Defects in tRNA anticodon loop 2′-O-methylation are implicated in nonsyndromic X-linked intellectual disability due to mutations in FTSJ1

摘要: tRNA modifications are crucial for efficient and accurate protein synthesis, modification defects frequently associated with disease. Yeast trm7Δ mutants grow poorly due to lack of 2'-O-methylated C32 (Cm32 ) Gm34 on tRNA(Phe) , catalyzed by Trm7-Trm732 Trm7-Trm734, respectively, which in turn results loss wybutosine at G37 . Mutations human FTSJ1, the likely TRM7 homolog, cause nonsyndromic X-linked intellectual disability (NSXLID), but role FTSJ1 is unknown. Here, we report that from two genetically independent cell lines NSXLID patients loss-of-function mutations nearly completely lacks Cm32 has reduced peroxywybutosine (o2yW37 ). Additionally, an patient a novel FTSJ1-p.A26P missense allele specifically normal levels o2yW37 corresponding Saccharomyces cerevisiae trm7-A26P mutant also not weaker Trm734 binding. These directly link defective 2'-O-methylation anticodon loop mutations, suggest NSXLID, may implicate as critical modification. underscore widespread conservation circuitry Trm7-dependent eukaryotic