Citation

Darvish H, Azcona LJ, Alehabib E, Jamali F, Tafakhori A, Ranji-Burachaloo S, Jen JC, Paisán-Ruiz C. Neurol. Genet. 2019; 5(5): e356.

Affiliation

Cancer Research Center (H.D.), Semnan University of Medical Sciences; Department of Medical Genetics (H.D., E.A., F.J.), School of Medicine, Semnan University of Medical Sciences, Iran; Department of Neurosciences (L.J.A.) and Department of Neurology (L.J.A., J.C.J., C.P.-R.), Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York; Iranian Center of Neurological Research (A.T.), Neuroscience Institute, Tehran University of Medical Sciences, Iran; Department of Otolaryngology (J.C.J.), Department of Neurosurgery (J.C.J.), Department of Psychiatry (C.P.-R.), Department of Genetics and Genomic Sciences (C.P.-R.), Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place; Mindich Child Health and Development Institute (C.P.-R.), Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place; and Friedman Brain Institute (C.P.-R.), Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York.

Copyright

(Copyright © 2019, American Academy of Neurology, Publisher Wolters Kluwer)

DOI

10.1212/NXG.0000000000000356

PMID

31583274

PMCID

PMC6745718

Abstract

Recently, homozygous PUS7 mutations causing premature stop and truncation of the gene product were identified in 3 independent consanguineous families presenting with intellectual disability (ID), speech delay, short stature, microcephaly, and aggressive behavior.1 PUS7 encodes for a pseudouridine synthase 7 that catalyzes the isomerization of RNA uridine to RNA pseudouridine (Psi), which is the most abundant modified nucleotide found in all cellular RNAs and which may function as an RNA chaperone. The encoded protein contains a pseudouridine synthase domain of the TruD family that modifies uracil-13 in tRNA. Two homozygous mutations c.89_90del (p.Thr30Lysfs20*) and c.1348C>T (p.Arg450*) resulted in nonsense-mediated mRNA decay, meaning that mRNA transcripts containing the premature stop codons were eliminated through surveillance mechanisms, while the third mutation, consisting of a homozygous deletion encompassing the penultimate exon 15, escaped the nonsense-mediated mRNA decay to encode a mutant protein missing the C terminus including the TruD catalytic domain. All identified PUS7 variants resulted in aberrant pseudouridylation of at least 10 cytosolic tRNAs at position 13.

Clinical and scientific findings

We report a novel PUS7 homozygous mutation resulting in p.Gly128Arg amino-acid translation in a consanguineous Afghani family presenting with similar but milder clinical features without microcephaly and short stature (table e-1, links.lww.com/NXG/A180), further confirming the pathogenic role of PUS7 in ID syndromes with autistic features, speech delays, and aggressive behaviors ...

Language: en