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Bi-allelic variants in the mitochondrial RNase P subunit PRORP cause mitochondrial tRNA processing defects and pleiotropic multisystem presentations

Lookup NU author(s): Dr Kyle Thompson, Professor Wyatt YueORCiD, Professor Robert Taylor



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


© 2021 The AuthorsHuman mitochondrial RNase P (mt-RNase P) is responsible for 5′ end processing of mitochondrial precursor tRNAs, a vital step in mitochondrial RNA maturation, and is comprised of three protein subunits: TRMT10C, SDR5C1 (HSD10), and PRORP. Pathogenic variants in TRMT10C and SDR5C1 are associated with distinct recessive or x-linked infantile onset disorders, resulting from defects in mitochondrial RNA processing. We report four unrelated families with multisystem disease associated with bi-allelic variants in PRORP, the metallonuclease subunit of mt-RNase P. Affected individuals presented with variable phenotypes comprising sensorineural hearing loss, primary ovarian insufficiency, developmental delay, and brain white matter changes. Fibroblasts from affected individuals in two families demonstrated decreased steady state levels of PRORP, an accumulation of unprocessed mitochondrial transcripts, and decreased steady state levels of mitochondrial-encoded proteins, which were rescued by introduction of the wild-type PRORP cDNA. In mt-tRNA processing assays performed with recombinant mt-RNase P proteins, the disease-associated variants resulted in diminished mitochondrial tRNA processing. Identification of disease-causing variants in PRORP indicates that pathogenic variants in all three subunits of mt-RNase P can cause mitochondrial dysfunction, each with distinct pleiotropic clinical presentations.

Publication metadata

Author(s): Hochberg I, Demain LAM, Richer J, Thompson K, Urquhart JE, Rea A, Pagarkar W, Rodriguez-Palmero A, Schluter A, Verdura E, Pujol A, Quijada-Fraile P, Amberger A, Deutschmann AJ, Demetz S, Gillespie M, Belyantseva IA, McMillan HJ, Barzik M, Beaman GM, Motha R, Ng KY, O'Sullivan J, Williams SG, Bhaskar SS, Lawrence IR, Jenkinson EM, Zambonin JL, Blumenfeld Z, Yalonetsky S, Oerum S, Rossmanith W, Yue WW, Zschocke J, Munro KJ, Battersby BJ, Friedman TB, Taylor RW, O'Keefe RT, Newman WG

Publication type: Article

Publication status: Published

Journal: American Journal of Human Genetics

Year: 2021

Volume: 108

Issue: 11

Pages: 2195-2204

Print publication date: 04/11/2021

Online publication date: 28/10/2021

Acceptance date: 07/10/2021

Date deposited: 15/11/2021

ISSN (print): 0002-9297

ISSN (electronic): 1537-6605

Publisher: Cell Press


DOI: 10.1016/j.ajhg.2021.10.002


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