Clinical and molecular delineation of <scp><i>PUS3</i></scp>‐associated neurodevelopmental disorders

Nøstvik, Miriam; Kateta, Sarah M.; Schönewolf‐Greulich, Bitten; Afenjar, Alexandra; Barth, Magalie; Boschann, Felix; Doummar, Diane; Haack, Tobias B.; Keren, Boris; Лившиц, Л. А.; Mei, Davide; Park, Joo Hyun; Pisano, Tiziana; Prouteau, Clément; Umair, Muhammad; Waqas, Ahmed; Ziegler, Alban; Guerrini, Renzo; Møller, Rikke S.; Tümer, Zeynep

doi:10.1111/cge.14051

Cited by 27 publications

(19 citation statements)

References 17 publications

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“…Novel gene discoveries have introduced a new emerging ID group associated with tRNA modifications, namely, the ADAT3 gene, which edits adenosine to inosine at the wobble position 34 of mature tRNA ( Alazami et al, 2013 ). Other genes include NSUN2 ( Abbasi-Moheb et al, 2012 ), WDR4 ( Shaheen et al, 2015 ), TRMT10A ( Igoillo-Esteve et al, 2013 ), TRIT1 ( Yarham et al, 2014 ; Kernohan et al, 2017 ), TRMT1 ( Najmabadi et al, 2011 ), ELP2 ( Najmabadi et al, 2011 ), PUS3 ( Nøstvik et al, 2021 ), and FTSJ1 ( Freude et al, 2004 ).…”

Section: Discussionmentioning

confidence: 99%

“…The human brain is susceptible, and defects in tRNA modifications and mutations in specific genes involved in posttranscriptional modifications can be attributed to causing severe neurological disorders ( Bednářová et al, 2017 ). tRNA modifications have been reported to cause ID phenotypes in humans, such as PUS3 (OMIM 616283), which isomerizes uracil to pseudouridine in human tRNA homozygous pathogenic mutations in PUS3 causing autosomal recessive ID (OMIM 617051; Nøstvik et al, 2021 ). In addition, methylation of tRNA at specific residues is performed by the FTSJ1 (OMIM 300499), and mutations in these genes lead to non-syndromic X-linked mental retardation and ID ( Guy et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

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Case Report: Biallelic Variant in the tRNA Methyltransferase Domain of the AlkB Homolog 8 Causes Syndromic Intellectual Disability

Waqas

Nayab

Shaheen³

et al. 2022

Front. Genet.

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Intellectual disability (ID) has become very common and is an extremely heterogeneous disorder, where the patients face many challenges with deficits in intellectual functioning and adaptive behaviors. A single affected family revealed severe disease phenotypes such as ID, developmental delay, dysmorphic facial features, postaxial polydactyly type B, and speech impairment. DNA of a single affected individual was directly subjected to whole exome sequencing (WES), followed by Sanger sequencing. Data analysis revealed a novel biallelic missense variant (c.1511G>C; p.(Trp504Ser)) in the ALKBH8 gene, which plays a significant role in tRNA modifications. Our finding adds another variant to the growing list of ALKBH8-associated tRNA modifications causing ID and additional phenotypic manifestations. The present study depicts the key role of the genes associated with tRNA modifications, such as ALKBH8, in the development and pathophysiology of the human brain.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Case Report: Biallelic Variant in the tRNA Methyltransferase Domain of the AlkB Homolog 8 Causes Syndromic Intellectual Disability

Waqas

Nayab

Shaheen³

et al. 2022

Front. Genet.

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“…PUS3 mutations can cause a rare neurodevelopmental disorder [144]. Recently, a novel homozygous truncating mutation in PUS3 was found to be associated with intellectual impairment, patients with this mutation had dropped levels of uracil isomerization at tRNA positions 38 and 39 [145].…”

Section: ψ and The Nervous Systemmentioning

confidence: 99%

tRNA Modifications and Modifying Enzymes in Disease, the Potential Therapeutic Targets

Cui¹,

Zhao²,

Jiang³

et al. 2023

Int. J. Biol. Sci.

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tRNA is one of the most conserved and abundant RNA species, which plays a key role during protein translation. tRNA molecules are post-transcriptionally modified by tRNA modifying enzymes. Since high-throughput sequencing technology has developed rapidly, tRNA modification types have been discovered in many research fields. In tRNA, numerous types of tRNA modifications and modifying enzymes have been implicated in biological functions and human diseases. In our review, we talk about the relevant biological functions of tRNA modifications, including tRNA stability, protein translation, cell cycle, oxidative stress, and immunity. We also explore how tRNA modifications contribute to the progression of human diseases. Based on previous studies, we discuss some emerging techniques for assessing tRNA modifications to aid in discovering different types of tRNA modifications.

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“…Mutations in PUS7 have been identified in several individuals suffering from severe neurodevelopmental and growth delay (de Brouwer et al, 2018 ). Several pathogenic PUS3 variants (MIM# 617051), including homozygous and compound heterozygous variants, have been suggested to be causative for intellectual disorder syndromes, microcephaly, and severe growth deficiency (Bykhovskaya et al, 2004 ; Metodiev et al, 2015 ; Nøstvik et al, 2021 ; Shaheen et al, 2016 , 2019 ). Most of the pathogenic/likely pathogenic variants were neither tested in vitro nor their effects in cells.…”

Section: Introductionmentioning

confidence: 99%

Destabilization of mutated human PUS3 protein causes intellectual disability

et al. 2022

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Pseudouridine (Ψ) is an RNA base modification ubiquitously found in many types of RNAs. In humans, the isomerization of uridine is catalyzed by different stand-alone pseudouridine synthases (PUS). Genomic mutations in the human pseudouridine synthase 3 gene (PUS3) have been identified in patients with neurodevelopmental disorders. However, the underlying molecular mechanisms that cause the disease phenotypes remain elusive. Here, we utilize exome sequencing to identify genomic variants that lead to a homozygous amino acid substitution (p.[(Tyr71Cys)];[(-Tyr71Cys)]) in human PUS3 of two affected individuals and a compound heterozygous substitution (p.[(Tyr71Cys)];[(Ile299Thr)]) in a third patient. We obtain wild-type and mutated full-length human recombinant PUS3 proteins and characterize the enzymatic activity in vitro. Unexpectedly, we find that the p.Tyr71Cys substitution neither affect tRNA binding nor pseudouridylation activity in vitro, but strongly impair the thermostability profile of PUS3, while the p.Ile299Thr mutation causes protein aggregation. Concomitantly, we observe that the PUS3 protein levels as well as the level of PUS3-dependent Ψ levels are strongly reduced in fibroblasts derived from all three patients. In summary, our results directly

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Clinical and molecular delineation of PUS3‐associated neurodevelopmental disorders

Cited by 27 publications

References 17 publications

Case Report: Biallelic Variant in the tRNA Methyltransferase Domain of the AlkB Homolog 8 Causes Syndromic Intellectual Disability

Case Report: Biallelic Variant in the tRNA Methyltransferase Domain of the AlkB Homolog 8 Causes Syndromic Intellectual Disability

tRNA Modifications and Modifying Enzymes in Disease, the Potential Therapeutic Targets

Destabilization of mutated human PUS3 protein causes intellectual disability

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