CHRNE

Role in health and disease

Congenital myasthenic syndrome (CMS) is associated with genetic defects that affect proteins of the neuromuscular junction. Postsynaptic defects are the most frequent cause of CMS and often result in abnormalities in the acetylcholine receptor (AChR). The majority of mutations causing CMS are found in the AChR subunits genes.

Out of all mutations associated with CMS, more than half are mutations in one of the four genes encoding the adult AChR subunits. Mutations of the AChR often result in endplate deficiency. The most common AChR gene mutation that underlies CMS is the mutation of the CHRNE gene. The CHRNE gene codes for the epsilon subunit of the AChR. Most mutations are autosomal recessive loss-of-function mutations and as a result there is endplate AChR deficiency. CHRNE is associated with changing the kinetic properties of the AChR. One type of mutation of the epsilon subunit of the AChR introduces an arginine (Arg) into the binding site at the α/ε subunit interface of the receptor. The addition of a cationic Arg into the anionic environment of the AChR binding site greatly reduces the kinetic properties of the receptor. The result of the newly introduced ARG is a 30-fold reduction of agonist affinity, 75-fold reduction of gating efficiency, and an extremely weakened channel opening probability. This type of mutation results in an extremely fatal form of CMS.

References

References

1. (July 1993). "Primary structure of the human muscle acetylcholine receptor. cDNA cloning of the gamma and epsilon subunits". European Journal of Biochemistry.
2. "Entrez Gene: CHRNE cholinergic receptor, nicotinic, epsilon".
3. (October 2006). "Diverse molecular mechanisms involved in AChR deficiency due to rapsyn mutations". Brain.
4. (October 2012). "Congenital myasthenic syndromes: achievements and limitations of phenotype-guided gene-after-gene sequencing in diagnostic practice: a study of 680 patients". Human Mutation.
5. (July 2012). "Highly fatal fast-channel syndrome caused by AChR ε subunit mutation at the agonist binding site". Neurology.