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 changes, 14 were nonsynonymous and 36 were synonymous.  Seven synonymous and five nonsynonymous mtDNA sequence changes were detected in the ND5 gene; four were novel.  The 12403C>T mutation was found in both PTC and control samples.  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.  Four nonsynonymous and two synonymous mutations were identified in the MT-ND5 gene, one of these mutations was probably damaging.  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.  Nine variants were identified within the MT-ND5 gene: C12346T, C12403T, T12782G, A12950G, A13379C, A13681G, G13708A, C13934T and T14110C.  Two of these variants were pathogenic (T12782G and A13379C).  The T12782G nucleotide change was heteroplasmic, and the G13708A mutation was present in both patients and in control subjects.

Tabebi et al. (2016) described a multiplex consanguineous Tunisian family affected by 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.