Abstract
SummaryHuman 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.
Highlights
We describe four families with overlapping phenotypes resulting from bi-allelic variants in PRORP
We investigated the steady-state levels of the mt-RNase P subunits TRMT10C, SDR5C1, and PRORP in dermal fibroblasts available from affected individuals in families Family 1 (F1) and family 3 (F3) by immunoblotting and detected a decrease in slightly reduces stability (DDG 1.61 kcal/mol)
We investigated whether the disease-associated variants in PRORP affected the catalytic activity of the mt-RNase P complex
Summary
Human mitochondrial RNase P (mt-RNase P) is responsible for 50 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. Transducing fibroblasts from the affected individual with PRORP decreased the levels of unprocessed mitochondrial transcripts in the cells to near wild-type levels (Figure 4B) This effect is not seen with the empty vector or the vector containing the coding sequence for TRMT10C. 2202 The American Journal of Human Genetics 108, 2195–2204, November 4, 2021 presentation is not uncommon for mitochondrial disorders and is increasingly being shown for genes associated with Perrault syndrome.[9] Bi-allelic hypomorphic variants in CLPP, for example, are associated with Perrault syndrome,[28] whereas more deleterious variants result in a more severe phenotype associated with SNHL, seizures, and brain white matter changes.[11] The clinical spectrum observed in individuals with different bi-allelic PRORP variants is consistent with this phenotypic range and most likely reflects altered mitochondrial dysfunction in different tissues at different time points. We demonstrate that biallelic variants in PRORP result in mitochondrial dysfunction and that all three subunits of mitochondrial RNase P have been associated with mitochondrial disease, each with distinct pleiotropic clinical presentations
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