologic, and genetic features of a CMS and to search for optimal therapy.Design, settings, and participantsTwo 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.ResultsQuantitative 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.

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Neurobeachin is essential for neuromuscular synaptic transmission.

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Neurobeachin is essential for neuromuscular synaptic transmission.

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