TRMT10A dysfunction is associated with abnormalities in glucose homeostasis, short stature and microcephaly
TRMT10A dysfunction is associated with abnormalities in glucose homeostasis, short stature and microcephaly
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DOI：
10.1136/jmedgenet-2014-102282
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发表时间：
2014-09-01
影响因子：
4
通讯作者：
Elpeleg, Orly
中科院分区：
文献类型：
--
作者：
Gillis, David;Krishnamohan, Aiswarya;Elpeleg, Orly
Trm10是一种tRNA m(1)G(9)甲基转移酶，在酵母中修饰12种不同的tRNA物种，但在标准生长条件下被认为对生存能力不是必需的。在人类中，有三个Trm10同源物，一个线粒体和两个假定的细胞质。最近，一种细胞质同源基因（TRMT10A）的无义突变与小头畸形、智力残疾、身材矮小和青少年发病糖尿病有关。方法与结果研究对象为小头畸形、智力残疾、身材矮小、青春期延迟、癫痫发作、糖代谢紊乱（以高胰岛素型低血糖为主）的3例患者。利用全外显子组测序技术鉴定了TRMT10A基因的Gly206Arg （G206R）纯合子突变。该突变在家族中分离，在大型对照队列中不存在。以P-32 -tRNA(GCC)（Gly）转录本为底物的野生型（WT）和变体TRMT10A酶的甲基化活性测定揭示了一个惊人的缺陷(
Background Trm10 is a tRNA m(1)G(9) methyltransferase, which in yeast modifies 12 different tRNA species, yet is considered non-essential for viability under standard growth conditions. In humans, there are three Trm10 orthologs, one mitochondrial and two presumed cytoplasmic. A nonsense mutation in one of the cytoplasmic orthologs (TRMT10A) has recently been associated with microcephaly, intellectual disability, short stature and adolescent onset diabetes.Methods and results The subjects were three patients who suffered from microcephaly, intellectual disability, short stature, delayed puberty, seizures and disturbed glucose metabolism, mainly hyperinsulinaemic hypoglycaemia. A homozygous Gly206Arg (G206R) mutation in the TRMT10A gene was identified using whole exome sequencing. The mutation segregated in the family and was absent from large control cohorts. Determination of the methylation activity of the expressed wild-type (WT) and variant TRMT10A enzymes with transcripts of P-32 -tRNA(GCC)(Gly) as a substrate revealed a striking defect (