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A novel homozygous variant in MICOS13/QIL1 causes hepato-encephalopathy with mitochondrial DNA depletion syndrome.

ABSTRACT: 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 MICOS13 cDNA 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) MICOS13 variant causes hepato-encephalopathy with MTDPS. We propose that MICOS13 is classified as the cause of MTDPS.

SUBMITTER: Kishita Y

PROVIDER: S-EPMC7549589 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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A novel homozygous variant in MICOS13/QIL1 causes hepato-encephalopathy with mitochondrial DNA depletion syndrome.

Kishita Yoshihito Y Shimura Masaru M Kohda Masakazu M Akita Masumi M Imai-Okazaki Atsuko A Yatsuka Yukiko Y Nakajima Yoko Y Ito Tetsuya T Ohtake Akira A Murayama Kei K Okazaki Yasushi Y

Molecular genetics & genomic medicine 20200804 10

<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>Here, whole-exome sequencing of a ...[more]

PMID: 32749073

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Project description:Mutations in mitochondrial DNA (mtDNA) have been linked to a variety of metabolic, neurological and muscular diseases which can present at any time throughout life. MtDNA is replicated by DNA polymerase gamma (Pol γ), twinkle helicase and mitochondrial single-stranded binding protein (mtSSB). The Pol γ holoenzyme is a heterotrimer consisting of the p140 catalytic subunit and a p55 homodimeric accessory subunit encoded by the nuclear genes POLG and POLG2, respectively. The accessory subunits enhance DNA binding and promote processive DNA synthesis of the holoenzyme. Mutations in either POLG or POLG2 are linked to disease and adversely affect maintenance of the mitochondrial genome, resulting in depletion, deletions and/or point mutations in mtDNA. A homozygous mutation located at Chr17: 62492543G>A in POLG2, resulting in R182W substitution in p55, was previously identified to cause mtDNA depletion and fatal hepatic liver failure. Here we characterize this homozygous R182W p55 mutation using in vivo cultured cell models and in vitro biochemical assessments. Compared to control fibroblasts, homozygous R182W p55 primary dermal fibroblasts exhibit a two-fold slower doubling time, reduced mtDNA copy number and reduced levels of POLG and POLG2 transcripts correlating with the reported disease state. Expression of R182W p55 in HEK293 cells impairs oxidative-phosphorylation. Biochemically, R182W p55 displays DNA binding and association with p140 similar to WT p55. R182W p55 mimics the ability of WT p55 to stimulate primer extension, support steady-state nucleotide incorporation, and suppress the exonuclease function of Pol γ in vitro. However, R182W p55 has severe defects in protein stability as determined by differential scanning fluorimetry and in stimulating function as determined by thermal inactivation. These data demonstrate that the Chr17: 62492543G>A mutation in POLG2, R182W p55, severely impairs stability of the accessory subunit and is the likely cause of the disease phenotype.

Dataset Information

A novel homozygous variant in MICOS13/QIL1 causes hepato-encephalopathy with mitochondrial DNA depletion syndrome.

Publications

A novel homozygous variant in MICOS13/QIL1 causes hepato-encephalopathy with mitochondrial DNA depletion syndrome.

Similar Datasets

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