Defects in tRNA Anticodon Loop 2'-O-Methylation Are Implicated in Nonsyndromic X-Linked Intellectual Disability due to Mutations in FTSJ1.
Defects in tRNA Anticodon Loop 2'-O-Methylation Are Implicated in Nonsyndromic X-Linked Intellectual Disability due to Mutations in FTSJ1.
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DOI：
10.1002/humu.22897
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发表时间：
2015-12
期刊：
影响因子：
3.9
通讯作者：
Phizicky EM
中科院分区：
文献类型：
--
作者：
Guy MP;Shaw M;Weiner CL;Hobson L;Stark Z;Rose K;Kalscheuer VM;Gecz J;Phizicky EM
TRNA修饰对于高效和准确的蛋白质合成是至关重要的，而修饰缺陷经常与疾病相关。酵母trm7Δ突变体由于在tRNAPhe上缺乏2‘-O-甲基化C32(Cm32)和Gm34而生长不良，分别由Trm7-Trm732和Trm7-Trm734催化，从而导致G37处Wybuosine的丢失。人类FTSJ1(可能是TRM7同源基因)的突变会导致非综合征性X-连锁智力残疾(NSXLID)，但FTSJ1在tRNA修饰中的作用尚不清楚。在这里，我们报告了来自两个遗传独立的FTSJ1突变缺失的NSXLID患者细胞系的tRNAPhe几乎完全缺乏Cm32和Gm34，并减少了过氧肌醇丁苷(O2yW37)。此外，一例具有新的FTSJ1-p.A26P错义等位基因的NSXLID患者的tRNAPhe特异性缺乏Gm34，但具有正常的Cm32和o2yW37水平。相应的酿酒酵母trm7-a26P突变体的tRNAPhe也特异性地缺乏Gm34，而Gm34的降低并不是由于Trm734结合较弱所致。这些结果直接将tRNA反密码子环的缺陷2‘-O甲基化与FTSJ1突变联系在一起，提示修饰缺陷导致NSXLID，并可能暗示tRNAPhe的Gm34是关键的修饰。这些结果也强调了真核生物tRNAPhe的Trm7依赖的反密码子环修饰电路的广泛保守性。
tRNA modifications are crucial for efficient and accurate protein synthesis, and modification defects are frequently associated with disease. Yeast trm7Δ mutants grow poorly due to lack of 2'-O-methylated C32 (Cm32) and Gm34 on tRNAPhe, catalyzed by Trm7-Trm732 and Trm7-Trm734 respectively, which in turn results in loss of wybutosine at G37. Mutations in human FTSJ1, the likely TRM7 homolog, cause non-syndromic X-linked intellectual disability (NSXLID), but the role of FTSJ1 in tRNA modification is unknown. Here we report that tRNAPhe from two genetically independent cell lines of NSXLID patients with loss of function FTSJ1 mutations nearly completely lacks Cm32 and Gm34, and has reduced peroxywybutosine (o2yW37). Additionally, tRNAPhe from an NSXLID patient with a novel FTSJ1-p.A26P missense allele specifically lacks Gm34, but has normal levels of Cm32 and o2yW37. tRNAPhe from the corresponding Saccharomyces cerevisiae trm7-A26P mutant also specifically lacks Gm34, and the reduced Gm34 is not due to weaker Trm734 binding. These results directly link defective 2'-O-methylation of the tRNA anticodon loop to FTSJ1 mutations, suggest that the modification defects cause NSXLID, and may implicate Gm34 of tRNAPhe as the critical modification. These results also underscore the widespread conservation of the circuitry for Trm7-dependent anticodon loop modification of eukaryotic tRNAPhe.