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Lookup NU author(s): Dr Kyle Thompson, Dr Monika Olahova, Dr Langping He, Dr Thomas McCorvieORCiD, Professor Wyatt Yue, Professor Robert Taylor
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2023, The Author(s).Biallelic hypomorphic variants in PRORP have been recently described as causing the autosomal recessive disorder combined oxidative phosphorylation deficiency type 54 (COXPD54). COXPD54 encompasses a phenotypic spectrum of sensorineural hearing loss and ovarian insufficiency (Perrault syndrome) to leukodystrophy. Here, we report three additional families with homozygous missense PRORP variants with pleiotropic phenotypes. Each missense variant altered a highly conserved residue within the metallonuclease domain. In vitro mitochondrial tRNA processing assays with recombinant TRMT10C, SDR5C1 and PRORP indicated two COXPD54-associated PRORP variants, c.1159A>G (p.Thr387Ala) and c.1241C>T (p.Ala414Val), decreased pre-tRNAIle cleavage, consistent with both variants impacting tRNA processing. No significant decrease in tRNA processing was observed with PRORP c.1093T>C (p.Tyr365His), which was identified in an individual with leukodystrophy. These data provide independent evidence that PRORP variants are associated with COXPD54 and that the assessment of 5′ leader mitochondrial tRNA processing is a valuable assay for the functional analysis and clinical interpretation of novel PRORP variants.
Author(s): Smith TB, Rea A, Thomas HB, Thompson K, Olahova M, Maroofian R, Zamani M, He L, Sadeghian S, Galehdari H, Lotan NS, Gilboa T, Herman KC, McCorvie TJ, Yue WW, Houlden H, Taylor RW, Newman WG, O'Keefe RT
Publication type: Article
Publication status: Published
Journal: European Journal of Human Genetics
Year: 2023
Volume: 31
Pages: 1190-1194
Online publication date: 09/08/2023
Acceptance date: 18/07/2023
Date deposited: 18/09/2023
ISSN (print): 1018-4813
ISSN (electronic): 1476-5438
Publisher: Springer Nature
URL: https://doi.org/10.1038/s41431-023-01437-2
DOI: 10.1038/s41431-023-01437-2
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