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The phenotypic landscape of a Tbc1d24 mutant mouse includes convulsive seizures resembling human early infantile epileptic encephalopathy.

ABSTRACT: Epilepsy, deafness, onychodystrophy, osteodystrophy and intellectual disability are associated with a spectrum of mutations of human TBC1D24. The mechanisms underlying TBC1D24-associated disorders and the functions of TBC1D24 are not well understood. Using CRISPR-Cas9 genome editing, we engineered a mouse with a premature translation stop codon equivalent to human S324Tfs*3, a recessive mutation of TBC1D24 associated with early infantile epileptic encephalopathy (EIEE). Homozygous S324Tfs*3 mice have normal auditory and vestibular functions but show an abrupt onset of spontaneous seizures at postnatal day 15 recapitulating human EIEE. The S324Tfs*3 variant is located in an alternatively spliced micro-exon encoding six perfectly conserved amino acids incorporated postnatally into TBC1D24 protein due to a micro-exon utilization switch. During embryonic and early postnatal development, S324Tfs*3 homozygotes produce predominantly the shorter wild-type TBC1D24 protein isoform that omits the micro-exon. S324Tfs*3 homozygotes show an abrupt onset of seizures at P15 that correlates with a developmental switch to utilization of the micro-exon. A mouse deficient for alternative splice factor SRRM3 impairs incorporation of the Tbc1d24 micro-exon. Wild-type Tbc1d24 mRNA is abundantly expressed in the hippocampus using RNAscope in situ hybridization. Immunogold electron microscopy using a TBC1D24-specific antibody revealed that TBC1D24 is associated with clathrin-coated vesicles and synapses of hippocampal neurons, suggesting a crucial role of TBC1D24 in vesicle trafficking important for neuronal signal transmission. This is the first characterization of a mouse model of human TBC1D24-associated EIEE that can now be used to screen for antiepileptogenic drugs ameliorating TBCID24 seizure disorders.

SUBMITTER: Tona R

PROVIDER: S-EPMC6466106 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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The phenotypic landscape of a Tbc1d24 mutant mouse includes convulsive seizures resembling human early infantile epileptic encephalopathy.

Tona Risa R Chen Wenqian W Nakano Yoko Y Reyes Laura D LD Petralia Ronald S RS Wang Ya-Xian YX Starost Matthew F MF Wafa Talah T TT Morell Robert J RJ Cravedi Kevin D KD du Hoffmann Johann J Miyoshi Takushi T Munasinghe Jeeva P JP Fitzgerald Tracy S TS Chudasama Yogita Y Omori Koichi K Pierpaoli Carlo C Banfi Botond B Dong Lijin L Belyantseva Inna A IA Friedman Thomas B TB

Human molecular genetics 20190501 9

Epilepsy, deafness, onychodystrophy, osteodystrophy and intellectual disability are associated with a spectrum of mutations of human TBC1D24. The mechanisms underlying TBC1D24-associated disorders and the functions of TBC1D24 are not well understood. Using CRISPR-Cas9 genome editing, we engineered a mouse with a premature translation stop codon equivalent to human S324Tfs*3, a recessive mutation of TBC1D24 associated with early infantile epileptic encephalopathy (EIEE). Homozygous S324Tfs*3 mice ...[more]

PMID: 30602030

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Project description:BackgroundSCN8A mutations have recently been associated with epilepsy and neurodevelopmental disorders. This study aimed to broaden the phenotypic-spectrum of disease related with SCN8A mutations.MethodsTo identify the pathogenic gene of a Chinese family, in which six members suffered from epilepsy, whole-exome sequencing was performed. In addition, target next-generation sequencing (NGS) was performed on 178 sporadic patients, who had epilepsy of unknown etiology within 6 months after birth. A detailed clinical history was obtained.ResultsA heterozygous missense mutation of SCN8A was identified in the Chinese family. Six de novo mutations of SCN8A were detected in 6 sporadic patients with epilepsy. In the family, six members developed seizures within a few years after birth. Five of them had milder clinical performance, that they had normal cognition and developmental milestones, and seizure-free was achieved by mono-therapy. The other one affected member presented with refractory epilepsy and developmental regression. She died from sudden unexpected death in epilepsy (SUDEP) at 17-year-old. Clinical features of six sporadic patients with SCN8A mutations were diverse, ranging from severe epileptic encephalopathy to benign epilepsy with normal cognition. Seizures started at the mean age of 3.9 months (from 2 months to 6 months). Seizure-free was achieved in four of them by mono- or multi-antiepileptic drugs. Five of them demonstrated mild or severe psychomotor retardation, whereas the other one was normal in development and intelligence.ConclusionsOur findings extend the spectrum of SCN8A mutations and the clinical features of patients with SCN8A mutations. The majority of SCN8A mutations were de novo, inherited mutations from the heterozygous parents can also occur. The phenotypic spectrum of SCN8A mutation varied largely. Most affected patients manifested as refractory epilepsy and severe intellectual disability, only a small number of patients presented with milder clinical patterns. Additionally, our study confirmed that the same mutation can lead to different phenotypes.

Project description:ObjectiveEpileptic encephalopathy (EE) is a heterogeneous condition associated with deteriorations of cognitive, sensory and/or motor functions as a consequence of epileptic activity. The phenomenon is the most common and severe in infancy and early childhood. Genetic-based diagnosis in EE patients is challenging owing to genetic and phenotypic heterogeneity of numerous monogenic disorders and the fact that thousands of genes are involved in neurodevelopment. Therefore, high-throughput next-generation sequencing (NGS) was used to investigate the genetic causes of non-syndromic cryptogenic neonatal/infantile EE (NIEE).MethodsWe have selected a cohort of 31 patients with seizure cryptogenic NIEE and seizure onset before 24 months. All investigations including metabolic work-up, were negative. Using NGS, we distinguished a panel of 430 epilepsy-associated genes by NGS was utilized to identify possible pathogenic variants in the patients. Segregation analysis and multiple silico analysis prediction tools were used for pathogenicity assessment. The identified variants were classified as "pathogenic," "likely pathogenic" and "uncertain significance," according to the American College of Medical Genetics (ACMG) guidelines.ResultsPathogenic or likely pathogenic variants were identified in six genes (ALG13 [1], CDKL5 [2], KCNQ2 [2], PNPO [1], SCN8A [1], SLC9A6 [2]) in 9 NIEE patients (9/31; 29%). Variants of uncertain significance (VUS) were found in DNM1 and TUBA8 in 2 NIEE patients (2/31; 6%). Most phenotypes in our cohort matched with those reported cases.SignificanceThe diagnostic rate (29%) of pathogenic and likely pathogenic variants was comparable to the recent studies of early-onset epileptic encephalopathy, indicating that gene panel analysis through NGS is a powerful tool to investigate cryptogenic NIEE in patients. Six percent of patients had neurometabolic disorders. Some of our diagnosed cases illustrated that successful molecular investigation may allow a better treatment strategy and avoid unnecessary and even invasive investigations. Functional analysis could be performed to further study the pathogenicity of the VUS identified in DNM1 and TUBA8.

Dataset Information

The phenotypic landscape of a Tbc1d24 mutant mouse includes convulsive seizures resembling human early infantile epileptic encephalopathy.

Publications

The phenotypic landscape of a Tbc1d24 mutant mouse includes convulsive seizures resembling human early infantile epileptic encephalopathy.

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