A non-sense mutation in the  Tripartite motif containing 8 (TRIM8 ) gene, mimicking collagenopathy

A non-sense mutation in the Tripartite motif containing 8 (TRIM8 ) gene, mimicking collagenopathy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article A non-sense mutation in the Tripartite motif containing 8 (TRIM8 ) gene, mimicking collagenopathy Rehna K Rahman, Harisankar T, Smilu Mohanlal, Divya Pachat, Shalini Kuruvilla, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5191613/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 21 Dec, 2024 Read the published version in Pediatric Nephrology → Version 1 posted 5 You are reading this latest preprint version Abstract Tripartite motif-containing 8 (TRIM8) gene mutations are associated with autosomal dominantly inherited neurorenal syndrome. The kidney manifestations range from nephrotic range proteinuria to nephrotic syndrome and kidney failure. The kidney histopathology was focal segmental glomerulosclerosis (FSGS) in all the reported cases. We now report a non-sense mutation in TRIM8 in a 1-year-old boy, mimicking collagenopathy in the kidney biopsy. TRIM8 Collagenopathy FSGS neurorenal syndrome Figures Figure 1 Figure 2 What is new? TRIM8 mutations are associated with monogenic nephrotic syndrome with subtle neurologic manifestations like febrile seizures. Histopathology mimicking collagenopathy can be seen in TRIM8 mutations. Case presentation A one-year-four-month-old boy, the first child of non-consanguineous parents, presented with an episode of gross hematuria and proteinuria during a febrile illness. He had fever, rhinitis, cough, and experienced simple febrile seizures. The parents noted reddish discolouration and frothing in the urine. The discolouration lasted for one day, but the frothing persisted. He had no oliguria, edema, or rash and reported no history of intake of non-steroidal anti-inflammatory agents. He was born at term, with a birth weight of 3 kg, and had an uneventful antenatal and postnatal period. There was no family history of kidney problems, hearing impairment, vision issues, or neurological illnesses. He has a healthy one-month-old sister. His developmental milestones were normal for his age, and he received routine vaccinations. On examination, he had no dysmorphic features, bony deformities, or edema. His weight was at the 10th centile and height at the 15th centile according to WHO growth charts. He was normotensive, and his nails and genitals appeared normal. Investigations showed a urine albumin dipstick of 4+, red blood cells greater than 25 per high-power field, and a urine protein/creatinine ratio of 14 mg/mg. His serum albumin was 3.1 g/dl, and serum cholesterol was 200 mg/dl. He had normal blood counts, kidney function tests, serum electrolytes, uric acid, calcium, phosphorus, and alkaline phosphatase. His complement levels (C3, C4) and ultrasound scan of the kidneys were normal. His viral serology (HIV, HBS Ag, HCV) was negative. Urine investigations remained almost the same upon rechecking after the subsidence of the febrile illness. We are dealing with a one-year-four-month-old boy with nephrotic range proteinuria, one episode of gross hematuria, and persistent microscopic hematuria, with normal kidney function and complement levels. We suspected we were dealing with a non-minimal change glomerular disease. The differential diagnoses at this point included a) Alport syndrome, b) IgA nephropathy, c) MCD/FSGS (monogenic), and d) Membranoproliferative glomerulonephritis (MPGN). His ophthalmologic evaluation and hearing test were normal. His antinuclear antibodies were negative. The screening urine analysis of his parents was normal. A urine spot beta 2 microglobulin test, considering Dent’s disease type 1 as a possibility, was performed and returned normal. He underwent a kidney biopsy. Pathology Light microscopy showed 19 unremarkable glomeruli. The tubulo-interstitium and vessels were normal. Immunofluorescence was negative. Electron microscopy (EM) showed irregular, thin, and thick areas in the glomerular basement membrane (GBM), ranging from 132.29 nm to 627.85nm (Fig. 1A). There was focal effacement of foot processes of visceral epithelial cells (about 50%). A few GBMs showed irregular contours on the outer sub-epithelial aspect (Fig. 1B). Intramembranous particles, likely from degenerating collagen and rarefied areas, were observed focally(Figs. 2A and 2B). No immune complex-type deposits or inclusions were seen. Tubules showed electron lucent vacuolar inclusions. Extra glomerular electron-dense deposits were not observed. However, no widespread alterations of collagen distribution like basket weave appearance/ GBM lamellations were evident. The normal GBM thickness we expect in a one-year-old is in the range of 194+/-6 nm. The variations of GBM thickness, irregular contours of GBM, and presence of intramembranous particles, along with rarefied areas, raised suspicion for collagenopathy. Genetic study Considering the possibility of hereditary collagenopathies and other genetic mutations showing basement membrane changes in electron microscopy, a clinical exome analysis was done. It showed a heterozygous likely pathogenic indel variant in exon 6 of the Tripartite motif containing 8 (TRIM8) gene(c.1359_1360delinsTT)(p.Gln453_Gln454delinsHisTer), resulting in a stop codon and premature truncation of the protein. This variant is associated with Focal segmental glomerulosclerosis ( FSGS) and neurodevelopmental syndrome inherited in an autosomal dominant pattern. No pathogenic or likely pathogenic variants in COL4A3, COL4A4, or COL4A5 genes were detected. His neurological examination and developmental assessment were normal. However, an electroencephalogram(EEG) was done, which was normal. He was started on angiotensin-converting enzyme (ACE)inhibitors, and his proteinuria remains status co at the last follow-up. Parents were advised for genetic screening, but it has not been done yet. Discussion The child’s clinical presentation and electron microscopy findings in the kidney biopsy were suggestive of collagenopathy. A mutation in genes associated with Alport syndrome (COL4A3, COL4A4, or COL4A5) was strongly suspected. However, electron microscopy findings mimicking Alport syndrome have been described in various other genetic mutations (refer to Table 1 ) [ 1 ],[ 2 ],[ 3 ]. Table 1 Alport syndrome mimickers in electron microscopy Gene Mode of inheritance Extra renal manifestations Glomerular basement membrane(GBM)changes LMX1B AD Dysplastic nails, Absent /hypoplastic patellae, Iliac horns (Nail patella syndrome) Irregular thick and thin areas in the GBM with moth eaten appearance and deposition of type III collagen fibrils MYH9 AD Macro platelets, bleeding diatheses, neutrophil granules ,hearing loss, cataract(Ebstein/Fetchner syndrome) Focal thickening, focal attenuation, and focal splitting of GBM MYO1E AR None reported Irregular GBM thickening with the splitting of the lamina densa into interwoven thin layers, and marked irregularity of the inner and outer contours with subepithelial projections P3H2 AR Eye manifestations (myopia, cataract) Irregular thick and thin areas in the GBM LMX1B- LIM homeobox transcription factor 1 beta, MYH9-Myosin heavy chain 9,non-muscle, MYO1E-Myosin 1 E, P3H2 - prolyl 3-hydroxylase 2, AD-Autosomal dominant, AR-Autosomal recessive The TRIM8 gene codes for a tripartite motif-containing protein comprising 551 amino acids, which is involved in various biological processes, like differentiation, proliferation, intracellular signalling, and immunity. It acts as an E3 ubiquitin ligase and is widely expressed in the human body, particularly in the kidney, brain, and eyes. The TRIM protein facilitates proteasomal degradation of suppression of cytokine signalling1(SOC1) [ 4 ]. To date, only 27 patients with TRIM8-mediated neurorenal syndrome have been reported, linked to 19 genetic variants in the TRIM8 gene, all of which were identified in exon 6 and resulted in a truncated protein [ 5 ]. The variant found in our patient was also reported in exon six and resulted in a truncated protein. The most common neurological manifestation observed was developmental delay, followed by epilepsy; focal seizures were more prevalent than generalised seizures. Kidney manifestations were reported in 89% of patients [ 5 ]. Various case reports from around the world describe kidney manifestations ranging from nephrotic range proteinuria and nephrotic syndrome to chronic kidney disease [ 5 ]. Similarly, neurological manifestations are quite variable, with severe epileptic encephalopathy to milder symptoms. Some cases have reported a complete absence of neurological symptoms [ 6 ]. Mutations near the N-terminal were associated with severe neurological manifestations, while those near the C-terminal were linked to milder manifestations. Focal segmental glomerulosclerosis (FSGS) has been observed in nearly all cases described so far [ 5 ]. Variable tubular manifestations, such as cystic dilatation of distal tubules, have also been noted. In contrast, our patient exhibited irregular thick and thin areas in the glomerular basement membrane, as shown in electron microscopy, which simulates collagenopathy. While we cannot definitively rule out unsampled FSGS with only 19 glomeruli examined in light microscopy. The basement membrane involvement resembling collagenopathy represents a novel finding that has not been documented previously. Conclusion Initially, we overlooked the subtle neurological manifestation of febrile seizures and did not consider the possibility of neurorenal syndrome. If we had performed a gene panel for Alport syndrome, we may have missed the diagnosis. This highlights the importance of identifying the mimickers of Alport syndrome and including relevant genes in the analysis of such patients. Written informed consent was obtained from the family for reporting this case. There are no conflicts of interest or financial funding involved in this case . References -Krendel M, Leh S, Garone ME, Edwards-Richards A, Lin JJ, Brackman D, Knappskog P, Mikhailov A (2023) Focal segmental glomerulosclerosis and proteinuria associated with Myo1E mutations: novel variants and histological phenotype analysis. Pediatr Nephrol 38(2):439–449. https://doi.org/10.1007/s00467-022-05634-x -Kopp JB (2010) Glomerular pathology in autosomal dominant MYH9 spectrum disorders: what are the clues telling us about disease mechanism? Kidney Int 78(2):130–133. https://doi.org/10.1038/ki.2010.82 -Deltas C (2022) Thin basement membrane lesion is not only a collagen IV nephropathy: Do not underestimate decorative additions to collagens. Kidney Int 102(6):1203–1205. https://doi.org/10.1016/j.kint.2022.08.014 -Weng PL, Majmundar AJ, Khan K, Lim TY, Shril S, Jin G, Musgrove J, Wang M, Ahram DF, Aggarwal VS Bier LE(2021)De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis. Am J Hum Genet 108(2):357–367. https://doi.org/10.1016/j.ajhg.2021.01.008 -Lv Q, Niu Y, Xu Z, Qin J, Yang Z(2024)Variants loci and phenotype correlation of TRIM8-related neuro-renal syndrome: three cases reports and literature review. Front Neurol 15:1410187. https://doi.org/10.3389/fneur.2024.1410187 -Shirai Y, Miura K, Kaneko N, Ishizuka K, Endo A, Hashimoto T, Kanda S, Harita Y, Hattori M(2021)A novel de novo truncating TRIM8 variant associated with childhood-onset focal segmental glomerulosclerosis without epileptic encephalopathy: a case report. BMC Nephrol 22:1–8. https://doi.org/10.1186/s12882-021-02626-1 Cite Share Download PDF Status: Published Journal Publication published 21 Dec, 2024 Read the published version in Pediatric Nephrology → Version 1 posted Reviewers agreed at journal 17 Nov, 2024 Reviewers invited by journal 14 Nov, 2024 Editor assigned by journal 14 Nov, 2024 First submitted to journal 13 Nov, 2024 Editorial decision: Minor Revisions Needed 25 Oct, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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16:16:55","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":490290,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5191613/v1/2be6198c-c313-4118-90d6-1ded45fa9907.pdf"}],"financialInterests":"","formattedTitle":"A non-sense mutation in the Tripartite motif containing 8 (TRIM8 ) gene, mimicking collagenopathy","fulltext":[{"header":"What is new?","content":"\u003cp\u003eTRIM8 mutations are associated with monogenic nephrotic syndrome with subtle neurologic manifestations like febrile seizures.\u003c/p\u003e\n\u003cp\u003eHistopathology mimicking collagenopathy can be seen in TRIM8 mutations.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eA one-year-four-month-old boy, the first child of non-consanguineous parents, presented with an episode of gross hematuria and proteinuria during a febrile illness. He had fever, rhinitis, cough, and experienced simple febrile seizures. The parents noted reddish discolouration and frothing in the urine. The discolouration lasted for one day, but the frothing persisted. He had no oliguria, edema, or rash and reported no history of intake of non-steroidal anti-inflammatory agents. He was born at term, with a birth weight of 3 kg, and had an uneventful antenatal and postnatal period. There was no family history of kidney problems, hearing impairment, vision issues, or neurological illnesses. He has a healthy one-month-old sister. His developmental milestones were normal for his age, and he received routine vaccinations.\u003c/p\u003e \u003cp\u003eOn examination, he had no dysmorphic features, bony deformities, or edema. His weight was at the 10th centile and height at the 15th centile according to WHO growth charts. He was normotensive, and his nails and genitals appeared normal. Investigations showed a urine albumin dipstick of 4+, red blood cells greater than 25 per high-power field, and a urine protein/creatinine ratio of 14 mg/mg. His serum albumin was 3.1 g/dl, and serum cholesterol was 200 mg/dl. He had normal blood counts, kidney function tests, serum electrolytes, uric acid, calcium, phosphorus, and alkaline phosphatase. His complement levels (C3, C4) and ultrasound scan of the kidneys were normal. His viral serology (HIV, HBS Ag, HCV) was negative. Urine investigations remained almost the same upon rechecking after the subsidence of the febrile illness.\u003c/p\u003e \u003cp\u003eWe are dealing with a one-year-four-month-old boy with nephrotic range proteinuria, one episode of gross hematuria, and persistent microscopic hematuria, with normal kidney function and complement levels. We suspected we were dealing with a non-minimal change glomerular disease. The differential diagnoses at this point included a) Alport syndrome, b) IgA nephropathy, c) MCD/FSGS (monogenic), and d) Membranoproliferative glomerulonephritis (MPGN).\u003c/p\u003e \u003cp\u003eHis ophthalmologic evaluation and hearing test were normal. His antinuclear antibodies were negative. The screening urine analysis of his parents was normal. A urine spot beta 2 microglobulin test, considering Dent\u0026rsquo;s disease type 1 as a possibility, was performed and returned normal. He underwent a kidney biopsy.\u003c/p\u003e\n\u003ch3\u003ePathology\u003c/h3\u003e\n\u003cp\u003eLight microscopy showed 19 unremarkable glomeruli. The tubulo-interstitium and vessels were normal. Immunofluorescence was negative. Electron microscopy (EM) showed irregular, thin, and thick areas in the glomerular basement membrane (GBM), ranging from 132.29 nm to 627.85nm (Fig.\u0026nbsp;1A). There was focal effacement of foot processes of visceral epithelial cells (about 50%). A few GBMs showed irregular contours on the outer sub-epithelial aspect (Fig.\u0026nbsp;1B). Intramembranous particles, likely from degenerating collagen and rarefied areas, were observed focally(Figs.\u0026nbsp;2A and 2B). No immune complex-type deposits or inclusions were seen. Tubules showed electron lucent vacuolar inclusions. Extra glomerular electron-dense deposits were not observed. However, no widespread alterations of collagen distribution like basket weave appearance/ GBM lamellations were evident. The normal GBM thickness we expect in a one-year-old is in the range of 194+/-6 nm. The variations of GBM thickness, irregular contours of GBM, and presence of intramembranous particles, along with rarefied areas, raised suspicion for collagenopathy.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eGenetic study\u003c/h2\u003e \u003cp\u003eConsidering the possibility of hereditary collagenopathies and other genetic mutations showing basement membrane changes in electron microscopy, a clinical exome analysis was done. It showed a heterozygous likely pathogenic indel variant in exon 6 of the Tripartite motif containing 8 (TRIM8) gene(c.1359_1360delinsTT)(p.Gln453_Gln454delinsHisTer), resulting in a stop codon and premature truncation of the protein. This variant is associated with Focal segmental glomerulosclerosis ( FSGS) and neurodevelopmental syndrome inherited in an autosomal dominant pattern. No pathogenic or likely pathogenic variants in COL4A3, COL4A4, or COL4A5 genes were detected. His neurological examination and developmental assessment were normal. However, an electroencephalogram(EEG) was done, which was normal. He was started on angiotensin-converting enzyme (ACE)inhibitors, and his proteinuria remains status co at the last follow-up. Parents were advised for genetic screening, but it has not been done yet.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe child\u0026rsquo;s clinical presentation and electron microscopy findings in the kidney biopsy were suggestive of collagenopathy. A mutation in genes associated with Alport syndrome (COL4A3, COL4A4, or COL4A5) was strongly suspected. However, electron microscopy findings mimicking Alport syndrome have been described in various other genetic mutations (refer to Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e],[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e],[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAlport syndrome mimickers in electron microscopy\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGene\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMode of inheritance\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eExtra renal manifestations\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGlomerular basement membrane(GBM)changes\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLMX1B\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDysplastic nails, Absent /hypoplastic patellae, Iliac horns (Nail patella syndrome)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIrregular thick and thin areas in the GBM with moth eaten appearance and deposition of type III collagen fibrils\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMYH9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMacro platelets, bleeding diatheses, neutrophil granules ,hearing loss, cataract(Ebstein/Fetchner syndrome)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFocal thickening, focal attenuation, and focal splitting of GBM\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMYO1E\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNone reported\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIrregular GBM thickening with the splitting of the lamina densa into interwoven thin layers, and marked irregularity of the inner and outer contours with subepithelial projections\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP3H2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEye manifestations (myopia, cataract)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIrregular thick and thin areas in the GBM\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eLMX1B- LIM homeobox transcription factor 1 beta, MYH9-Myosin heavy chain 9,non-muscle,\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eMYO1E-Myosin 1 E, P3H2\u003cb\u003e-\u003c/b\u003e prolyl 3-hydroxylase 2, AD-Autosomal dominant, AR-Autosomal recessive\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe TRIM8 gene codes for a tripartite motif-containing protein comprising 551 amino acids, which is involved in various biological processes, like differentiation, proliferation, intracellular signalling, and immunity. It acts as an E3 ubiquitin ligase and is widely expressed in the human body, particularly in the kidney, brain, and eyes. The TRIM protein facilitates proteasomal degradation of suppression of cytokine signalling1(SOC1) [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. To date, only 27 patients with TRIM8-mediated neurorenal syndrome have been reported, linked to 19 genetic variants in the TRIM8 gene, all of which were identified in exon 6 and resulted in a truncated protein [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. The variant found in our patient was also reported in exon six and resulted in a truncated protein. The most common neurological manifestation observed was developmental delay, followed by epilepsy; focal seizures were more prevalent than generalised seizures. Kidney manifestations were reported in 89% of patients [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Various case reports from around the world describe kidney manifestations ranging from nephrotic range proteinuria and nephrotic syndrome to chronic kidney disease [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Similarly, neurological manifestations are quite variable, with severe epileptic encephalopathy to milder symptoms. Some cases have reported a complete absence of neurological symptoms [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Mutations near the N-terminal were associated with severe neurological manifestations, while those near the C-terminal were linked to milder manifestations.\u003c/p\u003e \u003cp\u003eFocal segmental glomerulosclerosis (FSGS) has been observed in nearly all cases described so far [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Variable tubular manifestations, such as cystic dilatation of distal tubules, have also been noted. In contrast, our patient exhibited irregular thick and thin areas in the glomerular basement membrane, as shown in electron microscopy, which simulates collagenopathy. While we cannot definitively rule out unsampled FSGS with only 19 glomeruli examined in light microscopy. The basement membrane involvement resembling collagenopathy represents a novel finding that has not been documented previously.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eInitially, we overlooked the subtle neurological manifestation of febrile seizures and did not consider the possibility of neurorenal syndrome. If we had performed a gene panel for Alport syndrome, we may have missed the diagnosis. This highlights the importance of identifying the mimickers of Alport syndrome and including relevant genes in the analysis of such patients.\u003c/p\u003e \u003cp\u003e\u003cb\u003e Written informed consent was obtained from the family for reporting this case. There are no conflicts of interest or financial funding involved in this case\u003c/b\u003e.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003e-Krendel M, Leh S, Garone ME, Edwards-Richards A, Lin JJ, Brackman D, Knappskog P, Mikhailov A (2023) Focal segmental glomerulosclerosis and proteinuria associated with Myo1E mutations: novel variants and histological phenotype analysis. Pediatr Nephrol 38(2):439\u0026ndash;449. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s00467-022-05634-x\u003c/span\u003e\u003cspan address=\"10.1007/s00467-022-05634-x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e-Kopp JB (2010) Glomerular pathology in autosomal dominant MYH9 spectrum disorders: what are the clues telling us about disease mechanism? 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Am J Hum Genet 108(2):357\u0026ndash;367. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.ajhg.2021.01.008\u003c/span\u003e\u003cspan address=\"10.1016/j.ajhg.2021.01.008\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e-Lv Q, Niu Y, Xu Z, Qin J, Yang Z(2024)Variants loci and phenotype correlation of TRIM8-related neuro-renal syndrome: three cases reports and literature review. Front Neurol 15:1410187. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3389/fneur.2024.1410187\u003c/span\u003e\u003cspan address=\"10.3389/fneur.2024.1410187\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e-Shirai Y, Miura K, Kaneko N, Ishizuka K, Endo A, Hashimoto T, Kanda S, Harita Y, Hattori M(2021)A novel de novo truncating TRIM8 variant associated with childhood-onset focal segmental glomerulosclerosis without epileptic encephalopathy: a case report. BMC Nephrol 22:1\u0026ndash;8. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1186/s12882-021-02626-1\u003c/span\u003e\u003cspan address=\"10.1186/s12882-021-02626-1\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"pediatric-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pnep","sideBox":"Learn more about [Pediatric Nephrology](http://link.springer.com/journal/467)","snPcode":"467","submissionUrl":"https://www.editorialmanager.com/pnep/default2.aspx","title":"Pediatric Nephrology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"TRIM8, Collagenopathy, FSGS, neurorenal syndrome","lastPublishedDoi":"10.21203/rs.3.rs-5191613/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5191613/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eTripartite motif-containing 8 (TRIM8) gene mutations are associated with autosomal dominantly inherited neurorenal syndrome. The kidney manifestations range from nephrotic range proteinuria to nephrotic syndrome and kidney failure. The kidney histopathology was focal segmental glomerulosclerosis (FSGS) in all the reported cases. We now report a non-sense mutation in TRIM8 in a 1-year-old boy, mimicking collagenopathy in the kidney biopsy.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e","manuscriptTitle":"A non-sense mutation in the Tripartite motif containing 8 (TRIM8 ) gene, mimicking collagenopathy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-11-18 09:46:40","doi":"10.21203/rs.3.rs-5191613/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2024-11-17T14:23:59+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-11-14T16:16:38+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-11-14T16:15:42+00:00","index":"","fulltext":""},{"type":"submitted","content":"Pediatric Nephrology","date":"2024-11-14T03:46:49+00:00","index":"","fulltext":""},{"type":"decision","content":"Minor Revisions Needed","date":"2024-10-25T11:41:57+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"pediatric-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pnep","sideBox":"Learn more about [Pediatric Nephrology](http://link.springer.com/journal/467)","snPcode":"467","submissionUrl":"https://www.editorialmanager.com/pnep/default2.aspx","title":"Pediatric Nephrology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"12ce7455-ddde-4e08-a5f3-8da697818e23","owner":[],"postedDate":"November 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-12-23T16:13:52+00:00","versionOfRecord":{"articleIdentity":"rs-5191613","link":"https://doi.org/10.1007/s00467-024-06636-7","journal":{"identity":"pediatric-nephrology","isVorOnly":false,"title":"Pediatric Nephrology"},"publishedOn":"2024-12-21 15:57:32","publishedOnDateReadable":"December 21st, 2024"},"versionCreatedAt":"2024-11-18 09:46:40","video":"","vorDoi":"10.1007/s00467-024-06636-7","vorDoiUrl":"https://doi.org/10.1007/s00467-024-06636-7","workflowStages":[]},"version":"v1","identity":"rs-5191613","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5191613","identity":"rs-5191613","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}