Journal
MOLECULAR GENETICS & GENOMIC MEDICINE
Volume 8, Issue 10, Pages -Publisher
WILEY
DOI: 10.1002/mgg3.1427
Keywords
cristae; MICOS complex; mitochondrial disease; mitochondrial DNA depletion syndrome
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Funding
- Tokyo Biochemical Research Foundation
- Ministry of Education, Culture, Sports, Science and Technology (MEXT)
- Japan Society for the Promotion of Science [16K09973, 19H03624]
- Japan Agency for Medical Research and Development [JP18ek0109177, JP18kk0205002, JP19ek0109273, JP19kk0205014, JP20ek0109468]
- MEXT
- Grants-in-Aid for Scientific Research [19H03624, 16K09973] Funding Source: KAKEN
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Background: Mitochondrial DNA depletion syndrome (MTDPS) is part of a group of mitochondrial diseases characterized by a reduction in mitochondrial DNA copy number. Most MTDPS is caused by mutations in genes that disrupt deoxyribonucleotide metabolism. Methods: We performed the whole-exome sequencing of a hepato-encephalopathy patient with MTDPS and functional analyses to determine the clinical significance of the identified variant. Results: Here, whole-exome sequencing of a patient presenting with hepato-encephalopathy and MTDPS identified a novel homozygous frameshift variant, c.13_29del (p.Trp6Profs*71) in MICOS13. MICOS13 (also known as QIL1, MIC13, or C19orf70) is a component of the MICOS complex, which plays crucial roles in the maintenance of cristae junctions at the mitochondrial inner membrane. We found loss of MICOS13 protein and fewer cristae structures in the mitochondria of fibroblasts derived from the patient. Stable expression of a wild-type MICOS13c DNA in the patients fibroblasts using a lentivirus system rescued mitochondrial respiratory chain complex deficiencies. Conclusion: Our findings suggest that the novel c.13_29del (p.Trp6Profs*71)MICOS13variant causes hepato-encephalopathy with MTDPS. We propose thatMICOS13is classified as the cause of MTDPS.
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