Citation

de Brouwer APM, Abou Jamra R, Körtel N, Soyris C, Polla DL, Safra M, Zisso A, Powell CA, Rebelo-Guiomar P, Dinges N, Morin V, Stock M, Hussain M, Shahzad M, Riazuddin S, Ahmed ZM, Pfundt R, Schwarz F, de Boer L, Reis A, Grozeva D, Raymond FL, Riazuddin S, Koolen DA, Minczuk M, Roignant JY, van Bokhoven H, Schwartz S. Am. J. Hum. Genet. 2018; 103(6): 1045-1052.

Affiliation

Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel. Electronic address: schwartz@weizmann.ac.il.

Copyright

(Copyright © 2018, Elsevier Publishing)

DOI

10.1016/j.ajhg.2018.10.026

PMID

30526862

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.

Copyright © 2018 American Society of Human Genetics. All rights reserved.

Language: en

Keywords

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