PUS7 mutations impair pseudouridylation in humans and cause intellectual disability and microcephaly

Shaheen, Ranad; Tasak, Monika; Maddirevula, Sateesh; Abdel-Salam, Ghada M H; Sayed, Inas S. M.; Alazami, Anas M.; Al‐Sheddi, Tarfa; Alobeid, Eman; Phizicky, Eric M.; Alkuraya, Fowzan S.

doi:10.1007/s00439-019-01980-3

Cited by 64 publications

(37 citation statements)

References 44 publications

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“…31,[33][34][35] More recently, we have identified mutations in PUS3 (MIM: 616283) and PUS7 (MIM: 616261), encoding enzymes required for the modification of uridine in tRNA into pseudouridine, in individuals with ID. 36,37 Our finding of independent homozygous truncating variants in ALKBH8 in multiplex families with ID seems, therefore, consistent with above-described pattern of brain predilection to disorders of tRNA modification. 38 This is un-likely to be related to brain-specific expression of ALKBH8 because our analysis of LCL, derived from affected individuals' blood lymphocytes, seems to suggest a systemic deficiency of the wobble uridine modifications in tRNA.…”

supporting

confidence: 90%

Recessive Truncating Mutations in ALKBH8 Cause Intellectual Disability and Severe Impairment of Wobble Uridine Modification

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Alhomaidi

et al. 2019

The American Journal of Human Genetics

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The wobble hypothesis was proposed to explain the presence of fewer tRNAs than possible codons. The wobble nucleoside position in the anticodon stem-loop undergoes a number of modifications that help maintain the efficiency and fidelity of translation. AlkB homolog 8 (ALKBH8) is an atypical member of the highly conserved AlkB family of dioxygenases and is involved in the formation of mcm5s2U, (S)-mchm5U, (R)-mchm5U, mcm5U, and mcm5Um at the anticodon wobble uridines of specific tRNAs. In two multiplex consanguineous families, we identified two homozygous truncating ALKBH8 mutations causing intellectual disability. Analysis of tRNA derived from affected individuals showed the complete absence of these modifications, consistent with the presumptive loss of function of the variants. Our results highlight the sensitivity of the brain to impaired wobble modification and expand the list of intellectual-disability syndromes caused by mutations in genes related to tRNA modification.

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supporting

confidence: 90%

Recessive Truncating Mutations in ALKBH8 Cause Intellectual Disability and Severe Impairment of Wobble Uridine Modification

Monies

Vågbø

Alhomaidi

et al. 2019

The American Journal of Human Genetics

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“…Notably, defects in tRNA modification have emerged as the cause of diverse neurological and neurodevelopmental disorders, thereby highlighting the critical role of tRNA modification in human health and physiology (Angelova et al, 2018; Ramos & Fu, 2019). In particular, the brain appears to be sensitive to any perturbation in translation efficiency and fidelity brought about by defects in tRNA modifications, as evidenced from the numerous cognitive disorders linked to tRNA modification enzymes such as: the Elongator complex (Hawer et al, 2018; Kojic & Wainwright, 2016); ADAT3 (Alazami et al, 2013; El‐Hattab et al, 2016; Ramos, Han, et al, 2019); NSUN2 (Abbasi‐Moheb et al, 2012; Khan et al, 2012; Martinez et al, 2012); FTSJ1 (Dai et al, 2008; Freude et al, 2004; Froyen et al, 2007; Gong et al, 2008; Guy et al, 2015; Ramser et al, 2004; Takano et al, 2008); WDR4 (Chen et al, 2018; Shaheen et al, 2015; Trimouille et al, 2018); KEOPS complex (Braun et al, 2017); PUS3 (Abdelrahman, Al‐Shamsi, Ali, & Al‐Gazali, 2018; Shaheen, Han, et al, 2016); CTU2 (Shaheen, Al‐Salam, El‐Hattab, & Alkuraya, 2016; Shaheen, Mark, et al, 2019); TRMT10A (Gillis et al, 2014; Igoillo‐Esteve et al, 2013; Narayanan et al, 2015; Yew, McCreight, Colclough, Ellard, & Pearson, 2016; Zung et al, 2015); PUS7 (de Brouwer et al, 2018; Shaheen, Tasak, et al, 2019); and ALKBH8 (Monies, Vagbo, Al‐Owain, Alhomaidi, & Alkuraya, 2019).…”

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confidence: 99%

An intellectual disability‐associated missense variant in TRMT1 impairs tRNA modification and reconstitution of enzymatic activity

et al. 2020

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The human TRMT1 gene encodes an RNA methyltransferase enzyme responsible for catalyzing dimethylguanosine (m2,2G) formation in transfer RNAs (tRNAs). Frameshift mutations in TRMT1 have been shown to cause autosomal-recessive intellectual disability (ID) in the human population but additional TRMT1 variants remain to be characterized. Here, we describe a homozygous TRMT1 missense variant in a patient displaying developmental delay, ID, and epilepsy. The missense variant changes an arginine residue to a cysteine (R323C) within the methyltransferase domain and is expected to perturb protein folding. Patient cells expressing TRMT1-R323C exhibit a deficiency in m2,2G modifications within tRNAs, indicating that the mutation causes loss of function. Notably, the TRMT1 R323C mutant retains tRNA binding but is unable to rescue m2,2G formation in TRMT1-deficient human cells. Our results identify a pathogenic point mutation in TRMT1 that perturbs tRNA modification activity and demonstrate that m2,2G modifications are disrupted in the cells of patients with TRMT1-associated ID disorders.

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“…With recent advancements that unveiled various biomolecular functions of Y under different biological contexts, Y starts to capture broader interests of the scientific community (Schwartz et al, 2014;Carlile et al, 2014;Li X, et al, 2015;Karijolich et al, 2015;Dominissini et al, 2016;Penzo et al, 2017;Guzzi et al, 2018;Adachi et al, 2018;Shaheen et al, 2019). To date, a number of high-throughput approaches have been developed for profiling the transcriptome-wide distribution of Y (Adachi et al, 2019), including Pseudo-seq (Carlile et al, 2014), Y-seq (Schwartz et al, 2014), PSI-seq (Lovejoy et al, 2014), CeU-seq (Li X, et al, 2015), and RBS-seq (Khoddami et al, 2019).…”

Section: Resultsmentioning

confidence: 99%

PIANO: A Web Server for Pseudouridine-Site (Ψ) Identification and Functional Annotation

et al. 2020

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Known as the "fifth RNA nucleotide", pseudouridine (Y or psi) is the first-discovered and most abundant RNA modification occurring at the Uridine site, and it plays a prominent role in a number of biological processes. Thousands of Y sites have been identified within different biological contexts thanks to the advancement in high-throughput sequencing technology; nevertheless, the transcriptome-wide distribution, biomolecular functions, regulatory mechanisms, and disease relevance of pseudouridylation are largely elusive. We report here a web server-PIANO-for pseudouridine site (Y) identification and functional annotation. PIANO was built upon a high-accuracy predictor that takes advantage of both conventional sequence features and 42 additional genomic features. When tested on six independent datasets generated from four independent Y-profiling technologies (Y-seq, RBS-seq, Pseudo-seq, and CeU-seq) as benchmarks, PIANO achieved an average AUC of 0.955 and 0.838 under the full transcript and mature mRNA models, respectively, marking a substantial improvement in accuracy compared to the existing in silico Y-site prediction methods, i.e., PPUS (0.713 and 0.707), iRNA-PseU (0.713 and 0.712), and PseUI (0.634 and 0.652). Besides, PIANO web server systematically annotates the predicted Y sites with post-transcriptional regulatory mechanisms (miRNA-targets, RBP-binding regions, and splicing sites) in its prediction report to help the users explore potential machinery of Y. Moreover, a concise query interface was also built for 4,303 known Y sites, which is currently the largest collection of experimentally validated human Y sites. The PIANO website is freely accessible at: http:// piano.rnamd.com.

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PUS7 mutations impair pseudouridylation in humans and cause intellectual disability and microcephaly

Cited by 64 publications

References 44 publications

Recessive Truncating Mutations in ALKBH8 Cause Intellectual Disability and Severe Impairment of Wobble Uridine Modification

Recessive Truncating Mutations in ALKBH8 Cause Intellectual Disability and Severe Impairment of Wobble Uridine Modification

An intellectual disability‐associated missense variant in TRMT1 impairs tRNA modification and reconstitution of enzymatic activity

PIANO: A Web Server for Pseudouridine-Site (Ψ) Identification and Functional Annotation

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