A new case confirming and expanding the phenotype spectrum of ADAT3-related intellectual disability syndrome

Sharkia, Rajech; Zalan, Abdelnaser; Jabareen‐Masri, Azhar; Zahalka, Hazar; Mahajnah, Muhammad

doi:10.1016/j.ejmg.2018.10.001

Cited by 21 publications

(14 citation statements)

References 9 publications

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“…Sharkia et al described a consanguineous sibling pair from an Arab community in Israel who were also homozygous for the p.Val144Met ADAT3 variant. 6 They noted features consistent with those described by El-Hattab et al along with gait difficulties, balance problems, teeth abnormalities, neuropathy, and contractures of the hand, wrist, and fingers.…”

Section: Introductionsupporting

confidence: 72%

Novel Missense Variants in ADAT3 as a Cause of Syndromic Intellectual Disability

et al. 2019

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Autosomal recessive variants in the adenosine deaminase, tRNA specific 3 (ADAT3) gene cause a syndromic form of intellectual disability due to a loss of ADAT3 function. This disorder is characterized by developmental delay, intellectual disability, speech delay, abnormal brain structure, strabismus, microcephaly, and failure to thrive. A small subset of individuals with ADAT3 deficiency have other structural birth defects including atrial septal defect, patent ductus arteriosus, hypospadias, cryptorchidism, and micropenis. Here, we report a sibling pair with novel compound heterozygous missense variants that affect a conserved amino acid in the deaminase domain of ADAT3. These siblings have many of the features characteristic of this syndrome, including, intellectual disability, hypotonia, esotropia, failure to thrive, and microcephaly. Both had gastroesophageal reflux disease (GERD), feeding problems, and aspiration requiring thickening of feeds. Although they have no words, their communication abilities progressed rapidly when they began to use augmentative and alternative communication (AAC) devices. One of these siblings was born with an anterior congenital diaphragmatic hernia, which has not been reported previously in association with ADAT3 deficiency. We conclude that individuals with ADAT3 deficiency should be monitored for GERD, feeding problems, and aspiration in infancy. They may also benefit from the use of AAC devices and individualized educational programs that take into account their capacity for nonverbal language development. Additional studies in humans or animal models will be needed to determine if ADAT3 deficiency predisposes to the development of structural birth defects.

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Section: Introductionsupporting

confidence: 72%

Novel Missense Variants in ADAT3 as a Cause of Syndromic Intellectual Disability

et al. 2019

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“…For these assays, we transiently expressed either ADAT3-WT or -V144M fused to a carboxy-terminal Strep-tag for purification and elution of ADAT2/3. Since ADAT2 levels have been shown to be limiting for the formation of ADAT2/3 complexes in human cells (15), we coexpressed His-tagged ADAT2 with either ADAT3-Strep-WT or ADAT3-Strep-V144M to facilitate the detection of any associated ADAT2. After purification on Strep-Tactin resin, bound ADAT3 complexes were eluted with biotin and analyzed by immunoblotting.…”

Section: Resultsmentioning

confidence: 99%

“…Exome sequencing and autozygosity mapping have identified a single c.382G>A mutation in the human ADAT3 gene that is causative for autosomal recessive intellectual disability (ID) in multiple families of Saudi Arabian descent (13–15). All reported individuals homozygous for the V144M mutation exhibit cognitive deficits indicative of a neurodevelopmental disorder, with the majority displaying strabismus and growth delay.…”

Section: Introductionmentioning

confidence: 99%

Formation of tRNA Wobble Inosine in Humans Is Disrupted by a Millennia-Old Mutation Causing Intellectual Disability

Ramos

Han

et al. 2019

Molecular and Cellular Biology

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The formation of inosine at the wobble position of eukaryotic tRNAs is an essential modification catalyzed by the ADAT2/ADAT3 complex. In humans, a valine-to-methionine mutation (V144M) in ADAT3 that originated ∼1,600 years ago is the most common cause of autosomal recessive intellectual disability (ID) in Arabia. While the mutation is predicted to affect protein structure, the molecular and cellular effects of the V144M mutation are unknown. Here, we show that cell lines derived from ID-affected individuals expressing only ADAT3-V144M exhibit decreased wobble inosine in certain tRNAs. Moreover, extracts from the same cell lines of ID-affected individuals display a severe reduction in tRNA deaminase activity. While ADAT3-V144M maintains interactions with ADAT2, the purified ADAT2/3-V144M complexes exhibit defects in activity. Notably, ADAT3-V144M exhibits an increased propensity to form aggregates associated with cytoplasmic chaperonins that can be suppressed by ADAT2 overexpression. These results identify a key role for ADAT2-dependent folding of ADAT3 in wobble inosine modification and indicate that proper formation of an active ADAT2/3 complex is crucial for proper neurodevelopment.

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“…A single missense mutation identified in ADAT3 by exome sequencing can cause severe intellectual disability and strabismus [87,88,96], implicating another gene involved in protein translation in the development of neurological diseases (Figure 3; Table 1). Recently, a second mutation in ADAT3 was reported in a patient with mild intellectual disability [97].…”

Section: Deregulation Of Trna Modifications In Protein Conformatiomentioning

confidence: 99%

Impact of tRNA Modifications and tRNA-Modifying Enzymes on Proteostasis and Human Disease

Pereira

Francisco

Varanda

et al. 2018

IJMS

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Transfer RNAs (tRNAs) are key players of protein synthesis, as they decode the genetic information organized in mRNA codons, translating them into the code of 20 amino acids. To be fully active, tRNAs undergo extensive post-transcriptional modifications, catalyzed by different tRNA-modifying enzymes. Lack of these modifications increases the level of missense errors and affects codon decoding rate, contributing to protein aggregation with deleterious consequences to the cell. Recent works show that tRNA hypomodification and tRNA-modifying-enzyme deregulation occur in several diseases where proteostasis is affected, namely, neurodegenerative and metabolic diseases. In this review, we discuss the recent findings that correlate aberrant tRNA modification with proteostasis imbalances, in particular in neurological and metabolic disorders, and highlight the association between tRNAs, their modifying enzymes, translational decoding, and disease onset.

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A new case confirming and expanding the phenotype spectrum of ADAT3-related intellectual disability syndrome

Cited by 21 publications

References 9 publications

Novel Missense Variants in ADAT3 as a Cause of Syndromic Intellectual Disability

Novel Missense Variants in ADAT3 as a Cause of Syndromic Intellectual Disability

Formation of tRNA Wobble Inosine in Humans Is Disrupted by a Millennia-Old Mutation Causing Intellectual Disability

Impact of tRNA Modifications and tRNA-Modifying Enzymes on Proteostasis and Human Disease

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