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

Kaz M Knight; Emily Shelkowitz; Austin A Larson; David M Mirsky; Yue Wang; Ting Chen; Lee-Jun Wong; Marisa W Friederich; Johan L K Van Hove

doi:10.1016/j.mito.2020.08.009

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

Mitochondrion. 2020 Nov:55:8-13. doi: 10.1016/j.mito.2020.08.009. Epub 2020 Sep 12.

Authors

Kaz M Knight¹, Emily Shelkowitz¹, Austin A Larson¹, David M Mirsky², Yue Wang³, Ting Chen⁴, Lee-Jun Wong³, Marisa W Friederich⁵, Johan L K Van Hove⁶

Affiliations

¹ Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado, Aurora, CO, USA.
² Department of Radiology, University of Colorado, and Children's Hospital Colorado, Aurora, CO, USA.
³ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
⁴ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Department of Endocrinology, Genetics and Metabolism, Children's Hospital of Soochow University, Suzhou, China.
⁵ Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado, Aurora, CO, USA; Department of Pathology and Laboratory Medicine, Children's Hospital Colorado, 13121 East 16th Avenue, Aurora, CO, USA.
⁶ Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado, Aurora, CO, USA; Department of Pathology and Laboratory Medicine, Children's Hospital Colorado, 13121 East 16th Avenue, Aurora, CO, USA. Electronic address: Johan.Vanhove@childrenscolorado.org.

Abstract

Diagnosing complex V deficiencies caused by new variants in mitochondrial DNA is challenging due to the rarity, phenotypic diversity, and limited functional assessments. We describe a child with the m.9032T > C variant in MT-ATP6 encoding p.(Leu169Pro), with primary presentation of microcephaly, ataxia, hearing loss, and lactic acidosis. Functional studies reveal abnormal fragment F₁ of complex V on blue native gel electrophoresis. Respirometry showed excessively tight coupling through complex V depressing oxygen consumption upon ADP stimulation and an excessive increase following uncoupling, in the presence of upregulation of mitochondrial biogenesis. These data add evidence about pathogenicity and functional impact of this variant.

Keywords: Blue native PAGE; Complex V; MT-ATP6; Phenotype; Respirometry.

Publication types

Case Reports
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Substitution
Brain / diagnostic imaging
Child
High-Throughput Nucleotide Sequencing
Humans
Male
Mitochondrial Diseases / diagnostic imaging
Mitochondrial Diseases / genetics*
Mitochondrial Proton-Translocating ATPases / genetics*
Polymorphism, Single Nucleotide*
Sequence Analysis, DNA / methods*

Substances

MT-ATP6 protein, human
Mitochondrial Proton-Translocating ATPases

Grants and funding

U54 NS078059/NS/NINDS NIH HHS/United States