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). MT-ND2 (NADH dehydrogenase 2) is a core subunit of the mitochondrial NADH dehydrogenase (complex I) that catalyzes the transfer of electrons from NADH to ubiquinone with pumping protons across the mitochondrial inner membrane complexes to provide energy for the generation of ATP. The most prominent roles of mitochondria are production of adenosine triphosphate (ATP) and regulation of cellular metabolism.
Mutations within the NADH dehydrogenase 2 (MT-ND2) mitochondrial gene that could produce a change in the protein's secondary structure have been found in patients with the mitochondrial type of Alzheimer disease (AD-MT) and leber hereditary optic neuropathy (LHON).
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 sequence variants, 14 were nonsynonymous and 36 were synonymous. Three nonsynonymous mutations were found in the ND2 gene. One of these mutations (206C>T) was present in both PTC and normal populations. The 5298A>G mutation was present in two separate PTC samples. Also, one of these mutations was a single base pair deletion in nucleotide 5408. 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. Five nonsynonymous and two synonymous variants were found in the MT-ND2 gene. None of these mutations 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. Two nonpathogenic A4917G and A5319T variants were identified within the MT-ND2 gene. The A4917G secondary mutation was found in both patients and in control subjects.
Alila et al. (2016) studied the mitochondrial genome of two Tunisian families affected by dilated cardiomyopathy. The index patient from Family A was a 9-month-old female with a heteroplasmic m.3243A>G mutation in the MT-TL1 gene. Family B consisted of a 9-year-old female with dilated cardiomyopathy, congenital cataracts and facial dysmorphia such as a triangular face and wide forehead. She had a 20-year-old brother with congenital cataracts and two maternal uncles that had died before the age of 15 due to cardiomyopathy associated with deafness. Mitochondrial analysis revealed a homoplasmic m.5182C>T (p.238T>M) mutation in the patient’s MT-ND2 gene. In-silico analysis found the mutation to occur at the beginning of the eighth transmembrane helix of ND2. It was predicted to be ‘probably damaging’ and to increase hydrophobicity, altering the protein flexibility. It was noted that the mitochondrial variants identified in families’ A and B classify both in the same haplogroup H2a2a1. In addition, the missense mutations m.13708G>A (p.458A>T, MT-ND5 gene) and m.14766C>T (p.7T4I, MT-CYB gene) were also identified in the patient from Family B and her mother.
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