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Pseudouridylation is the most common post-transcriptional modification, wherein uridine is isomerized into 5-ribosyluracil (pseudouridine, Ψ). The resulting increase in base stacking and creation of additional hydrogen bonds are thought to enhance RNA stability. Pseudouridine synthases are encoded in humans by 13 genes, two of which are linked to Mendelian diseases: PUS1 and PUS3. Very recently, PUS7 mutations were reported to cause intellectual disability with growth retardation. We describe two families in which two different homozygous PUS7 mutations (missense and frameshift deletion) segregate with a phenotype comprising intellectual disability and progressive microcephaly. Short stature and hearing loss were variable in these patients. Functional characterization of the two mutations confirmed that both result in decreased levels of Ψ 13 in tRNAs. Furthermore, the missense variant of the S. cerevisiae ortholog failed to complement the growth defect of S. cerevisiae pus7Δ trm8Δ mutants. Our results confirm that PUS7 is a bona fide Mendelian disease gene and expand the list of human diseases caused by impaired pseudouridylation.

PUS7 mutations impair pseudouridylation in humans and cause intellectual disability and microcephaly