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

Irit Hochberg, Leigh Demain, Julie Richer, Kyle Thompson, Jill Urquhart, Alessandro Rea, Waheeda Pagarkar, Agusti Rodriguez-Palmero, Glenda Beaman, James O'Sullivan, Simon Williams, Sanjeev Bhaskar, Raymond O'Keefe, William Newman, Kevin Munro

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Abstract

Human 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.
Original languageEnglish
Pages (from-to)2195-2204
Number of pages10
JournalAmerican Journal of Human Genetics
Volume108
Issue number11
DOIs
Publication statusPublished - 28 Oct 2021

Keywords

  • Adult
  • Alleles
  • Female
  • Genetic Pleiotropy
  • Humans
  • Male
  • Mitochondria/enzymology
  • Pedigree
  • RNA, Mitochondrial/genetics
  • RNA, Transfer/genetics
  • Ribonuclease P/genetics

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