Weng PL, Majmundar AJ, Khan K, Lim TY, Shril S, Jin G, Musgrove J, Wang M, Ahram DF, Aggarwal VS, Bier LE, Heinzen EL, Onuchic-Whitford AC, Mann N, Buerger F, Schneider R, Deutsch K, Kitzler TM, Klämbt V, Kolb A, Mao Y, Moufawad El Achkar C, Mitrotti A, Martino J, Beck BB, Altmüller J, Benz MR, Yano S, Mikati MA, Gunduz T, Cope H, Shashi V; Undiagnosed Diseases Network; Trachtman H, Bodria M, Caridi G, Pisani I, Fiaccadori E, AbuMaziad AS, Martinez-Agosto JA, Yadin O, Zuckerman J, Kim A; UCLA Clinical Genomics Center; John-Kroegel U, Tyndall AV, Parboosingh JS, Innes AM, Bierzynska A, Koziell AB, Muorah M, Saleem MA, Hoefele J, Riedhammer KM, Gharavi AG, Jobanputra V, Pierce-Hoffman E, Seaby EG, O'Donnell-Luria A, Rehm HL, Mane S, D'Agati VD, Pollak MR, Ghiggeri GM, Lifton RP, Goldstein DB, Davis EE, Hildebrandt F, Sanna-Cherchi S. De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis. Am J Hum Genet. 2021 Feb 4;108(2):357-367. doi: 10.1016/j.ajhg.2021.01.008. Epub 2021 Jan 27. PMID: 33508234; PMCID: PMC7895901.
Abstract
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 = 3.28 × 10-11). In all six cases with available parental DNA, we demonstrated de novo inheritance (p = 2.21 × 10-15). 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.
Sakai Y, Fukai R, Matsushita Y, Miyake N, Saitsu H, Akamine S, Torio M, Sasazuki M, Ishizaki Y, Sanefuji M, Torisu H, Shaw CA, Matsumoto N, Hara T. De Novo Truncating Mutation of TRIM8 Causes Early-Onset Epileptic Encephalopathy. Ann Hum Genet. 2016 Jul;80(4):235-40. doi: 10.1111/ahg.12157. PMID: 27346735.
Abstract
Background: Early-onset epileptic encephalopathy (EOEE) is a heterogeneous group of neurodevelopmental disorders characterised by infantile-onset intractable epilepsy and unfavourable developmental outcomes. Hundreds of mutations have been reported to cause EOEE; however, little is known about the clinical features of individuals with rare variants.
Case report and methods: We present a 10-year-old boy with severe developmental delay. He started experiencing recurrent focal seizures at 2 months old. Serial electroencephalograms persistently detected epileptiform discharges from the left hemisphere. Whole-exome sequencing and array-comparative genome hybridization were performed to search for de novo variations. Two-week-old C57Bl/6 mice were used for immunofluorescence studies.
Results: This case had a paternally inherited, 0.2-Mb duplication at chromosome 22q11.22. The whole-exome sequencing identified a de novo truncating mutation of tripartite motif containing 8 (TRIM8) (NM_030912:c.1099_1100insG:p.C367fs), one of the epileptic encephalopathy-associated genes. We verified that the murine homologues of these genes are expressed in the postnatal mouse brain.
Conclusion: 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.
Li W, Guo H. De novo truncating variants of TRIM8 and atypical neuro-renal syndrome: a case report and literature review. Ital J Pediatr. 2023 Apr 15;49(1):46. doi: 10.1186/s13052-023-01453-4. PMID: 37061734; PMCID: PMC10105407.
Abstract
Background: The TRIM8 gene encodes a protein that participates in various biological processes. TRIM8 variants can lead to early termination of protein translation, which can cause a rare disease called neuro-renal syndrome. This syndrome is characterized by epilepsy, psychomotor retardation, and focal segmental glomerulosclerosis. However, we found that some patients may not present the above typical triad, and the reason may be related to their variant sites.
Case presentation: We report a case of a 6-year-old boy with nephrotic-range proteinuria as the first prominent manifestation of TRIM8 variant. He had stage 3 chronic kidney disease at the time of presentation, specific facial features, and a neurogenic bladder. He had not experienced seizures previously. There were no apparent abnormalities in his growth, intelligence, or motor development. The results of whole exome sequencing showed a TRIM8 variant. Renal biopsy revealed focal segmental glomerulosclerosis and renal tubular cystic dilatation. He did not respond to hormone and angiotensin-converting enzyme inhibitor treatment; however, the symptoms of neurogenic bladder were relieved after treatment with Solifenacin.
Conclusion: In this case, renal disease was the prominent manifestation; the patient had no other obvious neurological symptoms except a neurogenic bladder. Notably, the variant site is the closest to the C-terminal to date. Based on the analysis of previously reported cases, we found that as the TRIM8 variant became closer to the C-terminal, the renal lesions became more prominent, and there were fewer neurologic lesions. Our findings provide a new understanding of neuro-renal syndrome caused by TRIM8 variant. Patients may only have kidney disease as a prominent manifestation. At the same time, we found that we should also pay attention to the eye lesions of these patients. Therefore, gene analysis is helpful in identifying the etiology and guiding the prognosis of patients with hormone-resistant proteinuria. We suggest that TRIM8 should be included in gene panels designed for the genetic evaluation of hormone-resistant proteinuria.
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