American journal of human genetics · 2018
Variants in PUS7 Cause Intellectual Disability with Speech Delay, Microcephaly, Short Stature, and Aggressive Behavior.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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de Brouwer Arjan P M, Abou Jamra Rami, Körtel Nadine, Soyris Clara, Polla Daniel L, Safra Modi, Zisso Avia, Powell Christopher A, Rebelo-Guiomar Pedro, Dinges Nadja, Morin Violeta, Stock Michael, Hussain Mureed, Shahzad Mohsin, Riazuddin Saima, Ahmed Zubair M, Pfundt Rolph, Schwarz Franziska, de Boer Lonneke, Reis André, Grozeva Detilina, Raymond F Lucy, Riazuddin Sheikh, Koolen David A, Minczuk Michal, Roignant Jean-Yves, van Bokhoven Hans, Schwartz Schraga
Аннотация
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.