A missense mutation in the neuronal nicotinic acetylcholine receptor α4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy

Abstract

Epilepsy affects at least 2% of the population at some time in their lives. The epilepsies are a heterogeneous group of disorders, many with an inherited component. Although specific genes have been identified in a few rare diseases causing seizures as part of a more diffuse brain disorder, the molecular pathology of the common idiopathic epilepsies is still unknown. Linkage has been reported for some generalised epilepsy syndromes, but only very recently for familial partial epilepsy syndromes. Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a partial epilepsy causing frequent, violent, brief seizures at night, usually beginning in childhood. The gene for ADNFLE maps to chromosome 20q13.2-q13.3 in one large Australian kindred. The neuronal nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4) maps to the same region of 20q (ref. 12) and the gene is expressed in all layers of the frontal cortex. We screened affected family members for mutations within CHRNA4 and found a missense mutation that replaces serine with phenylalanine at codon 248, a strongly conserved amino acid residue in the second transmembrane domain. The mutation is present in all 21 available affected family members and in four obligate carriers, but not in 333 healthy control subjects.

Molecular Targets for Antiepileptic Drug Development

“…[212][213][214] A common feature of the ADNFLE mutations is that they reduce Ca 2ϩ potentiation of the ␣4␤2 nicotinic receptor response to acetylcholine. It has been proposed that the decrease in Ca 2ϩ potentiation could contribute to ADNFLE seizures by reducing presynaptic nicotinic receptor activation of inhibitory transmitter release in the cortex or by shifting the balance between nicotinic receptor-induced excitatory and inhibitory transmitter release during bouts of high-frequency cortical synaptic activity in favor of excitatory transmitter release.…”

Desensitization of neuronal nicotinic receptors

“…In this respect, the leucine 247 ␣7 subunit mutant exhibits markedly reduced desensitization (Revah et al, 1991;see above), and is lethal when genetically introduced into mice (Orr-Urtreger et al, 1997). Conversely, a polymorphism (serine to phenylalanine) at position 248 in the pore domain of ␣4 subunits results in faster desensitization of ␣4␤2 nAChRs, but causes a form of human cortical epilepsy (Steinlein et al, 1995;Weiland et al, 1996). While these studies provide some tantalizing evidence that desensitization of nAChRs is a critical feature of CNS functioning, the physiological importance of desensitization is still far from clear.…”

Unconventional ligands and modulators of nicotinic receptors

“…Over the past 10 years, there has been a remarkable expansion in research on the therapeutic potential of nAChR ligands, particularly because correlations have been traced between nicotinic cholinergic dysfunctions in the brain and the severity of certain symptoms of neurologic disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Down Syndrome (DS), schizophrenia, and some forms of epilepsy (Steinlein et al, 1995;Kuryatov et al, 1997;Hellstrom-Lindahl et al, 1999;Nordberg, 1999;Sihver et al, 1999;Perry et al, 1990Perry et al, , 2000Leonard et al, 2000;Court et al, 2001). A number of unconventional ligands that modulate nAChR activity have been discovered and, as a consequence of a continuum of basic and clinical research, the cholinesterase inhibitor galantamine, which also acts as a nicotinic allosteric potentiating ligand (APL), was recently approved by the Food and Drug Administration (FDA) for treatment of patients with AD in the United States.…”