A splicing variation in NPRL2 causing familial focal epilepsy with variable foci: additional cases and literature review

Wanlin Chen,Zuozhen Yang,Yajun Shen,Yang Li,Jia Zhang,Fan Yang,Jing Gan,Bo Yu

doi:10.1038/s10038-021-00969-z

Abstract

NPRL2 (nitrogen permease regulator like 2) is a component of the GATOR1(GAP activity towards rags complex 1) proteins, which is an inhibitor of the amino acid-sensing branch of the mTORC1 pathway. GATOR1 complex variations were reported to correlate with familial focal epilepsy with variable foci (FFEVF). However, FFEVF caused by NPRL2 variants has not been widely explored. Here, we describe a variant, 339+2T>C, in NPRL2 identified by trio whole-exome sequencing (WES) in a family. This splicing variant that occurred at the 5′ end of exon 3 was confirmed by minigene assays, which affected alternative splicing and led to exon 3 skipping in NPRL2. Our cases presented multiple seizure types (febrile seizures, infantile spasms, focal seizures, or focal to generalized tonic-clonic seizures). Electroencephalogram (EEG) showed frequent discharges in the left frontal and central regions. A favorable prognosis was achieved in response to vitamin B6 and topiramate when the patient was seven months old. Our study expands the phenotype and genotype spectrum of FFEVF and provides solid diagnostic evidence for FFEVF.

Highlights

NPRL2 is a component of the GATOR1 complex, along with nitrogen permease regulator like-3 (NPRL3) and DEPDC5
NPRL2 is known as tumor suppressor candidate 4 [2], which is upregulated in primary prostate cancer tissues [3]
The GATOR1 complex inhibits mechanistic target of rapamycin activation according to the amino acid levels in ambient cells [4]

Summary

Introduction

NPRL2 is a component of the GATOR1 complex, along with nitrogen permease regulator like-3 (NPRL3) and DEPDC5. The GATOR1 complex inhibits mechanistic target of rapamycin (mTOR) activation according to the amino acid levels in ambient cells [4]. It changes the nucleotide loading status (GTP or GDP) of the Rag proteins and deactivates them to release mTOR complex 1 (mTORC1) from the lysosome [5, 6]. Germline variants in the GATOR1 complex genes (DEPDC5, NPRL3, and NPRL2) are present in ~10% of focal epilepsy cases [9], which can be familial or sporadic, especially in familial focal epilepsy with variable foci (FFEVF). Loss-of-function variants in DEPDC5 and NPRL3 have been investigated extensively in both animal models and human tissues associated with mTORC1 hyperactivation [11, 12]. Variants in NPRL2 related to epileptogenesis are still not well understood

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