Biallelic variants in IBA57 with multiple mitochondrial dysfunction syndrome 3

Area of Science:

• Genetics
• Molecular Biology
• Biochemistry

Background:

• Multiple mitochondrial dysfunction syndrome type 3 (MMDS3) is a rare, autosomal recessive disorder.
• Causative mutations in the IBA57 gene are known, but its pathogenesis is not fully understood.

Purpose of the Study:

• To investigate the molecular mechanisms underlying MMDS3.
• To characterize the clinical and genetic features of patients with MMDS3.

Main Methods:

• Comprehensive clinical evaluation and genetic testing for IBA57 mutations.
• Western blotting, transcriptomic (RNA-seq), and metabolomic analyses of amniotic fluid cells.
• Respiratory chain enzyme assays in fetal liver tissue.

Main Results:

• Identified compound heterozygous IBA57 mutations (c.310G>T and c.826C>T) in the proband and affected siblings, leading to reduced IBA57 protein.
• Transcriptomic analysis revealed dysregulation of the PI3K-Akt signaling pathway.
• Metabolomic analysis showed disturbances in the TCA cycle, and enzyme assays indicated selective deficiency of respiratory chain complex II.

Conclusions:

• Compound heterozygous IBA57 mutations impair complex II activity and dysregulate the PI3K-Akt pathway.
• These molecular alterations contribute to the complex phenotype of MMDS3.
• The findings provide insights into the pathogenesis of MMDS3.