Expanding the genotypic spectrum of combined oxidative phosphorylation deficiency 54
Biallelic hypomorphic variants in PRORP cause the rare autosomal recessive disorder combined oxidative phosphorylation deficiency type 54 (COXPD54). COXPD54 encompasses a clinical spectrum of sensorineural hearing loss and ovarian insufficiency (Perrault syndrome) to leukodystrophy with developmental delay and epilepsy. Here, we report two new affected individuals with biallelic PRORP variants with clinical features consistent with COXPD54. One individual was homozygous for c.1505G > A p.Arg502Gln, whereas the other was compound heterozygous for c.1510C > T, p.His504Tyr and c.893C > A, p.Ser298Ter (NM_014672.4). In vitro tRNA processing assays revealed decreased mitochondrial 5′ tRNA leader cleavage by human RNase P complex with the two novel missense PRORP metallonuclease domain variants. These data provide further evidence that biallelic PRORP variants disrupt 5’ tRNA leader cleavage and are associated with a pleiotropic phenotype of COXPD54.
Authors
- Tamara S. Reynolds (ORCID: https://orcid.org/0009-0002-9407-6884)
- Swetha Ramadesikan (ORCID: https://orcid.org/0000-0002-8066-2500)
- Mihaela Atanasova (ORCID: https://orcid.org/0000-0003-0892-6687)
- Jesse M. Hunter (ORCID: https://orcid.org/0000-0002-5315-5693)
- Jorge Vidaurre
- Maha S. Zaki
- Wyatt W. Yue
- Reza Maroofian
- Raymond T. O’Keefe
- Brian D. Marsden
- Henry Houlden
- Robert W. Taylor
- King Lam Lai
- Daniel C. Koboldt
- Thomas B. Smith
- William G. Newman
Institutions
- Nationwide Children's Hospital (US)
- Newcastle upon Tyne Hospitals NHS Foundation Trust (GB)
- University of Manchester (GB)
- University of Oxford (GB)
- St Mary's Hospital (GB)
- National Human Genome Research Institute (US)
- Manchester University NHS Foundation Trust (GB)
- St Mary's Hospital (GB)
- Wellcome Centre for Mitochondrial Research (GB)
- National Hospital for Neurology and Neurosurgery (GB)
- University College London (GB)
- The Ohio State University (US)
- Newcastle University (GB)
Publication Details
- Journal
- Neurogenetics
- Published
- 2026-03-03
- DOI
- https://doi.org/10.1007/s10048-026-00892-5
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- LifeArc
- National Institute for Health and Care Research
- European Commission
- Manchester Biomedical Research Centre
- HORIZON EUROPE Framework Programme
- Medical Research Council
- Staatssekretariat für Bildung, Forschung und Innovation