Further delineation of <i>METTL23</i>‐associated intellectual disability

Almannai, Mohammed; Obaid, Osama; Faqeih, Eissa; Alasmari, Ali; Samman, Manar; Pinz, Hailey; Braddock, Stephen R.; Alkuraya, Fowzan S.

doi:10.1002/ajmg.a.61503

Cited by 8 publications

(9 citation statements)

References 15 publications

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“…Mutations in this gene have been associated with mild recessive ID. The METTL23 variant identified in our patients shows close clinical similarity with the features reported previously [ 16 , 17 , 20 , 21 , 22 ]. METTL23 (MIM 615262) belongs to a small family of methyltransferases, having several potential functions including the regulation of chaperone proteins, protein folding, DNA repair, histone modification, splicing factor regulation and signal transduction [ 17 ].…”

Section: Discussionsupporting

confidence: 87%

“…To date, nine disease-causing variants in METTL23 have been associated with ID ( Supplementary Table S1 ). While this small single domain protein seems to exclude specific genotype–phenotype correlations, all AR or compound heterozygous variants reported so far in METTL23 have been associated with ID with various degrees of facial dysmorphism [ 16 , 17 , 20 , 21 ]. This is also the case for the two patients presented here, who have several common features with previously reported cases including large eyes, short upturned nose, flat nasal bridge and thin lips.…”

Section: Discussionmentioning

confidence: 99%

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Two Cases of Recessive Intellectual Disability Caused by NDST1 and METTL23 Variants

Khan

Miao

Umair

et al. 2020

Genes

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Intellectual disability (ID) is a highly heterogeneous genetic condition with more than a thousand genes described so far. By exome sequencing of two consanguineous families presenting hallmark features of ID, we identified two homozygous variants in two genes previously associated with autosomal recessive ID: NDST1 (c.1966G>A; p.Asp656Asn) and METTL23 (c.310T>C; p.Phe104Leu). The segregation of the variants was validated by Sanger sequencing in all family members. In silico homology modeling of wild-type and mutated proteins revealed substantial changes in the secondary structure of both proteins, indicating a possible effect on function. The identification and validation of new pathogenic NDST1 and METTL23 variants in two cases of autosomal recessive ID further highlight the importance of these genes in proper brain function and development.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Two Cases of Recessive Intellectual Disability Caused by NDST1 and METTL23 Variants

Khan

Miao

Umair

et al. 2020

Genes

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“…We found that haploinsufficiency of METTL23 is sufficient to impede the dimethylation of histone H3R17, thereby inducing NTG. Several pathogenic variants of METTL23 are associated with familial intellectual disability in Caucasian, Arab, and Pakistani pedigrees (53)(54)(55)(56)(57), suggesting etiologic links between arginine methylation, nervous system disorders and glaucoma.…”

Section: Discussionmentioning

confidence: 99%

METTL23 mutation alters histone H3R17 methylation in normal-tension glaucoma

Pan¹,

Suga²,

Kimura³

et al. 2022

Journal of Clinical Investigation

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Normal-tension glaucoma (NTG) is a heterogeneous disease characterized by retinal ganglion cell (RGC) death leading to cupping of the optic nerve head and visual field loss at normal intraocular pressure (IOP). The pathogenesis of NTG remains unclear.Here, we describe a single nucleotide mutation in exon 2 of the methyltransferase like 23 (METTL23) gene identified in a three-generation Japanese NTG family. This mutation caused METTL23 mRNA aberrant splicing, which abolished normal protein production and altered subcellular localization. Mettl23 knock-in (Mettl23 +/G & Mettl23 G/G ) and knockout (Mettl23 +/-& Mettl23 -/-) mice developed a glaucoma phenotype without elevated IOP. METTL23 is a histone arginine methyltransferase expressed in murine and macaque RGCs. However, the novel mutation reduced Mettl23 expression in RGCs of Mettl23 G/G mice, which recapitulated both clinical and biological phenotypes. Moreover, our findings demonstrated that Mettl23 catalyzed the dimethylation of H3R17 in the retina, and was required for the transcription of pS2, an estrogen receptor α target gene that was critical to RGC homeostasis through the negative regulation of NF-κB-mediated TNF-α/IL-1β feedback. These findings suggest an etiologic role of METTL23 in NTG with tissue-specific pathology.

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“…Recent reports indicating a multifactorial role in foot-and-mouth disease virus (FMDV) infection 52 , in tumorigenesis and virological interactions 53 . METTL23 belongs to a family of methyltransferase like proteins ( METTL ) that transfer methyl group to various substrates and it is involved in human intellectual disability 54 . The same functionality has been attributed to the MFSD11 (major facilitator superfamily domain containing 11) gene 55 .…”

Section: Discussionmentioning

confidence: 99%

Identification of candidate genes associated with bacterial and viral infections in wild boars hunted in Tuscany (Italy)

Fabbri

Crovetti

Tinacci

et al. 2022

Sci Rep

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Wild boar (Sus scrofa L.) is one of the large mammals most spread worldwide, highly adaptable, and its population rapidly increased in many areas in Europe, including Italy, where Tuscany is considered particularly suitable for wild boar. Wild boars are potential hosts for different etiological agents, such as Brucella spp., Leptospira spp. and Pseudorabies virus and they can contribute to maintain and/or to disseminate some bacterial or viral pathogens to humans and domestic animals, above all-in free-range farms. In order to identify hypothetical genomic regions associated with these infection diseases, 96 samples of wild boars hunted in Tuscany during the 2018–2019 and 2019–2020 hunting seasons were considered. Diagnosis was achieved by serological tests and 42 Pseudorabies, 31 Leptospira and 15 Brucella positive animals were identified. All animals were genotyped with Geneseek Genomic Profiler Porcine HD (70 k) and a genome-wide scan was then performed. Significant markers were highlighted for Pseudorabies (two SNPs), Brucella (seven SNPs), and Leptospira (four SNPs) and they were located within, or nearby, 29 annotated genes on chromosome 6, 9, 12, 13, 14 and 18. Eight genes are implicated in viral (SEC14L1, JMJD6, SRSF2, TMPRSS2, MX1, MX2) or bacterial (COL8A1, SPIRE1) infections, seven genes (MFSD11, METTL23, CTTNBP2, BACE2, IMPA2, MPPE1 and GNAL) are involved in mental disorders and one gene (MGAT5B) is related to the Golgi complex. Results presented here provide interesting starting points for future research, validation studies and fine mapping of candidate genes involved in bacterial and viral infections in wild boar.

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Further delineation of METTL23‐associated intellectual disability

Cited by 8 publications

References 15 publications

Two Cases of Recessive Intellectual Disability Caused by NDST1 and METTL23 Variants

Two Cases of Recessive Intellectual Disability Caused by NDST1 and METTL23 Variants

METTL23 mutation alters histone H3R17 methylation in normal-tension glaucoma

Identification of candidate genes associated with bacterial and viral infections in wild boars hunted in Tuscany (Italy)

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