Biallelic variants in the mitochondrial ribosomal protein MRPL49 cause combined oxidative phosphorylation deficiency

Combined oxidative phosphorylation deficiency (COXPD) is a rare, multisystem disorder that exhibits significant clinical and genetic heterogeneity. Through genome sequencing, we identified biallelic variants in MRPL49 in individuals from five unrelated families. These individuals presented a spectrum of symptoms, ranging from Perrault syndrome (characterized by primary ovarian insufficiency and sensorineural hearing loss) to severe childhood-onset conditions such as developmental delay, leukodystrophy, microcephaly, and retinal dystrophy. Multiple assays demonstrated that the disease-associated MRPL49 variants disrupted the stability and function of the mitochondrial ribosome, particularly affecting the large subunit. This disruption led to a reduction in Complex I and Complex IV levels. We describe a new form of MRPL49 variant-associated COXPD, thereby expanding the understanding of how impaired assembly of the mitochondrial ribosomal large subunit results in multisystem phenotypes.