Characteristic spatial and frequency distribution of mutations in SCN1A  

作　　者：Mengwen Zhang Jing Guo Bin Li Kang Liu Jiayuan Zhao Jiayuan Zhang Xuqing Lin Bin Tang Jie Wang Weiping Liao Na He 

机构地区：[1]Department of Neurology,Institute of Neuroscience,Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China,The Second Afliated Hospital,Guangzhou Medical University,Guangzhou 510260,China [2]Department of Neurology,The Guangdong 999 Brain Hospital,Guangzhou 510510,China [3]Guangzhou Medical University,Guangzhou 511436,China

出　　处：《Acta Epileptologica》2024年第4期327-335,共9页癫痫学报(英文)

基　　金：funded by Research Foundation of China Association Against Epilepsy(CU-2024-042);Medical Scientifc Research Foundation of Guangdong Province(A2024536);the National Natural Science Foundation of China(Grant No.82071548,Grant No.82301639 and Grant No.82201609);Guangzhou Medical University Student Innovation Ability Promoting Program(Grant No.2022A045 and Grant No.02-408-240603131135).

摘　　要：Background SCN1A is the most well-recognized and commonly mutated gene related to epilepsy.This study analyzed the characteristic spatial and frequency distributions of SCN1A mutations,aiming to provide important insight into the mutagenesis etiopathology of SCN1A-associated epilepsy.Methods Epilepsy-associated SCN1A variants were retrieved from the SCN1A mutation database,the HGMD database,and literature reviews.The base substitutions,mutation frequencies in CpG dinucleotides,and spatial distributions of mutations in terms of exons and structural domains were analyzed.Results A total of 2621 SCN1A variants were identifed in 5106 unrelated cases.The most common type was missense mutation,followed by frameshift mutations and splice site mutations.Among the missense mutations,transitions within CpG dinucleotides were much more recurrently identifed than transitions within non-CpG dinucleotides,and the most common type was the G>A transition.Among the nonsense mutations,the most predominant type of single-base substitution was the C>T transition,among which 75.3%(235/312)were within CpG sites.The most common“hotspot”codons for missense mutations were codons 101,946,and 1783;while for nonsense mutations it was codon 712.One-base deletion or insertion was the most common type of frameshift mutation,causing protein truncation.The three most common frameshift mutations were c.5536_5539delAAAC,c.4554dupA,and c.5010_5013delGTTT.Splice mutations were the most frequently identifed in exon 4 with a hotspot site c.602+1G>A.The spatial distribution of missense mutations showed that exons 22 and 4 had the highest mutation density(111 and 84 mutations per 100 bp,respectively),and exon 12 had the lowest mutation density,with 4 mutations per 100 bp.Further distribution analysis of the protein domains revealed that missense mutations were more common in the pore region and voltage sensor(231 mutations per 100 amino acids,respectively),and the protein truncation mutations were distributed evenly among the domains.Conclusions SCN

关 键 词：Epilepsy SCN1A CpG dinucleotides Mutation hotspot Spatial and frequency distribution 

分 类 号：R51[医药卫生—内科学]