<i>ADAT3</i> variants disrupt the activity of the ADAT tRNA deaminase complex and impair neuronal migration

The ADAT2/ADAT3 (ADAT) complex catalyses the adenosine to inosine modification at the wobble position of eukaryotic tRNAs. Mutations in ADAT3, the catalytically inactive subunit of the ADAT2/ADAT3 complex, have been identified in patients presenting with severe neurodevelopmental disorders. Yet, the physiological function of the ADAT2/ADAT3 complex during brain development remains totally unknown. Here, we investigated the role of the ADAT2/ADAT3 complex in cortical development. First, we report 21 neurodevelopmental disorders patients carrying biallelic variants in ADAT3. Second, we used structural, biochemical and enzymatic assays to deeply characterize the impact of those variants on the ADAT2/ADAT3 structure, biochemical properties, enzymatic activity, and tRNAs editing and abundance. Finally, in vivo complementation assays were performed to correlate functional deficits with neuronal migration defects in the developing mouse cortex. Our results showed that maintaining a proper level of ADAT2/ADAT3 catalytic activity is essential for radial migration of projection neurons in the developing mouse cortex. We demonstrated that the identified ADAT3 variants significantly impaired the abundance and, for some, the activity of the complex, leading to a substantial decrease in inosine 34 levels with direct consequence on tRNAs steady state. We correlated the severity of the migration phenotype with the degree of loss of function caused by the variants. Altogether, our results highlight the critical role of ADAT2/ADAT3 during cortical development and provide cellular and molecular insights into the pathogenic mechanisms underlying ADAT3-related neurodevelopmental disorders.

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Journal
Brain
Published
2025-03-22
DOI
https://doi.org/10.1093/brain/awaf109
Citations
2
Primary Topic
RNA modifications and cancer
Type
article
Field-Weighted Citation Impact
1.61

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article

ADAT3 variants disrupt the activity of the ADAT tRNA deaminase complex and impair neuronal migration

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2 citations
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RNA modifications and cancer
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article

ADAT3 variants disrupt the activity of the ADAT tRNA deaminase complex and impair neuronal migration

Ehab Tous, Siddharth Srivastava, Laila Selim, Peggy Tilly, Christopher A. Walsh, Efil Bayam, Noémie Schwaller, Bashayer S. Alawam, Danny D. Nedialkova, Nihal Almenabawy, Gabriela E. Oprea, Laurence Drouard, Hamad Alzaidan, Maya Chopra, Eleina England, Elena Brivio, Thalia Salinas‐Giegé, Elizabeth Ramos‐Morales, Lynn Pais, Walaa Elnaggar, Nour M. Elkhateeb, Amal Alhashem, Melanie O’Leary, Lama AlAbdi, Omar Abu Adas Blanco, Laureline Mosser, Afaf Alsagheir, Majid Mojarrad, Alysia Kern Lovgren, Atieh Eslahi, Juliette D. Godin, Abolfazl Rad, Jordi Del-Pozo-Rodríguez, Aisha Alnuzha, Fowzan Sami Alkuraya, Masoome Alerasool, Hugo Rolando Vaca, Dustin L. Gable, Rebecca C. Yeh, Abdullah Tamim, Hesham Aldhalaan, Grace E. VanNoy, Anne O’Donnell‐Luria, Christophe Romier, Romain Lecat, Naomi Meave Ojeda, Mona Kamel, Joseph G. Gleeson, Jennifer E. Neil, Mohammed Al‐Owain, Till Balla, Marina Vitoria Gomes, Mais Hashem, Firdous Abdulwahab, Mehran Beiraghi Toosi, Khowlah Alfayez, Loai Z Sbeih, Muath Rakiz Alqurashi, Renad Abu Khater
article en
2 citations

Abstract

The ADAT2/ADAT3 (ADAT) complex catalyses the adenosine to inosine modification at the wobble position of eukaryotic tRNAs. Mutations in ADAT3, the catalytically inactive subunit of the ADAT2/ADAT3 complex, have been identified in patients presenting with severe neurodevelopmental disorders. Yet, the physiological function of the ADAT2/ADAT3 complex during brain development remains totally unknown. Here, we investigated the role of the ADAT2/ADAT3 complex in cortical development. First, we report 21 neurodevelopmental disorders patients carrying biallelic variants in ADAT3. Second, we used structural, biochemical and enzymatic assays to deeply characterize the impact of those variants on the ADAT2/ADAT3 structure, biochemical properties, enzymatic activity, and tRNAs editing and abundance. Finally, in vivo complementation assays were performed to correlate functional deficits with neuronal migration defects in the developing mouse cortex. Our results showed that maintaining a proper level of ADAT2/ADAT3 catalytic activity is essential for radial migration of projection neurons in the developing mouse cortex. We demonstrated that the identified ADAT3 variants significantly impaired the abundance and, for some, the activity of the complex, leading to a substantial decrease in inosine 34 levels with direct consequence on tRNAs steady state. We correlated the severity of the migration phenotype with the degree of loss of function caused by the variants. Altogether, our results highlight the critical role of ADAT2/ADAT3 during cortical development and provide cellular and molecular insights into the pathogenic mechanisms underlying ADAT3-related neurodevelopmental disorders.

BrainVol. 148(9)
Broad Institute (US), Boston Children's Hospital (US), Children’s Institute (US), Riyadh Armed Forces Hospital (SA), XLAB (Slovenia) (SI), Alfaisal University (SA), Howard Hughes Medical Institute (US), Harvard University (US), Cairo University (EG), Inserm (FR), Mashhad University of Medical Sciences (IR), King Faisal Specialist Hospital & Research Centre (SA), King Fahd Hospital of the University (SA), King Fahd Medical City (SA), King Fahad Specialist Hospital (SA), Cambridge University Hospitals NHS Foundation Trust (GB), University of California San Diego (US), Institut de génétique et de biologie moléculaire et cellulaire (FR), Rady Children's Hospital-San Diego (US), Centre National pour la Recherche Scientifique et Technique (CNRST) (MA), Institut de Biologie Moléculaire des Plantes (FR), Ministry of Health of the Russian Federation (RU), Ministry of Health (SA), Max Planck Institute of Biochemistry (DE), Broad Center (US), Child Development Center (QA), Khayyam University (IR), University of Rostock (DE), Technical University of Munich (DE), Université de Strasbourg (FR), Imam Abdulrahman Bin Faisal University (SA)
Broad Institute, Infrastructures en Biologie Santé et Agronomie, European Commission, Deutsche Forschungsgemeinschaft, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Fondation pour la Recherche Médicale, Université de Strasbourg, Max-Planck-Gesellschaft, Centre National de la Recherche Scientifique, French Infrastructure for Integrated Structural Biology, National Human Genome Research Institute, National Institute of Neurological Disorders and Stroke
Reduced inequalities
Openalex Percentile: Top 18%
RNA modifications and cancer
1.61
DOIOpen Access PDFOpenAlex
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