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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 publication

DOI

10.1038/s41431-023-01437-2

Type

Journal article

Journal

European journal of human genetics : EJHG

Publication Date

10/2023

Volume

31

Pages

1190 - 1194

Addresses

Division of Evolution, Infection and Genomics, School of Biological Sciences, University of Manchester, Manchester, M13 9PL, UK.

Keywords

Humans, Hearing Loss, Sensorineural, Mitochondrial Diseases, Ribonuclease P, RNA, Transfer, Genotype, Homozygote, Female