Association of a de novo nonsense mutation of the TRIM8 gene with childhood-onset focal segmental glomerulosclerosis

Warren, Mikako; Takeda, Moe; Partikian, Arthur; Opas, Lawrence; Fine, Richard Ν.; Yano, Shoji

doi:10.1007/s00467-020-04525-3

Cited by 8 publications

(20 citation statements)

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“…[44][45][46] TRIM8 disease-associated variants are restricted to the last exon (Figures 1C and S2). 23,[41][42][43] Combining our findings with previous reports showed that four individuals from distinct ethnic backgrounds share the identical variant at position c.1375 and two share nonsense variants at position c.1380 (Figure S2). 23,41 This observation suggests that this region is a recurrent germline variant hotspot (Figure S2, Table 1), as has been demonstrated for other rare dominant monogenic causes of syndromic epilepsy 47 and nephrotic syndrome.…”

supporting

confidence: 87%

“…All subjects were diagnosed with renal disease after (10/12) or at the time of (2/12) the development of neurologic disease. Previous case reports have described truncating DNVs in TRIM8 in a total of eight children with developmental delay and epilepsy, but only three of these subjects were described to have nephrotic syndrome (Figure S2), 23,[41][42][43] which left it unsolved whether the renal disease was associated to TRIM8 variants or just coincidental. The early ascertainment of these cases is also consistent with our observation that renal disease presents later in the course of these patients and may not have been apparent yet at the time of these reports.…”

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confidence: 98%

“…(2) it is exceedingly rare and, in fact, absent from the Genome Aggregation Database (gnomAD) population, which contains ES or GS data from 141,456 adults who are not known to have severe pediatric disease; 31,32 and (3) the TRIM8 locus exhibits high loss-of-function (LoF) intolerance (gnomAD probability for loss-of-function intolerance [pLI] 0.99; loss-of-function observed/expected upper bound fraction [LOEUF] 0.26), meaning LoF alleles are not frequently observed relative to gene size and expected mutation rate. 31 To determine whether TRIM8 DNVs are a monogenic cause of NS and establish whether NS and developmental delay/epilepsy are allelic in these cases, we aggregated and analyzed ES or GS from a cohort of 60,114 subjects, including 2,501 SRNS/FSGS-affected individuals, 48,556 This patient was independently recruited and reported 23 while the current manuscript was in preparation. control subjects, and 9,057 individuals with a broad diagnosis of epilepsy.…”

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confidence: 99%

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De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis

Weng¹,

Majmundar²,

Khan³

et al. 2021

The American Journal of Human Genetics

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Focal segmental glomerulosclerosis (FSGS) is the main pathology underlying steroid-resistant nephrotic syndrome (SRNS) and a leading cause of chronic kidney disease. Monogenic forms of pediatric SRNS are predominantly caused by recessive mutations, while the contribution of de novo variants (DNVs) to this trait is poorly understood. Using exome sequencing (ES) in a proband with FSGS/SRNS, developmental delay, and epilepsy, we discovered a nonsense DNV in TRIM8, which encodes the E3 ubiquitin ligase tripartite motif containing 8. To establish whether TRIM8 variants represent a cause of FSGS, we aggregated exome/genome-sequencing data for 2,501 pediatric FSGS/SRNS-affected individuals and 48,556 control subjects, detecting eight heterozygous TRIM8 truncating variants in affected subjects but none in control subjects (p ¼ 3.28 3 10 À11 ). In all six cases with available parental DNA, we demonstrated de novo inheritance (p ¼ 2.21 3 10 À15 ). Reverse phenotyping revealed neurodevelopmental disease in all eight families. We next analyzed ES from 9,067 individuals with epilepsy, yielding three additional families with truncating TRIM8 variants. Clinical review revealed FSGS in all. All TRIM8 variants cause protein truncation clustering within the last exon between residues 390 and 487 of the 551 amino acid protein, indicating a correlation between this syndrome and loss of the TRIM8 C-terminal region. Wild-type TRIM8 overexpressed in immortalized human podocytes and neuronal cells localized to nuclear bodies, while constructs harboring patient-specific variants mislocalized diffusely to the nucleoplasm. Co-localization studies demonstrated that Gemini and Cajal bodies frequently abut a TRIM8 nuclear body. Truncating TRIM8 DNVs cause a neuro-renal syndrome via aberrant TRIM8 localization, implicating nuclear bodies in FSGS and developmental brain disease.

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confidence: 87%

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confidence: 98%

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confidence: 99%

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De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis

Weng¹,

Majmundar²,

Khan³

et al. 2021

The American Journal of Human Genetics

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“…Assoum et al described five additional individuals of childhood-onset epileptic encephalopathy associated with heterozygous de novo variants in the C-terminus-encoding portion of TRIM8 , including three individuals who presented with proteinuria [ 4 ]. Recently, Warren et al reported an individual with epileptic encephalopathy and nephrotic syndrome with a TRIM8 variant, and his kidney specimen showed FSGS [ 5 ]. They also performed immunohistochemical (IHC) staining, using an anti-TRIM8 antibody, and demonstrated a lack of TRIM8 protein expression, with suppressor of cytokine signaling 1 (SOCS1) overexpression, which is regulated by TRIM8, in the podocytes and tubules [ 5 ].…”

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confidence: 99%

A novel de novo truncating TRIM8 variant associated with childhood-onset focal segmental glomerulosclerosis without epileptic encephalopathy: a case report

et al. 2021

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Background Heterozygous truncating variants in the Tripartite motif containing 8 (TRIM8) gene have been reported to cause epileptic encephalopathy, both with and without proteinuria. A recent study showed a lack of TRIM8 protein expression, with suppressor of cytokine signaling 1 (SOCS1) overexpression, in podocytes and tubules from a patient with a TRIM8 variant, who presented with epileptic encephalopathy and focal segmental glomerulosclerosis (FSGS). To date, no patients with TRIM8 variants who presented with nephrotic syndrome but without neurological manifestations have been described. Case presentation An 8-year-old girl presented with nephrotic syndrome, without epilepsy or developmental delay. Her kidney biopsy specimens showed FSGS and cystic dilatations of the distal tubules. Whole-exome sequencing identified a novel de novo heterozygous variant in the C-terminal encoding portion of TRIM8 (c.1461C > A), resulting in a premature stop codon (p.Tyr487*). Reverse transcription-polymerase chain reaction using peripheral blood mononuclear cells identified the mRNA sequence of the mutant allele, which confirmed an escape from nonsense-mediated mRNA decay. Immunofluorescence studies showed a lack of TRIM8 expression in glomerular and tubular cells and cystic dilatation of distal tubules. Immunohistochemical studies showed overexpression of SOCS1 in glomerular and tubular cells. Conclusions We reported a patient with FSGS, associated with a de novo heterozygous TRIM8 variant, without any neurological manifestations. Our results expanded the clinical phenotypic spectrum of TRIM8 variants.

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“… 36 , 37 De novo mutation on the C-terminal region of TRIM8 is also associated with focal segmental glomerulosclerosis (FSGS). 38 Liu et al. 39 reported that inhibition of TRIM8-mediated TAK1 polyubiquitination by hepatic TNIP3 can lead to the blocking of the progression of nonalcoholic steatohepatitis (NASH), a subtype of nonalcoholic fatty liver disease (NAFLD).…”

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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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Association of a de novo nonsense mutation of the TRIM8 gene with childhood-onset focal segmental glomerulosclerosis

Cited by 8 publications

References 8 publications

De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis

De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis

A novel de novo truncating TRIM8 variant associated with childhood-onset focal segmental glomerulosclerosis without epileptic encephalopathy: a case report

Rise of TRIM8: A Molecule of Duality

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