Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Department of Pathology, Keck School of Medicine, LAC+USC Medical Center, University of Southern California, Los Angeles, CA, USA.
Pediatr Nephrol. 2020 Jun;35(6):1129-1132. doi: 10.1007/s00467-020-04525-3. Epub 2020 Mar 19.
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.
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.
局灶节段性肾小球硬化症（FSGS）是一种病因异质性疾病。遗传性 FSGS 可能仅局限于肾脏，或作为伴有其他全身受累的遗传综合征的一部分。分别至少有 21 种和 34 种基因与肾脏局限性 FSGS 和综合征性 FSGS 相关。TRIM8 基因编码一种三联基序蛋白，是一种 E3 泛素蛋白连接酶，可促进细胞因子信号转导抑制因子 1（SOCS1）的蛋白酶体降解，并参与干扰素-γ信号的激活。TRIM8 基因在包括肾脏和中枢神经系统（CNS）在内的各种组织中表达。TRIM8 基因突变与儿童发病的 FSGS 之间的关联尚未得到很好的证实。
我们描述了一名 8 岁西班牙裔男性，有婴儿期起病的运动和发育迟缓、癫痫发作和 FSGS 继发的蛋白尿。下一代测序显示 TRIM8 基因存在杂合性新生致病性变异（C1380T>A，p.Tyr460*）。使用抗 TRIM8 和抗 SOCS1 抗体的免疫组织化学染色显示肾脏活检组织中 TRIM8 表达不明显，SOCS1 表达强烈。
先前已在儿童发病的癫痫性脑病中报道过 TRIM8 的新生截断突变。对于 FSGS 伴中枢神经系统临床异常的儿童，应考虑进行 TRIM8 的分子分析。
