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

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.

An intellectual disability‐associated missense variant in TRMT1 impairs tRNA modification and reconstitution of enzymatic activity

“…Notably, defects in tRNA modification have emerged as the cause of diverse neurological and neurodevelopmental disorders, thereby highlighting the critical role of tRNA modification in human health and physiology (Angelova et al, 2018; Ramos & Fu, 2019). In particular, the brain appears to be sensitive to any perturbation in translation efficiency and fidelity brought about by defects in tRNA modifications, as evidenced from the numerous cognitive disorders linked to tRNA modification enzymes such as: the Elongator complex (Hawer et al, 2018; Kojic & Wainwright, 2016); ADAT3 (Alazami et al, 2013; El‐Hattab et al, 2016; Ramos, Han, et al, 2019); NSUN2 (Abbasi‐Moheb et al, 2012; Khan et al, 2012; Martinez et al, 2012); FTSJ1 (Dai et al, 2008; Freude et al, 2004; Froyen et al, 2007; Gong et al, 2008; Guy et al, 2015; Ramser et al, 2004; Takano et al, 2008); WDR4 (Chen et al, 2018; Shaheen et al, 2015; Trimouille et al, 2018); KEOPS complex (Braun et al, 2017); PUS3 (Abdelrahman, Al‐Shamsi, Ali, & Al‐Gazali, 2018; Shaheen, Han, et al, 2016); CTU2 (Shaheen, Al‐Salam, El‐Hattab, & Alkuraya, 2016; Shaheen, Mark, et al, 2019); TRMT10A (Gillis et al, 2014; Igoillo‐Esteve et al, 2013; Narayanan et al, 2015; Yew, McCreight, Colclough, Ellard, & Pearson, 2016; Zung et al, 2015); PUS7 (de Brouwer et al, 2018; Shaheen, Tasak, et al, 2019); and ALKBH8 (Monies, Vagbo, Al‐Owain, Alhomaidi, & Alkuraya, 2019).…”

Pseudouridine synthase 7 impacts Candida albicans rRNA processing and morphological plasticity

“…Furthermore, mutation of human PUS7 leads to developmental defects including short stature, microcephaly, and aggressive behaviour (de Brouwer et al, 2018). Our data indicate that the absence of C. albicans…”

“…Humans express two Pus7 homologues and tRNA‐mediated modification by human Pus7 is thought to play important roles in stem cell differentiation (Guzzi et al, ). Furthermore, mutation of human PUS7 leads to developmental defects including short stature, microcephaly, and aggressive behaviour (de Brouwer et al, ). Our data indicate that the absence of C. albicans Pus7 leads to severe defects in morphological plasticity and slow growth.…”

Loss of pseudouridine synthases in the RluA family causes hypersensitive nociception inDrosophila

“…RNA-seq based global pseudouridine profiling has shown the presence of Ψ in many mRNAs and a large number of those sites were found to be dynamically regulated in yeast and human cells (30-33). Dysfunctional pseudouridylation has been linked to several human diseases (34-36). Since many sites of pseudouridylation in different organisms are evolutionarily conserved, Drosophila melanogaster may provide an excellent and genetically tractable metazoan system to elucidate some of these functions.…”