A loss‐of‐function mutation in the FTSJ1 gene causes nonsyndromic X‐linked mental retardation in a japanese family

Abstract

Mental retardation (MR) is a common trait, affecting approximately 2-3% of individuals in the general population. Although the etiology of MR remains largely unknown, genetics apparently play a major role. Recent molecular studies of X-linked form of MR in European and North American countries have revealed 24 nonsyndromic X-linked mental retardation (NS-XLMR) genes including FTSJ1, a human homolog of the Escherichia coli 2'-O-rRNA methyltransferase FtsJ/RrmJ gene. Here we identified a novel FTSJ1 mutation in an XLMR family through mutation screening of a cohort of 73 unrelated Japanese male probands with MR. Sequence analysis of the proband and his mother revealed a G > A substitution at the consensus for the donor splicing site in intron 8 (c.571 + 1G > A) of FTSJ1. This mutation prevented the removal intron 8 from the pre-mRNA, thereby leading to a frameshift in the mutant FTSJ1 mRNA and resulting in a premature termination in exon 9. Quantitative RT-PCR showed a significant reduction of mutant FTSJ1 mRNA in the patient's lymphoblast cells, which was restored by treatment with cycloheximide, a potent inhibitor of nonsense-mediated mRNA decay (NMD). Therefore, mRNAs carrying this mutation are likely subject to degradation by NMD. Together, loss-of-function of FTSJ1 may be a mechanism for the cognitive dysfunction observed in this family. Our study also suggested that the FTSJ1 mutation probably accounts for XLMR in Japanese at a similar frequency (1-2%) as in Europeans.

Conservation of an intricate circuit for crucial modifications of the tRNAPhe anticodon loop in eukaryotes

“…the wild type strain, whereas an S. cerevisiae trm734Δ mutant had 1.06-fold difference in generation time. Furthermore, our identification of FTSJ1 as the human Sc TRM7 ortholog suggests that defects in the human gene result in a relatively mild, albeit medically serious, condition, since FTSJ1 splice site, nonsense, and deletion mutations are consistently associated with NSXLID (Freude et al 2004;Ramser et al 2004;Froyen et al 2007;Takano et al 2008). NSXLID may occur in these patients because specific human tRNAs have a greater requirement for Trm7 modification in development of the central nervous system (CNS) than in other tissues; indeed, recent results suggest that mutation of a tRNA isodecoder expressed specifically in the CNS can lead to ribosome stalling and contribute to neurodegeneration in certain mutant mouse strains (Ishimura et al 2014).…”

“…NSXLID associated with defective FTSJ1 (Freude et al 2004;Ramser et al 2004;Froyen et al 2007;Takano et al 2008) adds to a growing list of neurological disorders associated with defective tRNA modification. This list includes intellectual disability associated with a point mutation in hADAT3 , the predicted homolog of a subunit of the yeast tRNA A 34 deaminase (Alazami et al 2013); a frameshift mutation in hTRMT1 (Najmabadi et al 2011), which has tRNA m 2,2 G 26 (N 2 ,N 2 -dimethylguanosine) methyltransferase activity (Liu and Strâby 2000); mutations in NSUN2 (AbbasiMoheb et al 2012;Khan et al 2012;Martinez et al 2012), which modifies C 34 , C 48 , C 49 , and C 50 on target tRNAs to m 5 C; and mutations in hELP2 (Najmabadi et al 2011), a member of the ELP complex responsible for formation of the cm 5 U moiety found on mcm 5 U 34 , ncm 5 U 34 , mcm 5 s 2 U 34 and related modifications.…”

“…It also appears that TRM7 has an important but differing biological impact on different organisms, since a high throughput screen in S. pombe indicated that the putative TRM7 gene was essential (Kim et al 2010), and since mutations in a putative human TRM7 homolog (FTSJ1) are associated with nonsyndromic X-linked intellectual disability (NSXLID) (Freude et al 2004;Ramser et al 2004;Froyen et al 2007;Takano et al 2008).…”

Yeast Trm7 interacts with distinct proteins for critical modifications of the tRNAPhe anticodon loop

“…Since both WD40 repeats (Stirnimann et al 2010) and Armadillo repeats (Tewari et al 2010) (Juhling et al 2009), and a substantial portion of the tRNA Phe from neuroblastoma cells and Ehrlich ascites tumors lacks Cm 32 and Gm 34 , and has m 1 G 37 instead of yW 37 (Kuchino et al 1982). Furthermore, high-throughput analysis suggests that the putative Schizosaccharomyces pombe TRM7 gene is essential (Kim et al 2010), and numerous studies implicate the putative human homolog FTSJ1 in nonsyndromic X-linked mental retardation (Freude et al 2004;Ramser et al 2004;Froyen et al 2007;Takano et al 2008). Based on these observations, it is tempting to speculate that the circuitry for Trm7 modification of the anticodon loop is conserved and that these modifications are widely important for tRNA Phe function.…”

“…Second, Trm7 and its modifications are associated with human disorders. Thus, mutations in the putative TRM7 homolog FTSJ1, which result in truncated polypeptides, have been strongly associated with nonsyndromic X-linked mental retardation in multiple studies (Freude et al 2004;Ramser et al 2004;Froyen et al 2007;Takano et al 2008), and tRNA…”