Novel Truncating and Missense Variants in SEMA6B in Patients With Early-Onset Epilepsy

Abstract

Progressive myoclonic epilepsy (PME) is a rare neurodegenerative disease, characterized by myoclonic seizures and tonic clonic seizures, with genetical and phenotypical heterogeneity. The semaphorin 6B (SEMA6B) gene has been recently reported a causal gene of PME. Independent studies are warranted to further support these findings. Here we report that one nonsense variant in NM_032108.3 exon17 c.2056C > T (p.Gln686∗) and one missense variant in exon14 c.1483G > T (p.Gly495Trp) of SEMA6B, both occurring de novo, underlie early-onset epilepsy with variable severity and different response to treatment in two patients. In vitro analyses have demonstrated that the nonsense variant, p.Gln686∗, results in a truncated protein with remarkably increased expression compared to that of the wild type. The truncated protein presented more homogeneous and failed to locate in the plasma membrane. The missense variant p.Gly495Trp affects evolutionarily conserved amino acid and is located in the sema domain, a key functional domain of SEMA6B. It was predicted to perturb the SEMA6B function by altering the tertiary structure of mutant protein, although neither change of protein length and expression nor difference of cellular distribution was observed. Co-immunoprecipitation studies have demonstrated that both variants influence protein binding of SEMA6B and PlxnA2 with varying degrees. Our results provide further evidence to support the initial findings of SEMA6B being causal to epilepsy and indicate that mediating Semaphorin/Plexin signaling is the potential mechanism of the SEMA6B-related disease.

Non-convulsive Status Epilepticus in SEMA6B-Related Progressive Myoclonic Epilepsy: A Case Report With Literature Review

“…All variants reported to date are truncation variants in the last exon of the gene, except for the c.1483G>T variant ( 16 ). The only missense mutation c.1483G>T, which was reported by Xiaozhen et al ( 16 ), was identified de novo in a 3-year-old boy who had apparently normal developmental milestones.…”

“…All variants reported to date are truncation variants in the last exon of the gene, except for the c.1483G>T variant ( 16 ). The only missense mutation c.1483G>T, which was reported by Xiaozhen et al ( 16 ), was identified de novo in a 3-year-old boy who had apparently normal developmental milestones. This child was referred to the hospital at the age of 2 years because of the onset of seizures with eye-rolling, cyanotic lips, consciousness lapses, and right upper limb jitter as well as a gelastic seizure lasting > 15 s. Furthermore, he had good response to combination treatment of levetiracetam and sodium valproate with no recurrence noted.…”

“…However, considering the doubtful pathogenicity of c.1483G>T, we have not included the case reported by Xiaozhen et al ( 16 ) (Patient 23) in our discussion of the clinical symptoms of all patients below. All patients with truncation mutations presented with epilepsy and varying degrees of delayed development.…”

Two novel heterozygous truncating variants in NR4A2 identified in patients with neurodevelopmental disorder and brief literature review

“…An IDTxGen ® Exome Research Panel (IDT, United States) was used to capture the exons, and HiseqX10 (Illumina, United States) was used to sequence the DNA fragments. FASTQ data analysis was conducted as described in previous studies ( Xiaozhen et al, 2021 ). The candidate pathogenic genes were confirmed by Sanger sequencing.…”

Clinical Study of 8 Cases of CHD2 Gene Mutation–Related Neurological Diseases and Their Mechanisms

“…2019R071-F03). Variants calling and interpretation have been described elsewhere ( Xiaozhen et al, 2021 ).…”