Mutation in<i>ADAT3</i>, encoding adenosine deaminase acting on transfer RNA, causes intellectual disability and strabismus

Alazami, Anas M.; Hijazi, Hadia; Al‐Dosari, Mohammed S.; Shaheen, Ranad; Hashem, Amal Al; Aldahmesh, Mohammed A.; Mohamed, Jawahir Y.; Kentab, Amal Y.; Salih, Mustafa A.; Awaji, Ali; Masoodi, Tariq; Alkuraya, Fowzan S.

doi:10.1136/jmedgenet-2012-101378

Cited by 94 publications

(88 citation statements)

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“…No single gene accounted for more than 2% of the cases, with the exception of ADAT3 (6.5%), which was recently reported to be a cause of ID with strabismus. 6 Valid molecular karyotyping data were obtained for 183 patients. Based on the American College of Medical Genetics and Genomics standards and guidelines for interpretation and reporting of postnatal constitutional CNVs, 3 38 (21%) patients (a father/two sons trio with the same pathogenic CNV were counted once) were found to have pathogenic CNVs.…”

Section: Resultsmentioning

confidence: 99%

The clinical utility of molecular karyotyping for neurocognitive phenotypes in a consanguineous population

Al-Qattan

Wakil

Anazi

et al. 2015

Genetics in Medicine

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Section: Resultsmentioning

confidence: 99%

The clinical utility of molecular karyotyping for neurocognitive phenotypes in a consanguineous population

Al-Qattan

Wakil

Anazi

et al. 2015

Genetics in Medicine

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“…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. In addition, familial disautonomia is associated with mutations in hELP1 (IKBAKP) (Anderson et al 2001).…”

Section: Discussionmentioning

confidence: 99%

Conservation of an intricate circuit for crucial modifications of the tRNA^Phe anticodon loop in eukaryotes

Guy

Phizicky

2014

RNA

103

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Post-transcriptional tRNA modifications are critical for efficient and accurate translation, and have multiple different roles. Lack of modifications often leads to different biological consequences in different organisms, and in humans is frequently associated with neurological disorders. We investigate here the conservation of a unique circuitry for anticodon loop modification required for healthy growth in the yeast Saccharomyces cerevisiae. S. cerevisiae Trm7 interacts separately with Trm732 and Trm734 to 2 ′ -O-methylate three substrate tRNAs at anticodon loop residues C 32 and N 34 , and these modifications are required for efficient wybutosine formation at m 1 G 37 of tRNA Phe . Moreover, trm7Δ and trm732Δ trm734Δ mutants grow poorly due to lack of functional tRNA Phe . It is unknown if this circuitry is conserved and important for tRNA Phe modification in other eukaryotes, but a likely human TRM7 ortholog is implicated in nonsyndromic X-linked intellectual disability. We find that the distantly related yeast Schizosaccharomyces pombe has retained this circuitry for anticodon loop modification, that S. pombe trm7Δ and trm734Δ mutants have more severe phenotypes than the S. cerevisiae mutants, and that tRNA Phe is the major biological target. Furthermore, we provide evidence that Trm7 and Trm732 function is widely conserved throughout eukaryotes, since human FTSJ1 and THADA, respectively, complement growth defects of S. cerevisiae trm7Δ and trm732Δ trm734Δ mutants by modifying C 32 of tRNA Phe , each working with the corresponding S. cerevisiae partner protein. These results suggest widespread importance of 2 ′ -O-methylation of the tRNA anticodon loop, implicate tRNA Phe as the crucial substrate, and suggest that this modification circuitry is important for human neuronal development.

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“…Mutation of one hetADAR subunit, ADAT3, is found in families with inherited intellectual disability. 105 …”

Section: Brain Disease and Neuronal Behaviormentioning

confidence: 99%

Role of RNA modifications in brain and behavior

Jung

Goldman

2018

Genes Brain and Behavior

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Much progress in our understanding of RNA metabolism has been made since the first RNA nucleoside modification was identified in 1957. Many of these modifications are found in noncoding RNAs but recent interest has focused on coding RNAs. Here, we summarize current knowledge of cellular consequences of RNA modifications, with a special emphasis on neuropsychiatric disorders. We present evidence for the existence of an “RNA code,” similar to the histone code, that fine-tunes gene expression in the nervous system by using combinations of different RNA modifications. Unlike the relatively stable genetic code, this combinatorial RNA epigenetic code, or epitranscriptome, may be dynamically reprogrammed as a cause or consequence of psychiatric disorders. We discuss potential mechanisms linking disregulation of the epitranscriptome with brain disorders and identify potential new avenues of research.

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Mutation inADAT3, encoding adenosine deaminase acting on transfer RNA, causes intellectual disability and strabismus

Cited by 94 publications

References 20 publications

The clinical utility of molecular karyotyping for neurocognitive phenotypes in a consanguineous population

The clinical utility of molecular karyotyping for neurocognitive phenotypes in a consanguineous population

Conservation of an intricate circuit for crucial modifications of the tRNA^Phe anticodon loop in eukaryotes

Role of RNA modifications in brain and behavior

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Mutation inADAT3, encoding adenosine deaminase acting on transfer RNA, causes intellectual disability and strabismus

Cited by 94 publications

References 20 publications

The clinical utility of molecular karyotyping for neurocognitive phenotypes in a consanguineous population

The clinical utility of molecular karyotyping for neurocognitive phenotypes in a consanguineous population

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

Role of RNA modifications in brain and behavior

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Conservation of an intricate circuit for crucial modifications of the tRNA^Phe anticodon loop in eukaryotes