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 ...
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", language="en", issn="2376-7839", doi="10.1212/NXG.0000000000000356", url="http://dx.doi.org/10.1212/NXG.0000000000000356" }