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  • Review Article
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Neurological diseases

Sleuthing molecular targets for neurological diseases at the neuromuscular junction

Nature Reviews Neuroscience volume 4, pages 339–352 (2003)Cite this article

Key Points

  • Congenital myasthenic syndromes (CMSs) are a heterogeneous group of disorders that affect the safety margin of neuromuscular transmission — the depolarization that is required for propagation of the change in membrane potential beyond the endplate.

  • Mutations in different synaptic molecules give rise to CMS. These molecules include choline acetyltransferase (CHAT), acetylcholinesterase (ACHE), the different acetylcholine receptor (ACHR) subunits and the AChR-associated molecule RAPSYN.

  • In CMSs that are caused by CHAT mutations, the amplitudes of the endplate potential declined abnormally with increases of firing frequency and showed a slow recovery. These properties pointed to a defect in the resynthesis or vesicular packaging of ACh, an idea that led to the subsequent discovery of mutations in CHAT being responsible for the abnormal phenotype.

  • In CMSs that are caused by ACHE mutations, the reduced degradation of acetylcholine causes the appearance of repetitive and decrementing muscle action potential in response to nerve stimulation. These properties of the action potential stem from repeated rebinding of ACh to the AChR. Importantly, mutations in COLQ, the gene that encodes a collagen tail that anchors ACHE to the basal lamina, also cause a similar CMS.

  • CMSs that are caused by AChR mutations fall in three broad categories. Two of them — slow-channel and fast-channel CMSs — are characterized by kinetic alterations in the receptor, which affect the safety margin for transmission. The third type of mutation does not show significant kinetic alterations; their effect might be mediated by structural alterations or effects on the level of channel expression.

  • CMSs that are related to rapsyn mutations are not accompanied by kinetic alterations on the AChR. Their effect might be related to the abnormal postsynaptic clustering of receptors.

  • Besides shedding light on the pathogenic mechanisms behind CMS, the candidate-gene approach has also provided unexpected insights into the function of different synaptic proteins. In addition, the genetic study of CMS is a paramount example of the power of this approach to bridge clinical, physiological, genetic and morphological analyses to unravel basic mechanisms of human disease.

Abstract

The analysis of congenital myasthenic syndromes (CMSs) has disclosed a diverse array of molecular targets at the motor endplate and has delineated their contribution to synaptic function. Clinical, electrophysiological and morphological studies have paved the way for detecting CMS-related mutations in proteins such as choline acetyltransferase, acetylcholinesterase, the acetylcholine receptor and rapsyn, and studies of the mutant proteins have allowed us to correlate the effects of the mutations with predicted alterations in protein structure. Here, we review the symptomatology of CMSs, consider the factors that impair neuromuscular transmission, survey the mutations that have been uncovered in the different synaptic proteins, and consider the functional implications of the identified mutations.

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Figure 1: The neuromuscular endplate.
Figure 2: Congenital myasthenic syndromes caused by defects in CHAT.
Figure 3: Congenital myasthenic syndromes caused by defects in acetylcholinesterase (ACHE).
Figure 4: Slow-channel congenital myasthenic syndromes.
Figure 5: Congenital myasthenic syndrome (CMS) mutations in the acetylcholine receptor binding site.
Figure 6: Fast-channel congenital myasthenic syndromes.
Figure 7: Congenital myasthenic syndromes caused by low-expression mutations.
Figure 8: RAPSYN domains and disease mutations in the RAPSYN coding region.

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Acknowledgements

Work carried out in the authors' laboratories was supported by grants to A.G.E. and S.M.S. from the National Institutes of Health, and a Muscular Dystrophy Association grant to A.G.E.

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Authors and Affiliations

  1. Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic, Rochester, 55905, Minnesota, USA

    Andrew G. Engel & Kinji Ohno

  2. Department of Physiology and Biophysics, Receptor Biology Laboratory, Mayo Clinic, Rochester, 55905, Minnesota, USA

    Steven M. Sine

Authors
  1. Andrew G. Engel
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  2. Kinji Ohno
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  3. Steven M. Sine
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Correspondence to Andrew G. Engel.

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DATABASES

LocusLink

ACHE

agrin

CHAT

COLQ

ERBB receptors

high-affinity choline transporter

MUSK

neuregulin

RAPSYN

VACHT

OMIM

CMS

Swiss-Prot

AChBP

FURTHER INFORMATION

Encyclopedia of Life Sciences

nicotinic acetylcholine receptors

Ligand-Gated Ion Channel Database

Glossary

COMPOUND MUSCLE ACTION POTENTIAL

A group of simultaneous action potentials from several muscle fibres in the same area.

QUANTAL RELEASE

A term commonly used to state the fact that neurotransmitters are released in discrete packets or quanta. Each of these quanta corresponds to the fusion of a single synaptic vesicle with the presynaptic membrane so as to release its content.

MINIATURE ENDPLATE POTENTIAL

The change in potential that a single quantum of transmitter elicits on the muscle membrane.

READILY RELEASABLE QUANTA

Synaptic vesicles that, on arrival of a nerve impulse, are available for rapid fusion with the presynaptic membrane. They are docked to the membrane and have been biochemically primed for release.

BULBAR

Related to the medulla oblongata.

INTERICTAL

A term that refers to events that occur between attacks or paroxysms.

QUANTAL CONTENT

The number of quanta that are released per action potential.

DECAY TIME CONSTANT

The initial decayn of an excitatory postsynaptic potential can usually be fit by a single exponential function that describes how quickly the potential decays.

BASAL LAMINA

A component of the neuromuscular junction that surrounds the muscle fibre. It is mainly produced by the muscle cells and consists of collagen, proteoglycans and other molecules of the extracellular matrix.

REFRACTORY PERIOD

The time immediately after the action potential during which the membrane repolarizes through inactivation of voltage-gated sodium channels and through activation of voltage-gated potassium channels.

OPHTHALMOPARESIS

Paralysis of the muscles that control eye movements.

CYS-LOOP

A 15-residue domain, the boundary of which are two cysteine residues that form a disulphide bond. This loop is a signature of the receptor superfamily that includes ionotropic acetylcholine, GABA (γ-aminobutyric acid), glycine and serotonin receptors.

MISSENSE MUTATIONS

Mutations that result in the substitution of an amino acid in a protein.

TETRATRICO PEPTIDE REPEATS

Degenerate motifs of 34 amino acids that are thought to form helix–turn structures, each with a 'knob' and a 'hole', therefore acting as helix-associating domains and mediating protein–protein interactions.

RING-H2 DOMAIN

One of a class of protein domains that consist of two loops that are held together at their base by Cys and His residues that complex two zinc ions.

CIS-ACTING

Regulatory genetic element that is located in the same DNA molecule as the gene that is being regulated.

FRAMESHIFT MUTATION

The addition or deletion of a nucleotide, which shifts the reading frame during translation such that the protein sequence from that point onwards is altered.

HAPLOTYPE

The allelic configuration of multiple genetic markers that are present on a single chromosome of a given subject.

MICROSATELLITE

A class of repetitive DNA that is made up of repeats that are 2–8 nucleotides in length. They are frequently used as molecular markers in studies of population genetics.

FOUNDER EFFECT

Genetic variability observed in a population founded by a small, non-representative sample of a larger population.

LUCIFERASE REPORTER ASSAY

An assay used to indirectly measure the expression of a gene of interest. The firefly luciferase gene is placed downstream of the relevant promoter. As the catalytic action of luciferase emits light, the levels of the enzyme can be quantified by measuring the light intensity.

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Engel, A., Ohno, K. & Sine, S. Sleuthing molecular targets for neurological diseases at the neuromuscular junction. Nat Rev Neurosci 4, 339–352 (2003). https://doi.org/10.1038/nrn1101

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