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The mitochondrial DNA variant m.9032T > C in MT-ATP6 encoding p.(Leu169Pro) causes a complex mitochondrial

Kaz M Knight1, Emily Shelkowitz1, Austin A Larson1

  • 1Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado, Aurora, CO, USA.

Mitochondrion
|September 15, 2020
PubMed

Insights

Diagnosing mitochondrial disease is hard. This study shows a new MT-ATP6 variant causes complex V deficiency, leading to severe symptoms in a child.

Area of Science:

  • Biochemistry
  • Genetics
  • Molecular Biology

Background:

  • Mitochondrial DNA (mtDNA) variants can cause complex V deficiencies, leading to severe clinical phenotypes.
  • Diagnosing these rare conditions is challenging due to limited functional assessments and diverse symptoms.

Observation:

  • A child presented with microcephaly, ataxia, hearing loss, and lactic acidosis.
  • Genetic analysis identified a novel m.9032T>C variant in the MT-ATP6 gene, encoding p.(Leu169Pro).

Findings:

  • Functional studies revealed an abnormal complex V fragment on blue native gel electrophoresis.
  • Respirometry demonstrated excessively tight coupling of complex V, impairing oxygen consumption and showing an abnormal response to uncoupling, despite upregulated mitochondrial biogenesis.

Implications:

  • This variant is pathogenic and impacts complex V function.
  • Understanding the functional consequences of novel mtDNA variants is crucial for accurate diagnosis and management of mitochondrial disorders.
Keywords:
Blue native PAGEComplex VMT-ATP6PhenotypeRespirometry

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