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

Monies, Dorota; Vågbø, Cathrine Broberg; Alhomaidi, Suzan; Alkuraya, Fowzan S.

doi:10.1016/j.ajhg.2019.03.026

Cited by 44 publications

(48 citation statements)

References 44 publications

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“…Neither had seizures, in contrast to the majority of subjects previously reported. Six out of seven affected individuals from both unrelated Saudi kindreds reported by Monies et al (2019) had a diagnosis of epilepsy with the latest age of onset being 2 years of age. Both affected siblings described herein display structural brain anomalies including mild to moderate cerebral volume loss, mild to moderate cerebellar vermian hypoplasia, variable degrees of thinning of the corpus callosum, and abnormal myelination for age on brain MRI, whereas abnormalities on brain MRI in the form of nonspecific arachnoid granulation were observed in only one out of the three affected individuals with brain imaging in Monies et al (2019).…”

Section: Discussionmentioning

confidence: 96%

Neurodevelopmental disorder in an Egyptian family with a biallelic ALKBH8 variant

Saad

Marafi

Mitani

et al. 2021

American J of Med Genetics Pt A

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Alkylated DNA repair protein AlkB homolog 8 (ALKBH8) is a member of the AlkB family of dioxygenases. ALKBH8 is a methyltransferase of the highly variable wobble nucleoside position in the anticodon loop of tRNA and thus plays a critical role in tRNA modification by preserving codon recognition and preventing errors in amino acid incorporation during translation. Moreover, its activity catalyzes uridine modifications that are proposed to be critical for accurate protein translation. Previously, two distinct homozygous truncating variants in the final exon of ALKBH8 were described in two unrelated large Saudi Arabian kindreds with intellectual developmental disorder and autosomal recessive 71 (MRT71) syndrome (MIM# 618504). Here, we report a third family—of Egyptian descent—harboring a novel homozygous frame‐shift variant in the last exon of ALKBH8. Two affected siblings in this family exhibit global developmental delay and intellectual disability as shared characteristic features of MRT71 syndrome, and we further characterize their observed dysmorphic features and brain MRI findings. This description of a third family with a truncating ALKBH8 variant from a distinct population broadens the phenotypic and genotypic spectrum of MRT71 syndrome, affirms that perturbations in tRNA biogenesis can contribute to neurogenetic disease traits, and firmly establishes ALKBH8 as a novel neurodevelopmental disease gene.

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Section: Discussionmentioning

confidence: 96%

Neurodevelopmental disorder in an Egyptian family with a biallelic ALKBH8 variant

Saad

Marafi

Mitani

et al. 2021

American J of Med Genetics Pt A

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“…For example, mouse KO of the tRNA modification enzyme Alkbh8 caused mismodification of several distinct tRNA isoacceptors at the critical wobble uridine position, but gave no overt phenotype 29 , 30 . However, later studies showed defects in selenoprotein synthesis and stress tolerance in the Alkbh8 KO mice 31 , 32 , and it was recently reported that homozygous inactivating mutations in the human ALKBH8 gene causes intellectual disability and general developmental delay 33 . Likewise, more detailed studies, e.g.…”

Section: Discussionmentioning

confidence: 99%

The methyltransferase METTL9 mediates pervasive 1-methylhistidine modification in mammalian proteomes

et al. 2021

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Post-translational methylation plays a crucial role in regulating and optimizing protein function. Protein histidine methylation, occurring as the two isomers 1- and 3-methylhistidine (1MH and 3MH), was first reported five decades ago, but remains largely unexplored. Here we report that METTL9 is a broad-specificity methyltransferase that mediates the formation of the majority of 1MH present in mouse and human proteomes. METTL9-catalyzed methylation requires a His-x-His (HxH) motif, where “x” is preferably a small amino acid, allowing METTL9 to methylate a number of HxH-containing proteins, including the immunomodulatory protein S100A9 and the NDUFB3 subunit of mitochondrial respiratory Complex I. Notably, METTL9-mediated methylation enhances respiration via Complex I, and the presence of 1MH in an HxH-containing peptide reduced its zinc binding affinity. Our results establish METTL9-mediated 1MH as a pervasive protein modification, thus setting the stage for further functional studies on protein histidine methylation.

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

Cited by 44 publications

References 44 publications

Neurodevelopmental disorder in an Egyptian family with a biallelic ALKBH8 variant

Neurodevelopmental disorder in an Egyptian family with a biallelic ALKBH8 variant

The methyltransferase METTL9 mediates pervasive 1-methylhistidine modification in mammalian proteomes

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

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