An insertion mutation of the CHRNA4 gene in a family with autosomal dominant nocturnal frontal lobe epilepsy

Human Molecular Genetics
Ortrud K SteinleinDaniel Bertrand

Abstract

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is the first, and to date only, idiopathic epilepsy for which a specific mutation has been found. A missense mutation in the critical M2 domain of the alpha4 subunit of the neuronal nicotinic acetylcholine receptor (CHRNA4) has been recently identified in one large Australian pedigree. Here we describe a novel mutation in the M2 domain of the CHRNA4 gene in a Norwegian family. Three nucleotides (GCT) were inserted at nucleotide position 776 into the coding region for the C-terminal end of the M2 domain. Physiological investigations of the receptor reconstituted with the mutated CHRNA4 subunit reveal that this insertion does not prevent the receptor function but increases its apparent affinity for ACh. In addition, this mutant receptor shows a significantly lower calcium permeability that, at the cellular level, may correspond to a loss of function. Comparison of the two mutations identified so far in families with ADNFLE illustrates that different mutations can result in similar phenotypes.

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Citations

Dec 7, 2000·Mental Retardation and Developmental Disabilities Research Reviews·C E Stafstrom, B L Tempel
Sep 11, 1999·Annals of Neurology·H LercheO K Steinlein
Jun 1, 2000·Movement Disorders : Official Journal of the Movement Disorder Society·K P BhatiaL J Ptácek
Sep 5, 2002·Movement Disorders : Official Journal of the Movement Disorder Society·Sian D SpaceyNicholas W Wood
Dec 13, 1997·Molecular Neurobiology·J Lindstrom
Jun 18, 2010·Naunyn-Schmiedeberg's Archives of Pharmacology·Ortrud K Steinlein
Dec 18, 2009·Pflügers Archiv : European journal of physiology·Ortrud K Steinlein, Daniel Bertrand
Jan 15, 2011·Current Neurology and Neuroscience Reports·Christopher P Derry
Nov 5, 2003·Experimental Neurology·Robert L MacdonaldHuajun Feng
Mar 23, 2004·Pediatric Neurology·Ching-Tien PengFuu-Jen Tsai
Mar 23, 2004·Pediatric Neurology·D Barry SinclairThomas Snyder
Apr 20, 2000·European Journal of Pharmacology·L CurtisD Bertrand
Apr 20, 2000·European Journal of Pharmacology·O K Steinlein
Apr 20, 2000·European Journal of Pharmacology·F ClementiC Gotti
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Apr 22, 2004·Nature Reviews. Neuroscience·Ortrud K Steinlein

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