A null variant in <i>PUS3</i> confirms its involvement in intellectual disability and further delineates the associated neurodevelopmental disease

Abdelrahman, Hanadi A.; Al‐Shamsi, Aisha M.; Ali, Bassam R.; Al‐Gazali, Lihadh

doi:10.1111/cge.13443

Cited by 25 publications

(17 citation statements)

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“…It was reported that mutations in the PUS3 gene caused mental retardation‐55 (MRT55; MIM# 616283; Shaheen et al, ). A homozygous pathogenic variant in PUS3 has also been reported to cause brain development problems with brain atrophy and progressive microcephaly in a 4‐year‐old boy born to a consanguineous family (Abdelrahman, Al‐Shamsi, Ali, & Al‐Gazali, ). In our study, the Case 10 family had four malformed fetuses with similar clinical phenotypes including hydramnios, heart malformation and brain malformations.…”

Section: Discussionmentioning

confidence: 99%

Trio‐whole‐exome sequencing and preimplantation genetic diagnosis for unexplained recurrent fetal malformations

et al. 2019

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Whole-exome sequencing (WES) is widely used to detect genetic mutations that cause Mendelian diseases, and has been successfully applied in combination with preimplantation genetic diagnosis (PGD) to avoid the transmission of genetic defects.We investigated 40 nonconsanguineous families with unexplained, recurrent fetal malformations (two or more malformed fetuses) from May 2016 to December 2018.Using Trio-WES, we identified 32 disease-associated variants in 40 families (80% positive rate), which were subsequently verified. Known Mendelian diseases were identified in 12 families (30%), highly suspected Mendelian diseases in 12 families (30%), variants with uncertain significance in 8 families (20%), and no noticeable variants for 8 families (20%). Further analysis showed variants in 22 genes may cause fetal malformations. Four gene variants were detected in fetuses for the first time, which expanded the spectrum of the disease phenotype. Two novel candidate genes may be related to fetal malformations. Of 26 couples receiving PGD on diseaseassociated genes, 3 healthy newborns were delivered, and 4 couples are undergoing pregnancies. We reported the fetal data and developed an optimized genetic testing strategy. Our finding strongly suggests the presence of single gene Mendelian disorders in 60% of those families, and PGD services for couples to have healthy babies.

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Section: Discussionmentioning

confidence: 99%

Trio‐whole‐exome sequencing and preimplantation genetic diagnosis for unexplained recurrent fetal malformations

et al. 2019

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“…This observation is consistent with the proposal that reduced codon translation rates in the absence of mcm 5 s 2 U cause protein folding defects and aggregation of the nascent polypeptide. The finding that protein aggregation may also be induced in yeast by defects in other modifications, such as Ψ 38/39 or t 6 A [143,148] and that the very same defects in human cells cause related neurodegenerative/neurodevelopmental syndromes [41,47,60] provide solid support for the assumption that protein aggregation may represent an important trigger of neurodegenerative disease correlated with mutations in tRNA modifiers.…”

Section: A Role Of Protein Aggregation In Neurodegenerationmentioning

confidence: 99%

Roles of Elongator Dependent tRNA Modification Pathways in Neurodegeneration and Cancer

Hawer

Hammermeister

Ravichandran

et al. 2018

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Transfer RNA (tRNA) is subject to a multitude of posttranscriptional modifications which can profoundly impact its functionality as the essential adaptor molecule in messenger RNA (mRNA) translation. Therefore, dynamic regulation of tRNA modification in response to environmental changes can tune the efficiency of gene expression in concert with the emerging epitranscriptomic mRNA regulators. Several of the tRNA modifications are required to prevent human diseases and are particularly important for proper development and generation of neurons. In addition to the positive role of different tRNA modifications in prevention of neurodegeneration, certain cancer types upregulate tRNA modification genes to sustain cancer cell gene expression and metastasis. Multiple associations of defects in genes encoding subunits of the tRNA modifier complex Elongator with human disease highlight the importance of proper anticodon wobble uridine modifications (xm5U34) for health. Elongator functionality requires communication with accessory proteins and dynamic phosphorylation, providing regulatory control of its function. Here, we summarized recent insights into molecular functions of the complex and the role of Elongator dependent tRNA modification in human disease.

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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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A null variant in PUS3 confirms its involvement in intellectual disability and further delineates the associated neurodevelopmental disease

Cited by 25 publications

References 4 publications

Trio‐whole‐exome sequencing and preimplantation genetic diagnosis for unexplained recurrent fetal malformations

Trio‐whole‐exome sequencing and preimplantation genetic diagnosis for unexplained recurrent fetal malformations

Roles of Elongator Dependent tRNA Modification Pathways in Neurodegeneration and Cancer

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

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