RINT1 Bi-allelic Variations Cause Infantile-Onset Recurrent Acute Liver Failure and Skeletal Abnormalities
RINT1 Bi-allelic Variations Cause Infantile-Onset Recurrent Acute Liver Failure and Skeletal Abnormalities
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RINT1 双等位基因变异导致婴儿期复发性急性肝衰竭和骨骼异常。
DOI：
10.1016/j.ajhg.2019.05.011
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发表时间：
2019-07-03
影响因子：
9.8
通讯作者：
Klee, Eric W.
中科院分区：
文献类型：
--
作者：
Cousin, Margot A.;Conboy, Erin;Klee, Eric W.
小儿急性肝衰竭（ALF）是危及生命的遗传，免疫和环境的病因。大约一半的病例仍然无法解释。复发性ALF （RALF）在婴儿描述严重肝损伤的反复发作与肝功能恢复之间的危机。我们将双等位基因RINT1改变描述为包括RALF和骨骼异常在内的多系统疾病的原因。三个不相关的RALF发病个体，在反式中有错义（p.Ala368Thr或p.Leu370Pro）或帧内缺失（p.Val618_Lys619del）。ALF发作伴发发热/感染，并不是所有患者在发作之间的肝功能检查都完全正常。肝活检显示非特异性肝损伤，包括纤维化、脂肪变性或Kupffer细胞轻度增加。骨骼成像显示异常影响脊椎和骨盆。真皮成纤维细胞显示剪接变异介导的外显子9跳变，导致框外产物和无义介导的转录物衰变。与对照组相比，成纤维细胞也显示RINT1蛋白减少，高尔基形态异常，自噬通量受损。RINT1与NBAS相互作用，最近涉及RALF和UVRAG，促进高尔基到内质网的逆行囊泡运输。在营养物质耗竭或感染时，高尔基体到内质网的转运受到抑制，mTOR通过UVRAG调控促进自噬。异常自噬与类似骨骼异常和肝脏疾病的发展有关，这表明这些RINT1功能的破坏可能解释了肝脏和骨骼的发现。阐明这种基因-疾病关系的病理机制可能为治疗提供机会。
Pediatric acute liver failure (ALF) is life threatening with genetic, immunologic, and environmental etiologies. Approximately half of all cases remain unexplained. Recurrent ALF (RALF) in infants describes repeated episodes of severe liver injury with recovery of hepatic function between crises. We describe bi-allelic RINT1 alterations as the cause of a multisystem disorder including RALF and skeletal abnormalities. Three unrelated individuals with RALF onset A or G>T) in trans with a missense (p.Ala368Thr or p.Leu370Pro) or in-frame deletion (p.Val618_Lys619del) in RINT1. ALF episodes are concomitant with fever/infection and not all individuals have complete normalization of liver function testing between episodes. Liver biopsies revealed nonspecific liver damage including fibrosis, steatosis, or mild increases in Kupffer cells. Skeletal imaging revealed abnormalities affecting the vertebrae and pelvis. Dermal fibroblasts showed splice-variant mediated skipping of exon 9 leading to an out-of-frame product and nonsense-mediated transcript decay. Fibroblasts also revealed decreased RINT1 protein, abnormal Golgi morphology, and impaired autophagic flux compared to control. RINT1 interacts with NBAS, recently implicated in RALF, and UVRAG, to facilitate Golgi-to-ER retrograde vesicle transport. During nutrient depletion or infection, Golgi-to-ER transport is suppressed and autophagy is promoted through UVRAG regulation by mTOR. Aberrant autophagy has been associated with the development of similar skeletal abnormalities and also with liver disease, suggesting that disruption of these RINT1 functions may explain the liver and skeletal findings. Clarifying the pathomechanism underlying this gene-disease relationship may inform therapeutic opportunities.