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

TitleVariants in PUS7 Cause Intellectual Disability with Speech Delay, Microcephaly, Short Stature, and Aggressive Behavior.
Publication TypeJournal Article
Year of Publication2018
Authorsde Brouwer, APM, Jamra, RAbou, 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, F Raymond, L, Riazuddin, S, Koolen, DA, Minczuk, MA, Roignant, J-Y, van Bokhoven, H, Schwartz, S
JournalAm J Hum Genet
Volume103
Issue6
Pagination1045-1052
Date Published2018 Dec 06
ISSN1537-6605
Abstract

We describe six persons from three families with three homozygous protein truncating variants in PUS7: c.89_90del (p.Thr30Lysfs20), 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.

DOI10.1016/j.ajhg.2018.10.026
Alternate JournalAm. J. Hum. Genet.
Citation Key10.1016/j.ajhg.2018.10.026
PubMed ID30526862
PubMed Central IDPMC6288278