Schlieben Lea D, Achleitner Melanie T, Bourke Billy, Diesner Max, Feichtinger René G, Fichtner Alexander, Flechtenmacher Christa, Hadzic Nedim, Hegarty Robert, Heilos Andreas, Janecke Andreas, Konstantopoulou Vassiliki, Lenz Dominic, Mayr Johannes A, Müller Thomas, Prokisch Holger, Vogel Georg F
School of Medicine, Institute of Human Genetics, Technical University of Munich, Munich, Germany.
Institute of Neurogenomics, Computational Health Center, Helmholtz Zentrum München, Neuherberg, Germany.
Hepatol Commun. 2024 Nov 29;8(12). doi: 10.1097/HC9.0000000000000598. eCollection 2024 Dec 1.
Pediatric acute liver failure (PALF) is a rare and life-threatening condition. In up to 50% of PALF cases, the underlying etiology remains unknown during routine clinical testing. This lack of knowledge complicates clinical management and liver transplantation decisions. Recently, whole-exome sequencing has identified genetic disorders in a large number of cases without specific laboratory biomarkers or metabolic fingerprints.
We describe how further analysis of whole-exome sequencing data combined with proteomic analyses in 5 previously unsolved PALF patients, where no pathogenic variants in genes previously associated with acute liver failure were identified, revealed rare biallelic variants in transient receptor potential cation channel subfamily M member 7 (TRPM7).
We establishe TRPM7 as a novel disease gene for PALF. Yet, the cation channel kinase TRPM7 has not been associated with any Mendelian disorder. No homozygous loss-of-function variants were found in in-house exomes or publicly available databases. Rare biallelic TRPM7-variants were significantly enriched in the PALF cohort compared with a pediatric control cohort. Viral infections preceded the majority of PALF episodes. Recurrent PALF episodes characterized the disease course with rapid progression, leading to early death in 3 cases. Proteomic analyses of patient fibroblasts unveiled significantly reduced TRPM7 protein levels, indicative of functional impairment. Severely reduced Mg2+ levels in one individual with a mutation in the channel domain suggests a potential interaction between disturbed Mg2+ homeostasis and PALF. The consistent presence of mutations in the TRPM7 protein-kinase-domain across all patients suggests its specific relevance in PALF.
Our data extend the genetic spectrum of recurrent PALF and prompt consideration of TRPM7 in children with unexplained liver failure.
小儿急性肝衰竭（PALF）是一种罕见且危及生命的疾病。在高达50%的PALF病例中，常规临床检测期间潜在病因仍不明确。这种知识的缺乏使临床管理和肝移植决策变得复杂。最近，全外显子测序在大量没有特定实验室生物标志物或代谢特征的病例中鉴定出了遗传疾病。
我们描述了如何对5例先前未解决的PALF患者的全外显子测序数据进行进一步分析，并结合蛋白质组学分析，这些患者在先前与急性肝衰竭相关的基因中未发现致病变异，但揭示了瞬时受体电位阳离子通道亚家族M成员7（TRPM7）中的罕见双等位基因变异。
我们确定TRPM7是PALF的一个新的疾病基因。然而，阳离子通道激酶TRPM7尚未与任何孟德尔疾病相关联。在内部外显子组或公开可用数据库中未发现纯合功能丧失变异。与儿科对照队列相比，罕见的双等位基因TRPM7变异在PALF队列中显著富集。大多数PALF发作之前有病毒感染。复发性PALF发作是该疾病病程的特征，进展迅速，导致3例患者早期死亡。对患者成纤维细胞的蛋白质组学分析显示TRPM7蛋白水平显著降低，表明功能受损。一名通道结构域突变个体中严重降低的Mg2+水平表明Mg2+稳态紊乱与PALF之间可能存在相互作用。所有患者的TRPM7蛋白激酶结构域中均一致存在突变，表明其在PALF中具有特定相关性。
我们的数据扩展了复发性PALF的遗传谱，并促使对不明原因肝衰竭儿童考虑TRPM7。
