In addition, decreased expression and function of α7-nAChR is associated agoniwith many neurological diseases including schizophrenia, bipolar disorder, learning disability, attention deficit hyperactivity disorder, Alzheimer disease, autism, and epilepsy.
Based on genetic studies in patients with epileptic disorders worldwide and animal models of seizure, it has been demonstrated that nAChR activity is altered in some specific types of epilepsy, including autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) and juvenile myoclonic epilepsy (JME).
The finding of an association between a monogenic form of epilepsy and a mutation in the gene encoding the neuronal nicotinic acetylcholine receptor subunit CHRNA4 marked, in 1995, a turning point in our understanding of epilepsy.
The CHRNA4 1674(+11)C>T polymorphism may be a susceptibility factor for epilepsy, and its higher frequency in patients with juvenile myoclonic epilepsy suggests that the CHRNA4 may be one of the candidate genes for this epileptic syndrome.
However, one SNP was associated with epilepsy with generalised tonic clonic seizures only (P=0.016), as was an SNP approximately 56 kb distant in the closely linked nicotinic acetylcholine gene CHRNA4 (P=0.014).
Analyses of functional properties of four nAChR mutants associated with ADNFLE indicate that a gain of function of these mutant receptors may be at the origin of the neuronal network dysfunction that causes the epileptic seizures.
An increasing number of epileptic syndromes belongs to this group of rare disorders: Autosomal dominant nocturnal frontal lobe epilepsy is caused by mutations in a neuronal nicotinic acetylcholine receptor (affected genes: CHRNA4, CHRNB2), benign familial neonatal convulsions by mutations in potassium channels constituting the M-current (KCNQ2, KCNQ3), generalized epilepsy with febrile seizures plus by mutations in subunits of the voltage-gated sodium channel or the GABA(A) receptor (SCN1B, SCN1A, GABRG2), and episodic ataxia type 1-which is associated with epilepsy in a few patients--by mutations within another voltage-gated potassium channel (KCNA1).
As a result of this finding, other subunits of the neuronal nAChR gene family are being considered as candidate genes for ADNFLE in families not linked to CHRNA4 and for other idiopathic epilepsies.
A candidate gene for the epilepsies, the gene coding for the alpha4 subunit of the nicotinic cholinergic receptor (CHRNA4), has previously been localized on chromosome 20.