Variants in PUS7 Cause Intellectual Disability with Speech Delay, Microcephaly, Short Stature, and Aggressive Behavior

Am J Hum Genet. 2018 Dec 6;103(6):1045-1052. doi: 10.1016/j.ajhg.2018.10.026.

Arjan P M de Brouwer ¹, Rami Abou Jamra ², Nadine Körtel ³, Clara Soyris ⁴, Daniel L Polla ⁵, Modi Safra ⁴, Avia Zisso ⁴, Christopher A Powell ⁶, Pedro Rebelo-Guiomar ⁶, Nadja Dinges ³, Violeta Morin ³, Michael Stock ³, Mureed Hussain ⁷, Mohsin Shahzad ⁸, Saima Riazuddin ⁹, Zubair M Ahmed ⁹, Rolph Pfundt ¹⁰, Franziska Schwarz ¹⁰, Lonneke de Boer ¹¹, André Reis ¹², Detilina Grozeva ¹³, F Lucy Raymond ¹³, Sheikh Riazuddin ¹⁴, David A Koolen ¹⁰, Michal Minczuk ⁶, Jean-Yves Roignant ³, Hans van Bokhoven ¹⁰, Schraga Schwartz ¹⁵

Affiliations

1 Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500HB Nijmegen, the Netherlands. Electronic address: [email protected].
2 Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany; Institute of Human Genetics, University Medical Center Leipzig, 04109 Leipzig, Germany.
3 Laboratory of RNA Epigenetics, Institute of Molecular Biology (IMB), 55128 Mainz, Germany.
4 Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
5 Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500HB Nijmegen, the Netherlands; CAPES Foundation, Ministry of Education of Brazil, 70040-020 Brasília, Brazil.
6 MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge CB2 0XY, UK.
7 Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500HB Nijmegen, the Netherlands; National Centre of Excellence in Molecular Biology, University of The Punjab, Lahore 53700, Pakistan; Department of Otorhinolaryngology-Head and Neck Surgery, University of Maryland, School of Medicine, Baltimore, MD 21201-1734, USA.
8 Center for Genetic Diseases, Shaheed Zulfiqar Ali Bhutto Medical University, Pakistan Institute of Medical Sciences, Islamabad 44000, Pakistan.
9 Department of Otorhinolaryngology-Head and Neck Surgery, University of Maryland, School of Medicine, Baltimore, MD 21201-1734, USA.
10 Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500HB Nijmegen, the Netherlands.
11 Department of Paediatrics, Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
12 Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
13 Department of Medical Genetics, University of Cambridge, Cambridge CB2 0QQ, UK.
14 National Centre of Excellence in Molecular Biology, University of The Punjab, Lahore 53700, Pakistan; Center for Genetic Diseases, Shaheed Zulfiqar Ali Bhutto Medical University, Pakistan Institute of Medical Sciences, Islamabad 44000, Pakistan; Allama Iqbal Medical College, University of Health Sciences, Lahore 54600, Pakistan.
15 Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel. Electronic address: [email protected].

PMID: 30526862 DOI: 10.1016/j.ajhg.2018.10.026

Abstract

We describe six persons from three families with three homozygous protein truncating variants in PUS7: c.89_90del (p.Thr30Lysfs^∗20), c.1348C>T (p.Arg450^∗), and a deletion of the penultimate exon 15. All these individuals have intellectual disability with speech delay, short stature, microcephaly, and aggressive behavior. PUS7 encodes the RNA-independent pseudouridylate synthase 7. Pseudouridylation is the most abundant post-transcriptional modification in RNA, which is primarily thought to stabilize secondary structures of RNA. We show that the disease-related variants lead to abolishment of PUS7 activity on both tRNA and mRNA substrates. Moreover, pus7 knockout in Drosophila melanogaster results in a number of behavioral defects, including increased activity, disorientation, and aggressiveness supporting that neurological defects are caused by PUS7 variants. Our findings demonstrate that RNA pseudouridylation by PUS7 is essential for proper neuronal development and function.

Keywords

Drosophila melanogaster; aggressive behavior; growth delay; intellectual disability; mRNA substrates; microcephaly; neurodevelopmental delay; pseudouridylation; speech delay; tRNA.

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