Mikako Warren1, Moe Takeda2, Arthur Partikian3, Lawrence Opas4, Richard Fine4, Shoji Yano5. 1. Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. 2. Department of Pathology, Keck School of Medicine, LAC+USC Medical Center, University of Southern California, Los Angeles, CA, USA. 3. Departments of Pediatrics and Neurology, LAC+USC Medical Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. 4. Pediatric Nephrology Division, LAC+USC Medical Center, Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. 5. Genetics Division, LAC+USC Medical Center, Department of Pediatrics, Keck School of Medicine, University of Southern California, 1801 Marengo Street General Laboratory Building Rm1G24, Los Angeles, CA, 90033, USA. syano@usc.edu.
Abstract
BACKGROUND: Focal segmental glomerulosclerosis (FSGS) is an etiologically heterogeneous disorder. Genetic FSGS may be either limited to the kidney or part of a genetic syndrome with other systemic involvement. At least 21 and 34 genes have been reported for renal-limited and syndromic FSGS, respectively. The TRIM8 gene encodes a tripartite motif protein, which is an E3 ubiquitin-protein ligase that promotes proteasomal degradation of the suppressor of cytokine signaling 1 (SOCS1) and participates in the activation of interferon-gamma signaling. The TRIM8 gene is expressed in various tissues including the kidney and the central nervous system (CNS). An association between a mutation in the TRIM8 gene and childhood-onset FSGS has not been well established. CASE-DIAGNOSIS: We describe an 8-year-old Hispanic male with infantile onset motor and developmental delay, seizures, and proteinuria secondary to FSGS. Next generation sequencing revealed a heterozygous de novo pathogenic variant in the TRIM8 gene (C1380T>A, p.Tyr460*). Immunohistochemical staining using anti-TRIM8 and anti-SOCS1 antibodies showed no significant TRIM8 expression and strong expression of SOCS1 in the renal biopsy tissue. TREATMENT AND CONCLUSIONS: De novo truncating mutations of TRIM8 have been previously reported in childhood-onset epileptic encephalopathy. A molecular analysis of TRIM8 should be considered in children with FSGS and clinical abnormalities of the central nervous system.
BACKGROUND:Focal segmental glomerulosclerosis (FSGS) is an etiologically heterogeneous disorder. Genetic FSGS may be either limited to the kidney or part of a genetic syndrome with other systemic involvement. At least 21 and 34 genes have been reported for renal-limited and syndromic FSGS, respectively. The TRIM8 gene encodes a tripartite motif protein, which is an E3 ubiquitin-protein ligase that promotes proteasomal degradation of the suppressor of cytokine signaling 1 (SOCS1) and participates in the activation of interferon-gamma signaling. The TRIM8 gene is expressed in various tissues including the kidney and the central nervous system (CNS). An association between a mutation in the TRIM8 gene and childhood-onset FSGS has not been well established. CASE-DIAGNOSIS: We describe an 8-year-old Hispanic male with infantile onset motor and developmental delay, seizures, and proteinuria secondary to FSGS. Next generation sequencing revealed a heterozygous de novo pathogenic variant in the TRIM8 gene (C1380T>A, p.Tyr460*). Immunohistochemical staining using anti-TRIM8 and anti-SOCS1 antibodies showed no significant TRIM8 expression and strong expression of SOCS1 in the renal biopsy tissue. TREATMENT AND CONCLUSIONS: De novo truncating mutations of TRIM8 have been previously reported in childhood-onset epilepticencephalopathy. A molecular analysis of TRIM8 should be considered in children with FSGS and clinical abnormalities of the central nervous system.
Entities:
Keywords:
Immunohistochemistry; Intellectual disability; Nephrotic syndrome; Nonsense mutation; Seizure; Suppressor of cytokine signaling 1 (SOCS1); Tripartite motif protein (TRIM)
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