Biallelic Loss-Of-Function Variant in ATP5ME Is Associated With Severe and Early Onset Oxidative Phosphorylation...

Area of Science:

• Mitochondrial biology
• Human genetics
• Biochemistry

Background:

• ATP synthase (complex V) is crucial for cellular energy production.
• The ATP5ME subunit of ATP synthase is vital for mitochondrial structure and function.
• Genetic mutations in ATP5ME have not been previously linked to human diseases.

Purpose of the Study:

• To investigate the role of ATP5ME in human disease.
• To identify the genetic cause of a patient's neurodevelopmental disorder.
• To elucidate the molecular mechanisms underlying ATP5ME deficiency.

Main Methods:

• Exome sequencing to identify genetic variants.
• Analysis of patient-derived fibroblasts for ATP5ME expression and mitochondrial function.
• In vitro assays to assess mitochondrial complex activities and cellular respiration.
• Zebrafish model (atp5me knockout) to study in vivo phenotypes.
• mRNA complementation in zebrafish to validate pathogenicity.

Main Results:

• A novel biallelic deletion in ATP5ME was identified in a patient with severe neuroregression and other symptoms.
• Patient fibroblasts showed reduced ATP5ME levels, impaired mitochondrial complexes (I, IV, V), and decreased ATP production.
• ATP5ME deficiency in zebrafish led to developmental defects, reduced locomotion, and impaired mitochondrial function.
• Phenotypes in zebrafish were rescued by human ATP5ME mRNA, confirming pathogenicity.

Conclusions:

• ATP5ME deficiency causes a severe mitochondrial disorder in humans.
• The identified ATP5ME mutation disrupts mitochondrial complex assembly and function, leading to disease.
• ATP5ME is essential for normal development and mitochondrial homeostasis.