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Title: Bi-allelic variants in the mitochondrial RNase P subunit PRORP cause mitochondrial tRNA processing defects and pleiotropic multisystem presentations
Author: Hochberg, Irit
Demain, Leigh A. M.
Richer, Julie
Thompson, Kyle
Urquhart, Jill E.
Rea, Alessandro
Pagarkar, Waheeda
Rodríguez Palmero, Agustí
Schlüter, Agatha
Verdura, Edgard
Pujol, Aurora
Quijada Fraile, Pilar
Amberger, Albert
Deutschmann, Andrea J.
Demetz, Sandra
Gillespie, Meredith
Belyantseva, Inna A.
Mcmillan, Hugh J.
Barzik, Melanie
Beaman, Glenda M.
Motha, Reeya
Ng, Kah Ying
O’sullivan, James
Williams, Simon G.
Bhaskar, Sanjeev S.
Lawrence, Isabella R.
Jenkinson, Emma M.
Zambonin, Jessica L.
Blumenfeld, Zeev
Yalonetsky, Sergey
Oerum, Stephanie
Rossmanith, Walter
Yue, Wyatt W.
Zschocke, Johannes
Munro, Kevin J.
Battersby, Brendan J.
Friedman, Thomas B.
Taylor, Robert W.
O’keefe, Raymond T.
Newman, William G.
Keywords: Malalties de l'ovari
Malalties rares
Ovary diseases
Rare diseases
Issue Date: 1-Oct-2021
Publisher: Elsevier BV
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.
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It is part of: The American Journal of Human Genetics, 2021, vol. 108, num. 11, p. 2195-2204
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Appears in Collections:Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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