Mitochondrial DNA is multicopy and maternally inherited. mtDNA has 16,500 basepairs and codes for 37 genes; 13 polypeptides, 22 transfer RNA (tRNA), and two ribosomal RNA (rRNA). The cytochrome c oxidase II (MT-CO2) is the component of the respiratory complex IV that catalyzes the reduction of oxygen to water. Subunits 1, 2, and 3 are the functional core of this enzyme complex. Subunit 2 transfers the electrons from cytochrome c via its binuclear copper A center to the bimetallic center of the catalytic subunit 1.
Mutations in the MT-CO2 gene have been associated with mitochondrial complex IV deficiency (MT-C4D), characterized with hypertrophic cardiomyopathy, hepatomegaly and liver dysfunction, hypotonia, muscle weakness, exercise intolerance, developmental delay, delayed motor development, and mental retardation.
In order to determine the role of mitochondrial DNA mutations in thyroid tumorigenesis, Abu-Amero et al. (2005) sequenced the entire mtDNA from 24 thyroid tumor specimens and four thyroid cancer cell lines. Somatic mutations were identified in 37% of primary thyroid carcinomas (PTC) and among 25% of multinodular hyperplasia cases. Most mutations were nucleotide substitutions resulting in missense mutations. Of these mutations, 14 were nonsynonymous and 36 were synonymous. One synonymous mtDNA variant was detected within the CO2 gene in both PTC and control population. In a later study, Abu-Amero et al. (2006) sequenced the entire coding region of mitochondrial DNA for 26 MTC patients and 119 normal population controls. Of the MTC patients, 13 were sporadic, nine had MEN 2A, one had MEN 2B, and three had FMTC. In 20 MTC samples, 41 nonsynonymous mutations were detected; nine were from sporadic MTC and 11 were from familial MTC and MEN2. Also, 15 synonymous mtDNA sequence variants were found in MTC samples, seven of them were novel. Twenty seven mutations were transversions; 22 nonsynonymous and six synonymous. These transversion variants were only detected in FMTC/MEN2 while transition variants were mainly found in sporadic MTC cases. A G>C transversion mutation was found in the MT-CO2 gene, with a possibility of being damaging to the protein structure or function. None of the mutations described were present in the normal controls, suggesting that mtDNA mutations may be involved in MTC tumorigenesis and progression. Abu-Amero and Bosley (2006) studied further the molecular and biological characteristics of mitochondria in patients with Leber hereditary optic neuropathy (LHON)-like optic neuropathies. Thirty five patients (21 males and 14 females) and 159 matched controls from Saudi Arabia were included in this study. Forty one non-synonymous mtDNA sequence variants were identified in LHON patients; 14 were pathogenic. Of these variants, 21 were in complex I, seven in complex III, five in complex IV, six in complex V, one in tRNA glutamine, and one in 12S rRNA. Similar to previous reports on mutation association with LHON, these mtDNA changes were transitions. One pathogenic variant (C7623T) was found within the MT-CO2 gene.
Tabebi et al. (2016) described a multiplex consanguineous Tunisian family affected by MIDD and aimed to ascertain the underlying genetic defect. The authors studied three patients: a mother, along with her son and daughter. All three patients suffered from mitochondrial diabetes, deafness and obesity. In addition, the son also suffered from diabetic retinopathy. A whole mitochondrial genome mutational analysis helped reveal a haplotype composed by “A750G, A1438G, G8860A, T12705, T14766C and T16519C”, in homoplasmic state in all 3 patients. The family was classified under the sub-haplogroup H2a2a1. The son also had two de-novo variations: a novel m.8241T>G (p. F219C) in the MT-CO2 gene and the known m.13276G>A (p. M314V) in the MT-ND5 gene. The son’s severe phenotype was suggested to be due to the coexistence of these two mutations. The MT-CO2 m.8241T>G mutation affected a residue in an evolutionarily stable domain and was predicted to be ‘probably damaging’. The MT-ND5 m.13276G>A mutation was predicted to be ‘tolerated’ but has been previously associated with retinopathy.
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