De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis
De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis
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DOI：
10.1016/j.ajhg.2021.01.008
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发表时间：
2021-02-04
影响因子：
9.8
通讯作者：
Sanna-Cherchi, Simone
中科院分区：
文献类型：
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作者：
Weng, Patricia L.;Majmundar, Amar J.;Sanna-Cherchi, Simone
局灶节段性肾小球硬化（FSGS）是激素抵抗性肾病综合征（SRNS）的主要病理基础，也是慢性肾脏疾病的主要原因。单基因形式的儿童SRNS主要是由隐性突变引起的，而从头变异（DNV）对这一性状的贡献知之甚少。使用外显子组测序（ES）在先证者与FSGS/SRNS，发育迟缓，癫痫，我们发现了一个无义DNV的TRIM 8，它编码的E3泛素连接酶三联基序含有8。为了确定TRIM 8变体是否代表FSGS的原因，我们汇总了2，501名儿科FSGS/SRNS受影响个体和48，556名对照受试者的外显子组/基因组测序数据，在受影响受试者中检测到8种杂合TRIM 8截短变体，但在对照受试者中没有检测到（p = 3.28 3 10（-11））。在所有6例具有可用亲本DNA的病例中，我们证明了从头遗传（p = 2.21 3 10（-15））。反向表型分析显示，在所有8个家庭的神经发育疾病。接下来，我们分析了来自9，067名癫痫患者的ES，产生了另外三个具有截短TRIM 8变体的家族。临床回顾显示所有患者均为FSGS。所有的TRIM 8变异体在551个氨基酸的蛋白质的残基390和487之间的最后一个外显子内引起蛋白质截短聚类，表明这种综合征与TRIM 8 C-末端区域的丢失之间的相关性。野生型TRIM 8在定位于核体的永生化人足细胞和神经元细胞中过表达，而含有患者特异性变体的构建体弥散性地错误定位于核质。共定位研究表明，双子座和卡哈尔机构经常邻接TRIM 8核体。截断TRIM 8 DNV通过异常TRIM 8定位引起神经肾综合征，涉及FSGS和发育性脑疾病中的核小体。
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 3 10(-11)). In all six cases with available parental DNA, we demonstrated de novo inheritance (p = 2.21 3 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.