Mitochondrial diabetes: investigation and identification of a novel mutation.

Lynn, Stephen; Wardell, Teressa M.; Johnson, Margaret; Chinnery, Patrick F.; Daly, Mark E.; Walker, Mark S.; Turnbull, D.M.

doi:10.2337/diabetes.47.11.1800

Cited by 52 publications

(21 citation statements)

References 11 publications

(8 reference statements)

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“…9 This clustering of mutations within MTTS2 suggests that an intact aminoacyl acceptor stem is of crucial importance for maintaining the unusual secondary structure of mt-tRNA Ser(AGY) , which lacks a DHU loop, and for preserving the correct function of the molecule. Although these pathogenic MTTS2 mutations are associated with a variety of clinical presentations including diabetes mellitus, myopathy, neurodevelopmental delay, encephalopathy and seizures, it is interesting to note that all four are also linked to deafness, [6][7][8] and, like the vast majority of deafness-associated mt-tRNA mutations, 33 both m.12264C4T and m.12261T4C were shown here to exhibit a high threshold for pathogenicity. Two additional MTTS2 sequence variants have also been linked to auditory symptoms; m.12236G4A has been associated with hearing loss 10 and m.12224C4T, associated with haplogroup D4, has been found to modulate the penetrance of hearing loss associated with the MT-RNR1 mutation, m.1555A4G.…”

Section: Discussionmentioning

confidence: 68%

“…[6][7][8] Interestingly, all four (m.12258C4A, m.12261T4C, m.12262C4A and m.12264C4T) are located within the 3¢-end of the aminoacyl acceptor stem of mt-tRNA Ser(AGY) , whereas a fifth 'probably pathogenic' MTTS2 mutation, m.12207G4A, has been identified within the 5¢ end of this stem. 9 This clustering of mutations within MTTS2 suggests that an intact aminoacyl acceptor stem is of crucial importance for maintaining the unusual secondary structure of mt-tRNA Ser(AGY) , which lacks a DHU loop, and for preserving the correct function of the molecule.…”

Section: Discussionmentioning

confidence: 99%

“…To date, only two MTTS2 mutations have been reported, for which sufficient evidence exists to support their classification as 'definitely pathogenic' according to recently revised canonical criteria. 4,5 These mutations are m.12258C4A, which can lead to progressive deafness and either diabetes mellitus 6 or retinitis pigmentosa, 7 and m.12262C4A, which has been shown to cause progressive mitochondrial myopathy, deafness and sporadic seizures. 8 A further three MTTS2 mutations have been described: m.12207G4A, which is associated with a MELAS-like phenotype, 9 m.12236G4A, which is linked to non-syndromic hearing impairment, 10 and m.12246C4A, which is associated with chronic intestinal pseudo-obstruction with myopathy and ophthalmoplegia.…”

Section: Introductionmentioning

confidence: 99%

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Mutations in the mitochondrial tRNASer(AGY) gene are associated with deafness, retinal degeneration, myopathy and epilepsy

et al. 2012

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Although over 200 pathogenic mitochondrial DNA (mtDNA) mutations have been reported to date, determining the genetic aetiology of many cases of mitochondrial disease is still not straightforward. Here, we describe the investigations undertaken to uncover the underlying molecular defect(s) in two unrelated Caucasian patients with suspected mtDNA disease, who presented with similar symptoms of myopathy, deafness, neurodevelopmental delay, epilepsy, marked fatigue and, in one case, retinal degeneration. Histochemical and biochemical evidence of mitochondrial respiratory chain deficiency was observed in the patient muscle biopsies and both patients were discovered to harbour a novel heteroplasmic mitochondrial tRNA (mt-tRNA) Ser(AGY) (MTTS2) mutation (m.12264C4T and m.12261T4C, respectively). Clear segregation of the m.12261T4C mutation with the biochemical defect, as demonstrated by single-fibre radioactive RFLP, confirmed the pathogenicity of this novel variant in patient 2. However, unusually high levels of m.12264C4T mutation within both COX-positive (98.4 ± 1.5%) and COX-deficient (98.2 ±2.1%) fibres in patient 1 necessitated further functional investigations to prove its pathogenicity. Northern blot analysis demonstrated the detrimental effect of the m.12264C4T mutation on mt-tRNA Ser(AGY) stability, ultimately resulting in decreased steady-state levels of fully assembled complexes I and IV, as shown by blue-native polyacrylamide gel electrophoresis. Our findings expand the spectrum of pathogenic mutations associated with the MTTS2 gene and highlight MTTS2 mutations as an important cause of retinal and syndromic auditory impairment.

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Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mutations in the mitochondrial tRNASer(AGY) gene are associated with deafness, retinal degeneration, myopathy and epilepsy

et al. 2012

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“…Methods. Frozen sections of muscle were cut at 8 m and stained for cytochrome c oxidase (COX) and succinate dehydrogenase (SDH) activity, as previously described (4). The remainder of the muscle sample was used for molecular analysis.…”

Section: Methodsmentioning

confidence: 99%

“…The first functional mutation was a C to A substitution at position 12258 in a tRNA serine gene. This mutation has been previously reported (4,11), and was associated with maternally inherited diabetes, sensorineural deafness, cataracts, and cerebellar ataxia. The second mutation was the previously reported T to C substitution at position 14709 in the tRNA glutamic acid gene (5).…”

mentioning

confidence: 99%

Defining the Importance of Mitochondrial Gene Defects in Maternally Inherited Diabetes by Sequencing the Entire Mitochondrial Genome

Choo-Kang

Lynn²,

Taylor³

et al. 2002

Diabetes

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For any mitochondrial DNA (mtDNA) mutation, the ratio of mutant to wild-type mtDNA (% heteroplasmy) varies across tissues, with low levels in leukocytes and high levels in postmitotic tissues (e.g., skeletal muscle). Direct sequencing is the gold-standard method used to detect novel mutations, but can only reliably detect % heteroplasmy >25%, which is rare in leukocytes. Therefore, we investigated the role of mtDNA defects in maternally inherited diabetes by first screening for the A3243G tRNA Leu(UUR) mutation by restriction assay, followed by sequencing of the entire mitochondrial genome using skeletal muscle derived mtDNA. A total of 28 patients had maternally inherited diabetes either alone (group 1, n ‫؍‬ 17) or with one or more additional features of mitochondrial disease, including bilateral sensori-neural deafness and neuromuscular disease (group 2, n ‫؍‬ 11). Three patients (all from group 2) carried the A3243G mutation. Skeletal muscle mtDNA from eight group 1 patients and six more group 2 patients was sequenced. No pathogenic mutations were found in the group 1 patients, while two patients from group 2 had mutations at positions 12258 and 14709 in the tRNA serine and glutamic acid genes, respectively. We conclude, therefore, that screening for mtDNA mutations should be considered in patients with maternally inherited diabetes, but only when additional features of mitochondrial disease are present. Diabetes

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m.6267G>A: a recurrent mutation in the human mitochondrial DNA that reduces cytochrome c oxidase activity and is associated with tumors

et al. 2006

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Complete sequencing of the mitochondrial genome of 13 cell lines derived from a variety of human cancers revealed nine novel mitochondrial DNA (mtDNA) variations. One of them, m.6267G>A, is a recurrent mutation that introduces the Ala122Thr substitution in the mitochondrially encoded cytochrome c oxidase I (MT-CO1): p.MT-CO1: Ala122Thr (GenBank: NP_536845.1). Biochemical analysis of the original cell lines and the transmitochondrial cybrids generated by transferring mitochondrial DNAs to a common nuclear background, indicate that cytochrome c oxidase (COX) activity, respiration, and growth in galactose are impaired by the m.6267G>A mutation. This mutation, found twice in the cancer cell lines included in this study, has been also encountered in one out of 63 breast cancer samples, one out of 64 colon cancer samples, one out of 260 prostate cancer samples, and in one out of 15 pancreatic cancer cell lines. In all instances the m.6267G>A mutation was associated to different mtDNA haplogroups. These findings, contrast with the extremely low frequency of the m.6267G>A mutation in the normal population (1:2264) and its apparent absence in other pathologies, strongly suggesting that the m.6267G>A missense mutation is a recurrent mutation specifically associated with cancer.

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Mitochondrial diabetes: investigation and identification of a novel mutation.

Cited by 52 publications

References 11 publications

Mutations in the mitochondrial tRNASer(AGY) gene are associated with deafness, retinal degeneration, myopathy and epilepsy

Mutations in the mitochondrial tRNASer(AGY) gene are associated with deafness, retinal degeneration, myopathy and epilepsy

Defining the Importance of Mitochondrial Gene Defects in Maternally Inherited Diabetes by Sequencing the Entire Mitochondrial Genome

m.6267G>A: a recurrent mutation in the human mitochondrial DNA that reduces cytochrome c oxidase activity and is associated with tumors

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