Gene variant effects across sodium channelopathies predict function and guide precision therapy.
Gene variant effects across sodium channelopathies predict function and guide precision therapy.
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DOI：
10.1093/brain/awac006
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发表时间：
2022-12-19
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影响因子：
--
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电压门控钠通道基因家族的致病变异可导致早发性癫痫、神经发育障碍、骨骼肌通道病、外周神经病和心律失常。与疾病相关的变异有不同的功能效应，从完全功能丧失到明显的功能获得。治疗策略可能取决于功能效果。实验研究提供了对渠道功能的重要见解，但是资源密集型的，而且只在少数情况下进行。考虑到钠通道基因在进化上的保守性，我们研究了不同电压门控钠通道之间生物物理特性的相似性是否可以预测功能并为跨钠通道病的精确治疗提供信息。我们进行了系统的文献搜索，确定了9个电压门控钠通道基因中任何一个的功能评估变异，直到2021年4月28日。我们在全细胞膜片钳记录中包括了在哺乳动物细胞中表现出电生理特征的错义变体。我们对所有钠通道基因和相关变体的线性蛋白质序列进行了比对，根据它们对生物物理特性的整体功能影响。在951条已鉴定的记录中，有437条钠通道变异符合我们的纳入标准，并对其功能特性进行了审查。其中，141个变异与癫痫相关(SCN1/2/3/8A)，79个具有神经肌肉表型(SCN4/9/10/11A)，149个与心脏表型相关(SCN5/10A)，68个(16%)被认为是良性的。我们检测到38对错义变异，在不同的钠通道基因中存在相同的疾病相关变异。38对中的35对导致了类似的功能结果，表明对应的钠通道变体之间高达92%的生物物理一致性(优势比=11.3；95%可信区间=2.8%至66.9%；P<；0.001)。致病错义变异体聚集在特定的功能区域，而群体变异体在非保守区的出现频率明显更高(优势比=18.6；95%可信区间=10.9-34.4；P<；0.001)。孔环区经常与功能丧失变异体相关，而失活部位与功能获得相关(优势比=42.195%可信区间=14.5%-122.4；P<；0.001)，而发生在电压敏感区的变异体包括一系列功能获得和丧失效应。我们的发现表明，在没有实验数据的情况下，一个SCN基因中变异的生物物理特征可以预测不同SCN基因之间的通道功能。收集到的数据代表了第一张SCN蛋白质功能得失的拓扑图，表明了生物物理效应的共同模式，有助于变异分析和指导精确治疗。我们将我们的发现整合到一个免费的在线网络工具中，以促进功能性钠通道基因变异解释(http://SCN-viewer.broadinstitute.org).Brunklaus等人。报道称，在没有实验数据的情况下，一个电压门控钠通道(SCN)基因变异的生物物理特征可以预测不同SCN基因的通道功能。共享的功能效应模式可以帮助不同的解释和指导精确治疗。本文的科学评论见Mantegazza和CESTèle(https://doi.org/10.1093/brain/awac397))。
Pathogenic variants in the voltage-gated sodium channel gene family lead to early onset epilepsies, neurodevelopmental disorders, skeletal muscle channelopathies, peripheral neuropathies and cardiac arrhythmias. Disease-associated variants have diverse functional effects ranging from complete loss-of-function to marked gain-of-function. Therapeutic strategy is likely to depend on functional effect. Experimental studies offer important insights into channel function but are resource intensive and only performed in a minority of cases. Given the evolutionarily conserved nature of the sodium channel genes, we investigated whether similarities in biophysical properties between different voltage-gated sodium channels can predict function and inform precision treatment across sodium channelopathies. We performed a systematic literature search identifying functionally assessed variants in any of the nine voltage-gated sodium channel genes until 28 April 2021. We included missense variants that had been electrophysiologically characterized in mammalian cells in whole-cell patch-clamp recordings. We performed an alignment of linear protein sequences of all sodium channel genes and correlated variants by their overall functional effect on biophysical properties. Of 951 identified records, 437 sodium channel-variants met our inclusion criteria and were reviewed for functional properties. Of these, 141 variants were epilepsy-associated (SCN1/2/3/8A), 79 had a neuromuscular phenotype (SCN4/9/10/11A), 149 were associated with a cardiac phenotype (SCN5/10A) and 68 (16%) were considered benign. We detected 38 missense variant pairs with an identical disease-associated variant in a different sodium channel gene. Thirty-five out of 38 of those pairs resulted in similar functional consequences, indicating up to 92% biophysical agreement between corresponding sodium channel variants (odds ratio = 11.3; 95% confidence interval = 2.8 to 66.9; P < 0.001). Pathogenic missense variants were clustered in specific functional domains, whereas population variants were significantly more frequent across non-conserved domains (odds ratio = 18.6; 95% confidence interval = 10.9–34.4; P < 0.001). Pore-loop regions were frequently associated with loss-of-function variants, whereas inactivation sites were associated with gain-of-function (odds ratio = 42.1, 95% confidence interval = 14.5–122.4; P < 0.001), whilst variants occurring in voltage-sensing regions comprised a range of gain- and loss-of-function effects. Our findings suggest that biophysical characterisation of variants in one SCN-gene can predict channel function across different SCN-genes where experimental data are not available. The collected data represent the first gain- versus loss-of-function topological map of SCN proteins indicating shared patterns of biophysical effects aiding variant analysis and guiding precision therapy. We integrated our findings into a free online webtool to facilitate functional sodium channel gene variant interpretation (http://SCN-viewer.broadinstitute.org). Brunklaus et al. report that biophysical characterization of variants in one voltage-gated sodium channel (SCN) gene can predict channel function across different SCN genes where experimental data are not available. Shared patterns of functional effects can aid variant interpretation and guide precision therapy. See Mantegazza and Cestèle (https://doi.org/10.1093/brain/awac397) for a scientific commentary on this article.
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影响因子：
5.6
作者：
Anderson LL;Thompson CH;Hawkins NA;Nath RD;Petersohn AA;Rajamani S;Bush WS;Frankel WN;Vanoye CG;Kearney JA;George AL Jr
通讯作者：
George AL Jr
影响因子：
4.8
作者：
Dhifallah S;Lancaster E;Merrill S;Leroudier N;Mantegazza M;Cestèle S
通讯作者：
Cestèle S
DOI：
10.1136/jnnp-2020-325932
发表时间：
2021-10
期刊：
Journal of neurology, neurosurgery, and psychiatry
影响因子：
--
作者：
Balestrini S;Chiarello D;Gogou M;Silvennoinen K;Puvirajasinghe C;Jones WD;Reif P;Klein KM;Rosenow F;Weber YG;Lerche H;Schubert-Bast S;Borggraefe I;Coppola A;Troisi S;Møller RS;Riva A;Striano P;Zara F;Hemingway C;Marini C;Rosati A;Mei D;Montomoli M;Guerrini R;Cross JH;Sisodiya SM
通讯作者：
Sisodiya SM
影响因子：
5.3
作者：
Cestele, Sandrine;Scalmani, Paolo;Mantegazza, Massimo
通讯作者：
Mantegazza, Massimo
影响因子：
6.1
作者：
Bechi, Giulia;Rusconi, Raffaella;Mantegazza, Massimo
通讯作者：
Mantegazza, Massimo