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

摘要

We describe six persons from three families with three homozygous protein truncating variants inPUS7: 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.PUS7encodes 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,pus7knockout inDrosophila melanogasterresults in a number of behavioral defects, including increased activity, disorientation, and aggressiveness supporting that neurological defects are caused byPUS7variants. Our findings demonstrate that RNA pseudouridylation by PUS7 is essential for proper neuronal development and function.