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常见 SCN1A 启动子变异对 SCN1A 相关表型严重程度的影响。

Influence of common SCN1A promoter variants on the severity of SCN1A-related phenotypes.

机构信息

Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.

Stichting Epilepsie Instellingen Nederland, Zwolle, The Netherlands.

出版信息

Mol Genet Genomic Med. 2019 Jul;7(7):e00727. doi: 10.1002/mgg3.727. Epub 2019 May 29.

DOI:10.1002/mgg3.727
PMID:31144463
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6625088/
Abstract

BACKGROUND

Pathogenic variants in SCN1A cause variable epilepsy disorders with different disease severities. We here investigate whether common variation in the promoter region of the unaffected SCN1A allele could reduce normal expression, leading to a decreased residual function of Nav1.1, and therefore to more severe clinical outcomes in patients affected by pathogenic SCN1A variants.

METHODS

Five different SCN1A promoter-haplotypes were functionally assessed in SH-SY5Y cells using Firefly and Renilla luciferase assays. The SCN1A promoter region was analyzed in a cohort of 143 participants with SCN1A pathogenic variants. Differences in clinical features and outcomes between participants with and without common variants in the SCN1A promoter-region of their unaffected allele were investigated.

RESULTS

All non-wildtype haplotypes showed a significant reduction in luciferase expression, compared to the wildtype promoter-region (65%-80%, p = 0.039-0.0023). No statistically significant differences in clinical outcomes were observed between patients with and without common promoter variants. However, patients with a wildtype promoter-haplotype on their unaffected SCN1A allele showed a nonsignificant trend for milder phenotypes.

CONCLUSION

The nonsignificant observed trends in our study warrant replication studies in larger cohorts to explore the potential modifying role of these common SCN1A promoter-haplotypes.

摘要

背景

SCN1A 中的致病性变异可引起不同严重程度的可变癫痫疾病。我们在此研究非致病 SCN1A 等位基因启动子区域的常见变异是否会降低正常表达，导致 Nav1.1 残余功能降低，从而导致携带致病性 SCN1A 变异的患者出现更严重的临床结局。

方法

使用萤火虫和海肾荧光素酶测定法，在 SH-SY5Y 细胞中对五种不同的 SCN1A 启动子-单倍型进行功能评估。对 143 名携带 SCN1A 致病性变异的参与者的 SCN1A 启动子区域进行了分析。研究了在非致病等位基因 SCN1A 启动子区域携带常见变异的参与者与不携带常见变异的参与者之间的临床特征和结局差异。

结果

与野生型启动子区域相比，所有非野生型单倍型的荧光素酶表达均显著降低（65%-80%，p=0.039-0.0023）。在有无常见启动子变异的患者之间，未观察到临床结局的统计学显著差异。然而，在非致病 SCN1A 等位基因上具有野生型启动子单倍型的患者表现出表型较轻的非显著趋势。

结论

我们的研究中观察到的非显著趋势需要在更大的队列中进行复制研究，以探索这些常见的 SCN1A 启动子单倍型的潜在修饰作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8c84/6625088/ece50a979901/MGG3-7-e00727-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8c84/6625088/ef0d322daa46/MGG3-7-e00727-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8c84/6625088/1a1b845164e2/MGG3-7-e00727-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8c84/6625088/b24d3d02a61f/MGG3-7-e00727-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8c84/6625088/2625a72558a3/MGG3-7-e00727-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8c84/6625088/bb56503394c7/MGG3-7-e00727-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8c84/6625088/3cb8acffbb46/MGG3-7-e00727-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8c84/6625088/4083a61ff404/MGG3-7-e00727-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8c84/6625088/ece50a979901/MGG3-7-e00727-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8c84/6625088/ef0d322daa46/MGG3-7-e00727-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8c84/6625088/1a1b845164e2/MGG3-7-e00727-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8c84/6625088/b24d3d02a61f/MGG3-7-e00727-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8c84/6625088/2625a72558a3/MGG3-7-e00727-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8c84/6625088/bb56503394c7/MGG3-7-e00727-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8c84/6625088/3cb8acffbb46/MGG3-7-e00727-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8c84/6625088/4083a61ff404/MGG3-7-e00727-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8c84/6625088/ece50a979901/MGG3-7-e00727-g008.jpg

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