Published on Dec. 6, 2018 in Am J Hum Genet volume 103(6).
PubMed ID: 30526862
We describe six persons from three families with three homozygous protein truncatingvariants in PUS7: c.89_90del (p.Thr30Lysfs(∗)20), c.1348C>T (p.Arg450(∗)), and adeletion of the penultimate exon 15. All these individuals have intellectualdisability with speech delay, short stature, microcephaly, and aggressive behavior.PUS7 encodes the RNA-independent pseudouridylate synthase 7. Pseudouridylation isthe most abundant post-transcriptional modification in RNA, which is primarilythought to stabilize secondary structures of RNA. We show that the disease-relatedvariants lead to abolishment of PUS7 activity on both tRNA and mRNA substrates.Moreover, pus7 knockout in Drosophila melanogaster results in a number of behavioraldefects, including increased activity, disorientation, and aggressiveness supportingthat neurological defects are caused by PUS7 variants. Our findings demonstrate thatRNA pseudouridylation by PUS7 is essential for proper neuronal development andfunction.CI - Copyright © 2018 American Society of Human Genetics. All rights reserved.