Abstract
Background
Lethal neonatal rigidity and multifocal seizure syndrome (RMFSL) is caused by variants in BRAT1 (BRCA1-associated protein required for ATM activation-1). However, the molecular mechanism of RMFSL is still unclear.
Methods
An RMFSL infant was recruited and the peripheral blood samples from his trio-family were collected. The genomic DNA was extracted, and then the whole-exome sequencing was performed. The expression of BRAT1 was analyzed by Western blotting. The subcellular localization of BRAT1 and MitoSOX (mitochondrial superoxide level) was investigated by confocal microscopy. The RNA samples were obtained from transfected cells, and then the RNA sequencing was performed.
Results
In this study, a novel homozygous BRAT1 variant c.233G > C with amino acid change of R with P at residue 78 (R78P) was identified. This variant altered the peptide structure and subcellular localization, as well as the expression in vitro. However, R78P did not alter the ability of BRAT1 to downregulate MitoSOX in mitochondria. Meanwhile, R78P BRAT1 was positively correlated with temporal lobe epilepsy, autosomal recessive primary microcephaly, defective/absent horizontal voluntary eye movements, and neuron apoptotic process as indicated by gene set enrichment analysis (GSEA).
Conclusions
The BRAT1 variant spectrum has been expanded, which will be helpful for genetic counseling. We also explored the molecular mechanism altered by R78P, which will provide a better understanding of the pathogenesis of RMFSL.
Impact
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The detailed course of an infant with lethal neonatal RMFSL was depicted.
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A novel disease-causing variant R78P in BRAT1 for lethal neonatal RMFSL was identified.
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R78P led to reduced BRAT1 expression and nuclear localization in vitro.
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R78P did not alter the ability of BRAT1 to downregulate MitoSOX in the mitochondria.
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The variant R78P in BRAT1 was positively correlated with temporal lobe epilepsy, autosomal recessive primary microcephaly, defective/absent horizontal voluntary eye movements, and neuron apoptotic process as indicated by GSEA.
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Acknowledgements
We would like to thank the family for joining in the study. We thank Jin Ma for the technical support. This work was supported by the National Natural Science Foundation of China (Nos. 81803116, 81570455, 81870365, and 81570125) for work designing and whole-exome sequencing, the Basic Research Project for Medical and Health Applications of Suzhou City (Nos. SYS2018077, SYS2019083, and SYS201757) for reagent purchasing, the Jiangsu Province’s Science Technology Support Program (Social Development) Project (BE2017658) and Startup fund (Q410800320) from Soochow University for data collection, and Jiangsu Province Medical Key Talents (ZDRCA2016049) for analyzing data and writing the report.
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W.L. and X. Zhao were responsible for the diagnosis and treatment of the patient. Y.P. analyzed the EEG results. H.H. analyzed the RNA-seq results. H.L., X. Zhu, H.X., and Y.L. designed the project. W.L., S.W., and H.X. performed the experiments. Y.L. wrote the manuscript and H.X. revised it.
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Li, W., Wu, S., Xu, H. et al. Novel variant in BRAT1 with the lethal neonatal rigidity and multifocal seizure syndrome. Pediatr Res 91, 565–571 (2022). https://doi.org/10.1038/s41390-021-01468-9
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DOI: https://doi.org/10.1038/s41390-021-01468-9
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