Dravet综合征
多重连接依赖探针扩增
遗传学
错义突变
单倍率不足
点突变
突变
编码区
肌阵挛性癫痫
外显子
生物
基因
癫痫
表型
分子生物学
神经科学
作者
Christel Depienne,Oriane Trouillard,Cécile Saint‐Martin,Isabelle Gourfinkel‐An,Delphine Bouteiller,Wassila Carpentier,Boris Keren,B Abert,Agnès Gautier,Stéphanie Baulac,Alexis Arzimanoglou,Cécile Cazeneuve,Rima Nabbout,Eric LeGuern
标识
DOI:10.1136/jmg.2008.062323
摘要
Mutations in the voltage-gated sodium channel SCN1A gene are the main genetic cause of Dravet syndrome (previously called severe myoclonic epilepsy of infancy or SMEI).To characterise in more detail the mutation spectrum associated with Dravet syndrome.A large series of 333 patients was screened using both direct sequencing and multiplex ligation-dependent probe amplification (MLPA). Non-coding regions of the gene that are usually not investigated were also screened.SCN1A point mutations were identified in 228 patients, 161 of which had not been previously reported. Missense mutations, either (1) altering a highly conserved amino acid of the protein, (2) transforming this conserved residue into a chemically dissimilar amino acid and/or (3) belonging to ion-transport sequences, were the most common mutation type. MLPA analysis of the 105 patients without point mutation detected a heterozygous microrearrangement of SCN1A in 14 additional patients; 8 were private, partial deletions and six corresponded to whole gene deletions, 0.15-2.9 Mb in size, deleting nearby genes. Finally, mutations in exon 5N and in untranslated regions of the SCN1A gene that were conserved during evolution were excluded in the remaining negative patients.These findings widely expand the SCN1A mutation spectrum identified and highlight the importance of screening the coding regions with both direct sequencing and a quantitative method. This mutation spectrum, including whole gene deletions, argues in favour of haploinsufficiency as the main mechanism responsible for Dravet syndrome.
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