A biallelic MRPL42 variant causes a combined oxidative phosphorylation deficiency syndrome revealed by multi-omics.

Pathogenic variants affecting components of the mitochondrial translation machinery lead to various impairments of mitochondrial function and thereby cause a spectrum of multisystem diseases. In an infant with a fatal, metabolic multisystem condition we performed a comprehensive multi-omics approach and detected the intronic biallelic variant NM_014050.4:c.219+6 T > A in MRPL42 (mitochondrial ribosomal protein L42) encoding a component of the large mitochondrial ribosomal subunit. RNA-seq revealed a strong reduction and aberrant splicing of the majority of MRPL42 transcripts leading to a frameshift and thereby to a premature termination codon: p.(Asn46Leufs*18). However, additional use of the canonical splice site led to a low residual expression of the wildtype transcript and MRPL42 protein abundance was consequently strongly reduced. Complex I and IV activity of the oxidative phosphorylation (OXPHOS) system were reduced and a decrease of complex I, III, IV, and mitoribosomal-related proteins was identified by proteomics. Complementation with wildtype MRPL42 corrected most of these phenotypes confirming that they were a direct consequence of the limited availability of MRPL42. Our multi-omics data confirm biallelic MRPL42 loss-of-function as the underlying cause of the fatal mitochondrial disease in our patient. Therefore, we propose MRPL42 deficiency as the cause of a mitochondrial ribosome-related combined OXPHOS-deficiency syndrome.