A splice site mutation in the TSEN2 causes a new syndrome with craniofacial and central nervous system malformations, and atypical hemolytic uremic syndrome.
A splice site mutation in the TSEN2 causes a new syndrome with craniofacial and central nervous system malformations, and atypical hemolytic uremic syndrome.
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编码 tRNA 剪接核酸内切酶复合物四个亚基（TSEN54、TSEN34、TSEN15 和 TSEN2）的基因的隐性突变会导致各种形式的脑桥小脑发育不全，这是一种以小脑和脑桥发育不全、小头畸形、畸形和其他可变临床特征为特征的疾病。在这里，我们报告了基因 TSEN2 中的一个内含子隐性创始人变异，该变异导致来自四个近亲家庭的 6 名患有小头畸形、多发性颅面畸形、中枢神经系统放射学异常和不同严重程度的认知迟缓的个体中该基因的 mRNA 剪接异常。值得注意的是，与之前描述的 TSEN 复合体成分发生突变的患者不同，我们报告的所有个体在生命早期都出现了伴有血栓性微血管病、微血管病性溶血性贫血、血小板减少症、蛋白尿、严重高血压和终末期肾病 (ESKD) 的非典型溶血性尿毒症综合征 (aHUS)。对四名受影响个体的外周血细胞进行批量 RNA 测序，结果显示 tRNA 转录物异常，表明 tRNA 生物发生发生了改变。吗啡啉介导的斑马鱼 tsen2 外显子 10 的跳跃产生了与人类患者相似的表型。因此，我们发现了一种伴有 aHUS 的新综合征，表明 tRNA 生物学与血管内皮稳态之间存在联系，我们建议将其命名为缩写 TRACK 综合征（TSEN2 相关的非典型溶血性尿毒症综合征、颅面畸形、肾功能衰竭）。
Recessive mutations in the genes encoding the four subunits of the tRNA splicing endonuclease complex (TSEN54, TSEN34, TSEN15, and TSEN2) cause various forms of pontocerebellar hypoplasia, a disorder characterized by hypoplasia of the cerebellum and the pons, microcephaly, dysmorphisms, and other variable clinical features. Here, we report an intronic recessive founder variant in the gene TSEN2 that results in abnormal splicing of the mRNA of this gene, in six individuals from four consanguineous families affected with microcephaly, multiple craniofacial malformations, radiological abnormalities of the central nervous system, and cognitive retardation of variable severity. Remarkably, unlike patients with previously described mutations in the components of the TSEN complex, all the individuals that we report developed atypical hemolytic uremic syndrome (aHUS) with thrombotic microangiopathy, microangiopathic hemolytic anemia, thrombocytopenia, proteinuria, severe hypertension, and end-stage kidney disease (ESKD) early in life. Bulk RNA sequencing of peripheral blood cells of four affected individuals revealed abnormal tRNA transcripts, indicating an alteration of the tRNA biogenesis. Morpholino-mediated skipping of exon 10 of tsen2 in zebrafish produced phenotypes similar to human patients. Thus, we have identified a novel syndrome accompanied by aHUS suggesting the existence of a link between tRNA biology and vascular endothelium homeostasis, which we propose to name with the acronym TRACK syndrome (TSEN2 Related Atypical hemolytic uremic syndrome, Craniofacial malformations, Kidney failure).
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