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A homozygous truncating mutation in PUS3 expands the role of tRNA modification in normal cognition

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Abstract

Intellectual disability is a common and highly heterogeneous disorder etiologically. In a multiplex consanguineous family, we applied autozygosity mapping and exome sequencing and identified a novel homozygous truncating mutation in PUS3 that fully segregates with the intellectual disability phenotype. Consistent with the known role of Pus3 in isomerizing uracil to pseudouridine at positions 38 and 39 in tRNA, we found a significant reduction in this post-transcriptional modification of tRNA in patient cells. Our finding adds to a growing list of intellectual disability disorders that are caused by perturbation of various tRNA modifications, which highlights the sensitivity of the brain to these highly conserved processes.

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Acknowledgments

We thank the family for their enthusiastic participation. We also thank the Sequencing and Genotyping Facilities at KFSHRC for their technical help. This work was supported in part by KACST Grant 13-BIO1113-20 (FSA) and National Institutes of Health Grant GM052347 (EMP).

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    Authors and Affiliations

    1. Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

      Ranad Shaheen, Nour Ewida, Eman Alobeid & Fowzan S. Alkuraya

    2. Department of Biochemistry and Biophysics, Center for RNA Biology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA

      Lu Han & Eric M. Phizicky

    3. Department of Pediatric Subspecialties, Children’s Hospital, King Fahad Medical City, Riyadh, Saudi Arabia

      Eissa Faqeih

    4. Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia

      Fowzan S. Alkuraya

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    1. Ranad Shaheen
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    Correspondence to Eric M. Phizicky or Fowzan S. Alkuraya.

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    R. Shaheen, L. Han, E. Faqeih authors have contributed equally.

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    Shaheen, R., Han, L., Faqeih, E. et al. A homozygous truncating mutation in PUS3 expands the role of tRNA modification in normal cognition. Hum Genet 135, 707–713 (2016). https://doi.org/10.1007/s00439-016-1665-7

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