Abstract
Intellectual disability is a common and highly heterogeneous disorder etiologically. In a multiplex consanguineous family, we applied autozygosity mapping and exome sequencing and identified a novel homozygous truncating mutation in PUS3 that fully segregates with the intellectual disability phenotype. Consistent with the known role of Pus3 in isomerizing uracil to pseudouridine at positions 38 and 39 in tRNA, we found a significant reduction in this post-transcriptional modification of tRNA in patient cells. Our finding adds to a growing list of intellectual disability disorders that are caused by perturbation of various tRNA modifications, which highlights the sensitivity of the brain to these highly conserved processes.
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Acknowledgments
We thank the family for their enthusiastic participation. We also thank the Sequencing and Genotyping Facilities at KFSHRC for their technical help. This work was supported in part by KACST Grant 13-BIO1113-20 (FSA) and National Institutes of Health Grant GM052347 (EMP).
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R. Shaheen, L. Han, E. Faqeih authors have contributed equally.
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Shaheen, R., Han, L., Faqeih, E. et al. A homozygous truncating mutation in PUS3 expands the role of tRNA modification in normal cognition. Hum Genet 135, 707–713 (2016). https://doi.org/10.1007/s00439-016-1665-7
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DOI: https://doi.org/10.1007/s00439-016-1665-7