Acute Infantile Liver Failure Due to Mutations in the TRMU Gene
Acute Infantile Liver Failure Due to Mutations in the TRMU Gene
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DOI：
10.1016/j.ajhg.2009.08.004
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发表时间：
2009-09-11
影响因子：
9.8
通讯作者：
Elpeleg, Orly
中科院分区：
文献类型：
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作者：
Zeharia, Avraham;Shaag, Avraham;Elpeleg, Orly
婴儿期急性肝功能衰竭伴乳酸性酸血症先前被证明是mtDNA耗竭的结果。我们报告了13例无血缘关系的婴儿，他们表现为急性肝衰竭和乳酸性酸血症，但mtDNA含量正常。其中4人在急性发作期间死亡，幸存者从未复发。最长的随访期为14年。通过纯合子定位，我们发现了TRMU基因的突变，该基因编码线粒体特异性tRNA修饰酶，tRNA 5-甲基胺甲基-2-硫尿嘧啶甲基转移酶。因此，线粒体trna的2-硫脲嘧啶化水平明显降低。鉴于硫是一种TRMU底物，其在新生儿期的可用性有限，我们建议存在TRMU突变患者发生肝功能衰竭的风险增加的时间窗口。
Acute liver failure in infancy accompanied by lactic acidemia was previously shown to result from mtDNA depletion. We report on 13 unrelated infants who presented with acute liver failure and lactic acidemia with normal mtDNA content. Four died during the acute episodes, and the survivors never had a recurrence. The longest follow-up period was 14 years. Using homozygosity mapping, we identified mutations in the TRMU gene, which encodes a mitochondria-specific tRNA-modifying enzyme, tRNA 5-methylaminomethyl-2-thiouridylate methyltransferase. Accordingly, the 2-thiouridylation levels of the mitochondrial tRNAs were markedly reduced. Given that sulfur is a TRMU substrate and its availability is limited during the neonatal period, we propose that there is a window of time whereby patients with TRMU mutations are at increased risk of developing liver failure.