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

      Hochberg, Irit; Demain, Leigh A M; Richer, Julie; Thompson, Kyle; Urquhart, Jill E; Rea, Alessandro; Pagarkar, Waheeda; Rodríguez-Palmero, Agustí; Schlüter, Agatha; Verdura, Edgard; et al. (2021-10-28)
      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. [Abstract copyright: Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.]
    • Biallelic loss of function variants in STAG3 result in primary ovarian insufficiency.

      Demain, Leigh A M; Boetje, Eline; Edgerley, Jonathan J; Miles, Emma; Fitzgerald, Cheryl T; Busby, Gail; Beaman, Glenda M; O'Sullivan, James; O'Keefe, Raymond T; Newman, William G; email: william.newman@manchester.ac.uk (2021-07-16)
      Does a genetic condition underlie the diagnosis of primary ovarian insufficiency (POI) in a 21-year-old woman with primary amenorrhoea? A karyotype and genetic testing for Fragile X syndrome was undertaken. A next-generation sequencing panel of 24 genes associated with syndromal and non-syndromal POI was conducted. A nonsense variant c.1336G>T, p.(Glu446Ter) and whole gene deletion in STAG3 were identified. Biallelic loss of function variants in STAG3 are associated with primary ovarian failure type 8 and are a rare cause of POI. [Abstract copyright: Copyright © 2021 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.]