# Congenital Myasthenic Syndromes

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2021 · $443,849

## Abstract

PROJECT SUMMARY
Support is requested for a multifaceted investigation of congenital myasthenic syndromes (CMS). The CMS
are heterogeneous and disabling diseases in which the safety margin of neuromuscular transmission is
compromised by one or more specific mechanism(s). We will use the candidate gene approach combined with
whole exome sequencing to find the cause of different CMS, determine the mechanism by which the mutant
gene causes the CMS, and then use this information to generate structure-function correlations and devise
strategies for therapy.
The candidate gene approach rests on determining (1) the clinical phenotype, (2) the morphologic phenotype
based on cytochemical and ultrastructural features of the endplate (EP), (3) the number of acetylcholine (ACh)
receptors (AChRs) per EP, (4) the electrophysiologic phenotype reflected by parameters of neuromuscular
transmission in vitro. The mechanism by which the mutant gene causes a CMS is investigated by engineering
the mutant and corresponding wild-type gene into a suitable expression system which is then interrogated by
appropriate electrophysiologic and biochemical tests. Structure–function correlations rest on further
mutagenesis studies and on analysis of the mechanism by which a change in the structure of the mutated
protein alters the function of that protein, and how this alteration affects the safety margin of neuromuscular
transmission. Strategies for therapy are based on determining the molecular defect caused by the mutation
and whether the identified defect increases or decreases the synaptic response to ACh.

## Key facts

- **NIH application ID:** 10087975
- **Project number:** 5R01NS109491-03
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** ANDREW George ENGEL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $443,849
- **Award type:** 5
- **Project period:** 2019-02-15 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10087975

## Citation

> US National Institutes of Health, RePORTER application 10087975, Congenital Myasthenic Syndromes (5R01NS109491-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10087975. Licensed CC0.

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