ATP5F1A deficiency causes developmental delay and motor dysfunction in humans and zebrafish

Area of Science:

• Genetics
• Molecular Biology
• Developmental Biology

Background:

• The ATP synthase F1 subunit α (ATP5F1A) gene is crucial for mitochondrial complex V.
• Mutations in ATP5F1A cause mitochondrial complex V deficiency diseases.
• Limited understanding exists regarding genotype-phenotype correlations and molecular mechanisms of ATP5F1A deficiency.

Purpose of the Study:

• To investigate the pathogenic mechanisms of ATP5F1A deficiency.
• To functionally analyze a recurrent missense variant in the ATP5F1A gene.

Main Methods:

• Whole-exome sequencing and trio analysis identified the causative variant in a Han Chinese family.
• Bioinformatic predictions and structural modeling assessed pathogenicity.
• HEK293T cells and zebrafish models were used for functional analysis.
• RNA sequencing explored underlying molecular pathways.

Main Results:

• A de novo missense variant (c.1252G>A, p.Gly418Arg) in ATP5F1A was identified, reducing protein stability and expression.
• Zebrafish atp5fa1 knockdown resulted in growth retardation, motor dysfunction, and impaired motor neuron development.
• Transcriptomic analysis revealed enrichment in neurotransmission and apelin signaling pathways, with downregulated autophagy-related genes.

Conclusions:

• This study reports the first pathogenic ATP5F1A mutations in the Chinese population.
• ATP5F1A dysfunction in zebrafish models leads to multi-system defects and disease phenotypes.
• Inhibition of autophagy activation mechanisms may mediate the observed phenotypes.