Abstract
We report the second case of early infantile epileptic encephalopathy (EIEE) arising from a homozygous truncating variant of NECAP1. The boy developed infantile-onset tonic-clonic and tonic seizures, then spasms in clusters. His electroencephalogram (EEG) showed a burst suppression pattern, leading to the diagnosis of Ohtahara syndrome. Whole-exome sequencing revealed the canonical splice-site variant (c.301 + 1 G > A) in NECAP1. In rodents, Necap1 protein is enriched in neuronal clathrin-coated vesicles and modulates synaptic vesicle recycling. cDNA analysis confirmed abnormal splicing that produced early truncating mRNA. There has been only one previous report of a mutation in NECAP1 in a family with EIEE; this was a nonsense mutation (p.R48*) that was cited as EIEE21. Decreased mRNA levels and the loss of the WXXF motif in both the families suggests that loss of NECAP1 function is a common pathomechanism for EIEE21. This study provided additional support that synaptic vesicle recycling plays a key role in epileptogenesis.
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Acknowledgements
We would like to thank all of the subjects for participating in this study. We also thank N. Watanabe, T. Miyama, M. Sato, and K. Takabe for their technical assistance. This work was supported by AMED under grant numbers JP18ek0109280, JP18dm0107090, JP18ek0109301, JP18ek0109348, and JP18kk020500; by JSPS KAKENHI under grant numbers JP17K15630, JP17H01539, JP17K10080, and JP17K15630; the Ministry of Health, Labour, and Welfare; and Takeda Science Foundation. We thank Natasha Beeton-Kempen, Ph.D., from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.
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Mizuguchi, T., Nakashima, M., Moey, L.H. et al. A novel homozygous truncating variant of NECAP1 in early infantile epileptic encephalopathy: the second case report of EIEE21. J Hum Genet 64, 347–350 (2019). https://doi.org/10.1038/s10038-018-0556-2
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DOI: https://doi.org/10.1038/s10038-018-0556-2
