Study of novel variants in patient of combined oxidative phosphorylation deficiency 24.

BACKGROUND

catalyzes the attachment of asparagine amino acids to mitochondrial tRNA and is critical for efficient mitochondrial protein synthesis. Biallelic variants in are associated with combined oxidative phosphorylation deficiency 24 (COXPD24) and autosomal recessive deafness-94.

METHODS

Patient information was obtained after recruitment. Genetic tests were performed using whole exome sequencing (WES) and Sanger sequencing. Structure prediction was based on the RaptorX and SWISS-MODEL platforms. The mRNA analysis of paternal variant was performed. Expression levels and dimerization of wild-type (WT) and mutant were detected in human embryonic kidney (HEK) 293T cells. Mitochondrial localization of variants was determined using immunofluorescence staining.

RESULTS

The patient presented early onset generalized epilepsy, myoclonic seizures, severe bilateral hearing impairment and affected liver and heart. WES identified two compound heterozygous variants in : c.1141A>G/p.Asn381Asp and c.1290G>C/p.Trp430Cys. In silico analysis predicted that both variants would cause significant and pathogenic changes in secondary structure. c.1290G>C is a variant at the first nucleotide of an exon, a location thought to affect mRNA splicing. Although transcriptional experiments did not identify aberrant splicing, we observed a lower proportion of transcripts from the 2 c.1290G>C variant. An experiment showed that both variants impaired expression, while mitochondrial localization and dimerization remained unaffected.

CONCLUSIONS

The patient was diagnosed with COXPD24 caused by novel variations. The cardiac dysfunction is identified for the first time. study revealed impairment of variants on expression. These data enrich our knowledge regarding the phenotypic and genotypic spectra of .