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

Thomas B. Smith, Alessandro Rea, Huw B. Thomas, Kyle Thompson, Monika Oláhová, Reza Maroofian, Mina Zamani, Langping He, Saeid Sadeghian, Hamid Galehdari, Nava Shaul Lotan, Tal Gilboa, Kristin C. Herman, Thomas J. McCorvie, Wyatt W. Yue, Henry Houlden, Robert W. Taylor, William G. Newman*, Raymond T. O’Keefe

*Corresponding author for this work

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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.

Original languageEnglish
Pages (from-to)1190-1194
Number of pages5
JournalEuropean Journal of Human Genetics
Issue number10
Early online date9 Aug 2023
Publication statusPublished - 1 Oct 2023

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