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

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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.

Original languageEnglish
Pages (from-to)357-367
Number of pages11
JournalAmerican Journal of Human Genetics
Volume108
Issue number2
DOIs
Publication statusPublished - 4 Feb 2021

Bibliographical note

Funding Information:
F.H. is the William E. Harmon Professor of Pediatrics. This research is supported by grants from the NIH to F.H. ( DK-076683-13 ) and to S.S.-C., F.H., and M.R.P. ( RC2-DK122397 ); from the DoD to S.S.-C. ( GRANT12019690 ); and by the NCATS to S.S.-C. ( UL1-TR001873 ). A.J.M. was supported by grants from the NIH ( T32DK-007726 , 5K12HD052896-13 ), ASN Lipps Research Program PKD Foundation Fellowship and Foundation for Kidney Research ( FP01025169 ), and by Boston Children’s Hospital Manton Center for Orphan Disease Research. K.K. was funded by an International Research Support Initiative Program fellowship from the Higher Education Commission of Pakistan . Sequencing by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) was funded by the NHGRI , the NEI , and the NHLBI grant UM1-HG008900 and, partly, NHGRI ( R01-HG009141 ). CUIMC cohort sequencing was partly supported by AstraZeneca Centre for Genomics Research , Precision Medicine and Genomics, IMED Biotech Unit, Cambridge, United Kingdom. The Yale CMG ( UM1-HG006504 ) is funded by the NHGRI . The GSP Coordinating Center ( U24-HG008956 ) provided logistical and general study coordination. Research reported in this manuscript was supported by the NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH ( U01-HG007672 and U01-HG007942 ). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Sequencing for studies by M.A.S. was funded by the NIHR Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, London, UK. M.A.S is supported by a Medical Research Council , Precision Medicine award.

Funding Information:
F.H. is the William E. Harmon Professor of Pediatrics. This research is supported by grants from the NIH to F.H. (DK-076683-13) and to S.S.-C. F.H. and M.R.P. (RC2-DK122397); from the DoD to S.S.-C. (GRANT12019690); and by the NCATS to S.S.-C. (UL1-TR001873). A.J.M. was supported by grants from the NIH (T32DK-007726, 5K12HD052896-13), ASN Lipps Research Program PKD Foundation Fellowship and Foundation for Kidney Research (FP01025169), and by Boston Children's Hospital Manton Center for Orphan Disease Research. K.K. was funded by an International Research Support Initiative Program fellowship from the Higher Education Commission of Pakistan. Sequencing by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) was funded by the NHGRI, the NEI, and the NHLBI grant UM1-HG008900 and, partly, NHGRI (R01-HG009141). CUIMC cohort sequencing was partly supported by AstraZeneca Centre for Genomics Research, Precision Medicine and Genomics, IMED Biotech Unit, Cambridge, United Kingdom. The Yale CMG (UM1-HG006504) is funded by the NHGRI. The GSP Coordinating Center (U24-HG008956) provided logistical and general study coordination. Research reported in this manuscript was supported by the NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH (U01-HG007672 and U01-HG007942). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Sequencing for studies by M.A.S. was funded by the NIHR Biomedical Research Centre based at Guy's and St Thomas? NHS Foundation Trust and King's College London, London, UK. M.A.S is supported by a Medical Research Council, Precision Medicine award.

Publisher Copyright:
© 2021 American Society of Human Genetics

Keywords

  • Adult
  • Animals
  • Carrier Proteins/chemistry
  • Cell Line
  • Child
  • Child, Preschool
  • Codon, Nonsense
  • Developmental Disabilities/genetics
  • Epilepsy/genetics
  • Female
  • Glomerulosclerosis, Focal Segmental/genetics
  • Humans
  • Intranuclear Space/metabolism
  • Kidney/metabolism
  • Male
  • Mice
  • Mutation
  • Nephrotic Syndrome/genetics
  • Nerve Tissue Proteins/chemistry
  • Phenotype
  • Podocytes/metabolism
  • Whole Exome Sequencing

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