Identification of novel NDUFA3 variants in a patient with mitochondrial disorders

Mitochondrial respiratory chain (RC) dysfunction constitutes the biochemical defect underlining a group of heterogenous clinical presentations known as mitochondrial disorders. NDUFA3 is an accessory subunit of Complex I (CI) and has recently been associated with Leigh Syndrome. However, the genetic evidence is limited and no functional analysis is available on the molecular mechanism.

We investigated the clinical features of the second family with biallelic NDUFA3 variants. The patient's cells and HEK293T cells with NDUFA3 knock down (KD) were assessed to study the RC dysfunction. A zebrafish model with the morpholino targeting on ndufa3 were generated to study the phenotypes caused by ndufa3 disruption.

The affected boy demonstrated global developmental delay, neurosensory hearing impairment, strabismus, muscle weakness, and hypertonia. He harbored a paternal exonic deletion NC_000019.9:g.54608143_54614387delinsCG and a maternally-inherited missense variant NM_004542.4:c.173G>A; p.(Arg58His). In patient's cells and HEK293T cells with NDUFA3 KD, reduced levels of NDUFA3 and CI and Complex IV (CIV) were observed, which further impaired endogenous respiration and ATP generation. Re-expression of the wild-type but not the mutant NDUFA3 restored the CI and CIV levels in NDUFA3 deficient cells. Zebrafish with ndufa3 disruption demonstrated ndufa3 KD affected locomotor development.

Our findings confirm the association between NDUFA3 molecular defects and Leigh syndrome spectrum.

NDUFA3 deficiency causes a mitochondrial respiration complex deficiency disorder. A family with biallelic NDUFA3 variants demonstrates phenotype resembling mitochondrial respiration complex defects. NDUFA3 defects reduce the amount of respiration complex I and IV; impair endogenous respiration and ATP generation. Zebrafish with ndufa3 knock down manifests delayed locomotor development. With this reported patient, the relationship between the gene and disease can be upgraded from "limited" to "moderate".