2. Academic Validation
  3. A homozygous variant in NDUFA8 is associated with developmental delay, microcephaly, and epilepsy due to mitochondrial complex I deficiency

A homozygous variant in NDUFA8 is associated with developmental delay, microcephaly, and epilepsy due to mitochondrial complex I deficiency

  • Clin Genet. 2020 Aug;98(2):155-165. doi: 10.1111/cge.13773.
Yukiko Yatsuka 1 2,  Yoshihito Kishita 1 2,  Luke E Formosa 3,  Masaru Shimura 4,  Fumihito Nozaki 5,  Tatsuya Fujii 5,  Kazuhiro R Nitta 1 2,  Akira Ohtake 6 7,  Kei Murayama 4,  Michael T Ryan 3,  Yasushi Okazaki 1 2 8
Affiliations

Affiliations

  • 1 Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan.
  • 2 Diagnostics and Therapeutics of Intractable Diseases, Graduate School of Medicine, Juntendo University, Tokyo, Japan.
  • 3 Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.
  • 4 Department of Metabolism, Chiba Children's Hospital, Chiba, Japan.
  • 5 Department of Pediatrics, Shiga Medical Center for Children, Moriyama, Japan.
  • 6 Center for Intractable Diseases, Saitama Medical University Hospital, Saitama, Japan.
  • 7 Department of Pediatrics and Clinical Genomics, Faculty of Medicine, Saitama Medical University, Saitama, Japan.
  • 8 Laboratory for Comprehensive Genomic Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
PMID: 32385911 DOI: 10.1111/cge.13773
Abstract

Mitochondrial complex I deficiency is caused by pathogenic variants in mitochondrial and nuclear genes associated with complex I structure and assembly. We report the case of a patient with NDUFA8-related mitochondrial disease. The patient presented with developmental delay, microcephaly, and epilepsy. His fibroblasts showed apparent biochemical defects in mitochondrial complex I. Whole-exome Sequencing revealed that the patient carried a homozygous variant in NDUFA8. His fibroblasts showed a reduction in the protein expression level of not only NDUFA8, but also the other complex I subunits, consistent with assembly defects. The Enzyme activity of complex I and oxygen consumption rate were restored by reintroducing wild-typeNDUFA8 cDNA into patient fibroblasts. The functional properties of the variant in NDUFA8 were also investigated using NDUFA8 knockout cells expressing wild-type or mutated NDUFA8 cDNA. These experiments further supported the pathogenicity of the variant in complex I assembly. This is the first report describing that the loss of NDUFA8, which has not previously been associated with mitochondrial disease, causes severe defect in the assembly of mitochondrial complex I, leading to progressive neurological and developmental abnormalities.

Keywords

CX9C motif; OXPHOS; complex I deficiency; disulfide relay import pathway; mitochondrial disease; mitochondrial intermembrane space.

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