<i>De Novo</i> Truncating Mutation of <i>TRIM8</i> Causes Early‐Onset Epileptic Encephalopathy

Sakai, Yasunari; Fukai, Ryoko; Matsushita, Yuki; Miyake, Noriko; Saitsu, Hirotomo; Akamine, Satoshi; Torio, Michiko; Sasazuki, Momoko; Ishizaki, Yoshito; Sanefuji, Masafumi; Torisu, Hiroyuki; Shaw, Chad A.; Matsumoto, Naomichi; Hara, Toshiro

doi:10.1111/ahg.12157

Cited by 25 publications

(19 citation statements)

References 14 publications

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“…Mutations in TRIM8 have been reported as a rare cause of epilepsy and intellectual disability (Assoum et al, 2018;Sakai et al, 2016). In this report, we describe a seventh individual with a de novo heterozygous truncating mutation in the C-terminal region of TRIM8.…”

Section: Discussionmentioning

confidence: 86%

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Focal segmental glomerulosclerosis and mild intellectual disability in a patient with a novel de novo truncating TRIM8 mutation

McClatchey

Toit

Vaughan

et al. 2020

European Journal of Medical Genetics

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Mutations in the TRIM8 gene have been described in patients with severe developmental delay, intellectual disability and epilepsy. Only six patients have been described to date. All the previous mutations were truncating variants clustered in the C-terminus of the protein. A previous patient with TRIM8-related epileptic encephalopathy was reported to have nephrotic syndrome. Here we describe the clinical, radiological and histological features of an 8-yearold male patient with a TRIM8 mutation who, in contrast to previous patients, had only mild intellectual disability and well-controlled epilepsy. The patient was found to have proteinuria at 2 years of age. Renal biopsy findings were suggestive of focal segmental glomerulosclerosis. His kidney function declined and peritoneal dialysis was started at 5 years of age. He underwent renal transplant at 7 years of age. Trio-based whole genome sequencing identified a novel de novo heterozygous frameshift mutation in TRIM8 (NM_030912.2) c.1198_1220del, p.(Tyr400ArgfsTer2). This patient is further evidence that TRIM8 mutations cause a syndrome with both neurological and renal features. Our findings suggest the spectrum of TRIM8-related disease may be wider than previously thought with the possibility of milder neurodevelopmental problems and/or a more severe, progressive renal phenotype. We highlight the need for proteinuria screening in patients with TRIM8 mutations.

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Section: Discussionmentioning

confidence: 86%

“…TRIM8 mutations have recently been described in patients with epilepsy, developmental delay and learning disability (Assoum et al, 2018;Sakai et al, 2016). To date, only six previous patients have been reported.…”

Section: Introductionmentioning

confidence: 99%

Focal segmental glomerulosclerosis and mild intellectual disability in a patient with a novel de novo truncating TRIM8 mutation

McClatchey

Toit

Vaughan

et al. 2020

European Journal of Medical Genetics

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“…Children with a mutation in POU3F2 possess varying degrees of developmental delay and intellectual disability 49 , 50 . According to two other studies, children with TRIM8 mutations also exhibit developmental delays, limited language development, and abnormalities in brain magnetic resonance imaging 51 , 52 . POU3F2 has shown influence over neurogenesis with the regulation of neurodevelopmental genes, such as Delta1 , Hes5 , and Tbr2 53 , 54 .…”

Section: Discussionmentioning

confidence: 94%

Transcription factor POU3F2 regulates TRIM8 expression contributing to cellular functions implicated in schizophrenia

et al. 2020

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Schizophrenia (SCZ) is a neuropsychiatric disorder with aberrant expression of multiple genes. However, identifying its exact causal genes remains a considerable challenge. The brain-specific transcription factor POU3F2 (POU domain, class 3, transcription factor 2) has been recognized as a risk factor for SCZ, but our understanding of its target genes and pathogenic mechanisms are still limited. Here we report that POU3F2 regulates 42 SCZ-related genes in knockdown and RNA sequencing experiments of human neural progenitor cells (NPCs). Among those SCZ-related genes, TRIM8 (Tripartite motif containing 8) is located in SCZ-associated genetic locus and is aberrantly expressed in patients with SCZ. Luciferase reporter and electrophoretic mobility shift assays (EMSA) showed that POU3F2 induces TRIM8 expression by binding to the SCZ-associated SNP (single nucleotide polymorphism) rs5011218, which affects POU3F2 binding efficiency at the promoter region of TRIM8 . We investigated the cellular functions of POU3F2 and TRIM8 as they co-regulate several pathways related to neural development and synaptic function. Knocking down either POU3F2 or TRIM8 promoted the proliferation of NPCs, inhibited their neuronal differentiation, and impaired the excitatory synaptic transmission of NPC-derived neurons. These results indicate that POU3F2 regulates TRIM8 expression through the SCZ-associated SNP rs5011218, and both genes may be involved in the etiology of SCZ by regulating neural development and synaptic function.

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“…Pathogenicity of TRIM8 mutations on its C terminus has been established as the causative agent for EE, possibly associated with nephrotic syndrome. 36 , 37 De novo mutation on the C-terminal region of TRIM8 is also associated with focal segmental glomerulosclerosis (FSGS). 38 Liu et al.…”

Section: Main Textmentioning

confidence: 99%

Rise of TRIM8: A Molecule of Duality

Bhaduri

Merla

2020

Molecular Therapy - Nucleic Acids

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The human tripartite motif containing protein 8 (TRIM8), a member of TRIM family proteins, is known to play a dual role as both tumor suppressor and oncogene, and to function at the crosstalk of cancer and innate immunity. In this review, in addition to accumulating recent corroborations that endorse this dual character of TRIM8, we appraise the game-changing capacity of TRIM8 under stress conditions against the backdrop of cell proliferation, apoptosis, and cancer, and also highlight the duality of TRIM8 in multiple contexts like cellular localization, stress-induced conditions, and E3 ubiquitin ligase activity. Finally, we discuss the emerging role of TRIM8 during bipolar spindle formation and mitotic progression, and its growing sphere of influence across multiple human cancers and pathologies, and suggest TRIM8-linked axes that can be modulated further for anti-cancer therapeutics development.

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De Novo Truncating Mutation of TRIM8 Causes Early‐Onset Epileptic Encephalopathy

Abstract: This is the second case of EOEE caused by a de novo truncating mutation of TRIM8. Further studies are required to determine the functional roles of TRIM8 in the postnatal development of the human brain and its functional relationships with other EOEE-associated genes.

Cited by 25 publications

References 14 publications

Focal segmental glomerulosclerosis and mild intellectual disability in a patient with a novel de novo truncating TRIM8 mutation

Focal segmental glomerulosclerosis and mild intellectual disability in a patient with a novel de novo truncating TRIM8 mutation

Transcription factor POU3F2 regulates TRIM8 expression contributing to cellular functions implicated in schizophrenia

Rise of TRIM8: A Molecule of Duality

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