Expanding the genotypic spectrum of combined oxidative phosphorylation deficiency 54.
Lai KL., Smith TB., Maroofian R., Zaki MS., Ramadesikan S., Reynolds T., Koboldt DC., Hunter JM., Vidaurre J., Atanasova M., Marsden BD., Yue WW., Houlden H., Taylor RW., Newman WG., O'Keefe RT.
UNLABELLED: 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10048-026-00892-5.