Zeharia Avraham, Shaag Avraham, Pappo Orit, Mager-Heckel Anne-Marie, Saada Ann, Beinat Marine, Karicheva Olga, Mandel Hanna, Ofek Noa, Segel Reeval, Marom Daphna, Rötig Agnes, Tarassov Ivan, Elpeleg Orly
Department of Human Genetics and Metabolic Diseases, Hadassah, the Hebrew University Medical Center, Jerusalem, Israel.
Am J Hum Genet. 2009 Sep;85(3):401-7. doi: 10.1016/j.ajhg.2009.08.004.
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.
先前研究表明，婴儿期急性肝衰竭伴乳酸血症是由线粒体DNA耗竭所致。我们报告了13例无亲缘关系的婴儿，他们表现为急性肝衰竭和乳酸血症，但线粒体DNA含量正常。4例在急性发作期死亡，幸存者均未复发。最长随访期为14年。通过纯合子定位，我们在TRMU基因中发现了突变，该基因编码一种线粒体特异性tRNA修饰酶，即tRNA 5-甲基氨基甲基-2-硫尿苷酸甲基转移酶。相应地，线粒体tRNA的2-硫尿苷酸化水平显著降低。鉴于硫是TRMU的底物，且在新生儿期其可用性有限，我们提出，存在一个时间窗，在此期间TRMU突变患者发生肝衰竭的风险增加。
