Evidence for S284L Mutation of the CHRNA4 in a White Family with Autosomal Dominant Nocturnal Frontal Lobe Epilepsy

Abstract

Summary:Purpose: To identify mutations of the neuronal nicotinic acetylcholine receptor α4 subunit gene (CHRNA4) responsible for autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) in a group of white patients.Methods: A group of 47 patients from 21 unrelated families with ADNFLE were screened for mutations in CHRNA4. Clinical features and EEG findings in the patients were consistent with those reported in the literature for other affected families. The entire gene was amplified from genomic DNA by polymerase chain reaction (PCR) followed by multitemperature singlestrand conformation polymorphism analysis (MSSCP) and sequencing.Results: A c.851C>T transition in exon 5 of CHRNA4 was identified in three affected individuals from two generations of the same family, but not in the remaining patients or in 100 healthy volunteers. This mutation caused an S284L substitution in the transmembrane domain M2 segment of the α4 subunit of the neuronal nicotinic acetylcholine receptor. The same mutation had previously been detected in a single Japanese family with ADNFLE, and in an Australian woman with a sporadic form of NFLE.Conclusions: This is the first report of an occurrence of c.851C>T transition in a white family with ADNFLE.

Validation criteria for genetic animal models of epilepsy

“…CBZ reduces both the frequency and complexity of nocturnal seizures in more than 60% of patients with ADNFLE/NFLE, including those with S280F and insL mutations [28,30,31]. However, some cases (especially, individuals with S284L [32][33][34], T293I [35], V287M [36] and I312M [37]) are resistant to CBZ but respond to other antiepileptic drugs such as acetazolamide, benzodiazepine (BZP), topiramate and zonisamide (ZNS), or antiepileptic drugs-resistant [28,30,32,33,36,38,39]. (The amino acid numbering of CHRNA4 mutations used here is based on the deduced amino acid sequence of human α4 subunit and accordingly differs from those in the original articles that were based on the Torpedo sequence and nomenclature system).…”

Autosomal dominant nocturnal frontal lobe epilepsy: a genotypic comparative study of Japanese and Korean families carrying the CHRNA4 Ser284Leu mutation

“…[16][17][18][19] It has been assumed that founder effect is not relevant to ADNFLE, because most of the families studied come from different countries, 20 and a previous haplotype study of the Australian and Norwegian family 14 showed no genetic connection.…”

“…11 Among the four mutations in CHRNA4 (Ser280Phe, Ser284Leu, Leu291dup and Thr293Ile), Ser280Phe and Ser284Leu have been identified in several unrelated families (mutation names may be different from those of previous papers; we use NP_000735.1): the Ser280Phe in an Australian, Spanish, Norwegian and Scottish families, [12][13][14][15] and the Ser284Leu in a Japanese, Korean, Polish and Lebanese families. [16][17][18][19] It has been assumed that founder effect is not relevant to ADNFLE, because most of the families studied come from different countries, 20 and a previous haplotype study of the Australian and Norwegian family 14 showed no genetic connection.…”

Design, synthesis and preliminary pharmacological evaluation of rigid analogues of the nicotinic agonist 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP)

“…2 Moreover, some genetic forms of epilepsy (ADNFLE) and congenital myasthenic syndrome are associated to mutations in the gene coding for nAChR subunits. [3][4][5] Other therapeutically important applications of nicotinic ligands are the treatment of nicotine addiction and the management of pain. 6 For a long time the nicotinic receptor extracted from Torpedo fishes has been studied using electron microscopy to obtain valuable information about the structure and functioning of the receptor, [7][8][9][10] but an important step toward the understanding of nAChR structure has come from the resolution of X-ray crystallography of the molluscan acetylcholine-binding protein (AChBP) 11 which has been used to model the extracellular domain of the nicotinic receptor where the agonist binding site is located.…”