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Novel homozygous variants in PRORP expand the genotypic spectrum of combined oxidative phosphorylation deficiency 54

Lookup NU author(s): Dr Kyle Thompson, Dr Monika Olahova, Dr Langping He, Dr Thomas McCorvieORCiD, Professor Wyatt YueORCiD, Professor Robert Taylor

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 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.


Publication metadata

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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Funding

Funder referenceFunder name
203105/Z/16/ZWellcome Trust
Lily Foundation
G0800674
Medical Research Council
Mito Foundation
Mitochondrial Disease Patient Cohort
MR/S005021/1Medical Research Council (MRC)
Medical Research Council International Centre for Genomic Medicine in Neuromuscular Disease
MR/W019027/1
NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children
NIHR 203308
NIHR Biomedical Research Centre
Pathological Society
NIHR Manchester Biomedical Research Centre
S60_Newman
Royal National Institute for the Deaf/Masonic Charitable Foundation
Wellcome Centre for Mitochondrial Research

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