Biallelic variants in IBA57 with multiple mitochondrial dysfunction syndrome 3

Multiple mitochondrial dysfunction syndrome type 3 (MMDS3; OMIM #615330) is a rare autosomal recessive disorder caused by mutations in IBA57. Its complex clinical presentation and molecular pathogenesis remain incompletely understood.

The study included comprehensive clinical evaluation, IBA57 genetic testing, Western Blotting for protein expression, and transcriptomic and metabolomic analyses of amniotic fluid cells.

The proband presented with typical MMDS3 features, and both affected siblings carried compound heterozygous IBA57 missense mutations (c.310G>T and c.826C>T) leading to reduced IBA57 protein expression. RNA-seq revealed transcriptional dysregulation of the PI3K-Akt signaling pathway, and metabolomics demonstrated TCA cycle disturbances in amniocytes. Respiratory chain enzyme assays showed a selective deficiency of complex II activity in fetal liver.

The compound heterozygous IBA57 mutations c.310G>T and c.826C>T lead to reduced IBA57 protein expression, selective impairment of respiratory chain complex II, and transcriptional dysregulation of the PI3K-Akt pathway, together contributing to the MMDS3 phenotype in the proband and the affected fetus.