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

• DOI: 10.1016/j.ajhg.2021.10.002
• Publication Date: 2021-10-28T14:34:10Z
• Authors: Irit Hochberg; Leigh A.M. Demain; Julie Richer; Kyle Thompson; Jill E. Urquhart; Alessandro Rea; Waheeda Pagarkar; Agustí Rodríguez-...; Agatha Schlüter; Edgard Verdura; Aurora Pujol; Pilar Quijada-Fraile; Albert Amberger; Andrea J. Deutsch...; Sandra Demetz; Meredith Gillespie; Inna A. Belyantseva; Hugh J. McMillan; Melanie Barzik; Glenda M. Beaman; Reeya Motha; Kah Ying Ng; James O’Sullivan; Simon G. Williams; Sanjeev S. Bhaskar; Isabella R. Lawrence; Emma M. Jenkinson; Jessica L. Zambonin; Zeev Blumenfeld; Sergey Yalonetsky; Stephanie Oerum; Walter Rossmanith; Wyatt W. Yue; Johannes Zschocke; Kevin J. Munro; Brendan J. Battersby; Thomas B. Friedman; Robert W. Taylor; Raymond T. O’Keefe; William G. Newman
• Keywords: RNase MRP; Mitochondrial disease

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