C2orf69 mutations disrupt mitochondrial function and cause a multisystem human disorder with recurring...

Area of Science:

• Genetics and Molecular Biology
• Cellular Biology
• Human Pathophysiology

Background:

• Understanding uncharacterized genes is crucial for comprehending cellular functions and diseases.
• The C2orf69 gene was previously uncharacterized, prompting investigation into its biological role.

Purpose of the Study:

• To elucidate the function of the uncharacterized C2orf69 gene.
• To investigate the genetic basis of observed clinical phenotypes.

Main Methods:

• Whole-exome sequencing to identify mutations.
• Yeast 2-hybrid and transcriptome analyses for protein interactions and gene expression.
• Molecular characterization including CRISPR/Cas9 gene editing and cellular assays.

Main Results:

• Loss-of-function mutations in C2orf69 were found in individuals with hypomyelination, microcephaly, liver dysfunction, and autoinflammation.
• C2orf69 localizes to mitochondria and its deficiency causes respiratory chain defects.
• Patient cells showed altered immune signaling and impaired glycogen metabolism, indicated by PAS-positive material and reduced GBE1 activity.

Conclusions:

• C2orf69 is identified as a key regulator of human mitochondrial function.
• The gene also influences other metabolic pathways, including glycogen metabolism.
• Defects in C2orf69 contribute to a complex syndrome affecting multiple organ systems.