Pathogenic mitochondrial DNA mutations in protein‐coding genes

Wong, Lee‐Jun C.

doi:10.1002/mus.20807

Cited by 109 publications

(69 citation statements)

References 115 publications

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“…However, most mtDNA SNPs are homoplasmic and are often related to age, neurodegeneration, or metabolic disorders. Some SNPs in control regions are also associated with mitochondrial content (Brownlee, 2001;Wong, 2007;Lu et al, 2010;Tanaka et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Role of mitochondrial DNA variants and copy number in diabetic atherogenesis

Chien¹,

Huang²,

Wang³

et al. 2012

Genet. Mol. Res.

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ABSTRACT. Hyperglycemia-induced reactive oxygen species production can cause diabetes and its complications, including atherosclerosis. The role of mitochondrial DNA variants and mitochondrial copy number in the pathogenesis of diabetic atherogenesis is not well understood. We examined 36 diabetic patients who had undergone amputation for diabetic foot and seven non-diabetic patients who had undergone amputation after traumatic injury. Mitochondrial DNA was extracted and used for sequencing. Single nucleotide polymorphisms (SNPs) relative to the Cambridge reference sequence were analyzed. Mitochondrial DNA copy number was quantified by real-time PCR. Twenty-one novel variants were detected in 29 diabetic patients with arterial stenosis; six of the variants were heteroplasmic, and most occurred in highly evolutionarily conserved residues. These variants were more prevalent in patients with arterial stenosis than in those without stenosis. The novel ©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 11 (3): 3339-3348 (2012) M.C. Chien et al. 3340

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Section: Introductionmentioning

confidence: 99%

Role of mitochondrial DNA variants and copy number in diabetic atherogenesis

Chien¹,

Huang²,

Wang³

et al. 2012

Genet. Mol. Res.

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“…Other homoplasmic complex I mtDNA mutations are associated with a spectrum of phenotypes from subtle symptoms to severe multisystem disorders. As an example, the homoplasmic m.14459G>A mutation in the MT-ND6 gene can cause LHON, dystonia, and Leigh-like disease but can also be found in asymptomatic individuals within the same family (Wong 2007). The family in our study expresses a new phenotype for homoplasmic mutations in MT-ND1 ranging from mild myopathic symptoms and reduced complex I activity to myopathic features on muscle biopsy and recurrent episodes of myoglobinuria, rhabdomyolysis, and muscle cramps.…”

Section: Discussionmentioning

confidence: 67%

“…The remaining 39 subunits are encoded by nuclear DNA (Wong 2007). The most common clinical phenotype caused by a mtDNA mutation in complex I is Leber hereditary optic neuropathy (LHON), a condition associated with subacute visual failure, which is often caused by a mutation in the mitochondrial ND1 subunit gene (Schapira 2006).…”

Section: Introductionmentioning

confidence: 99%

Exercise Intolerance and Myoglobinuria Associated with a Novel Maternally Inherited MT-ND1 Mutation

Rafiq¹,

Dunø

Østergaard

et al. 2015

JIMD Reports

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The most common clinical phenotype caused by a mtDNA mutation in complex I of the mitochondrial respiratory chain is Leber hereditary optic neuropathy. We report a family with a novel maternally inherited homoplasmic mtDNA m.4087A>G mutation in the ND1 gene (MT-ND1) associated with isolated myopathy, recurrent episodes of myoglobinuria, and rhabdomyolysis. DNA from blood in seven family members and muscle from four family members were PCR amplified and sequenced directly and assessed for the m.4087A>G variation in MT-ND1. Mitochondrial enzyme activity in all muscle biopsies was measured. PCR and direct sequencing of the MT-ND1 genes from blood showed that all seven family members were homoplasmic for the m.4087A>G mutation (NC_012920.1:c.781A>G). The mutation predicts a threonine to alanine substitution at position 261 (p.T261A). The same mutation was found in muscle of all four family members available for muscle biopsy, and biochemical analyses revealed an isolated complex I defect in muscle of all family members (range 22-52% of normal). Muscle morphology showed severe myopathic changes with internal nuclei in multiple fibers of all family members. Monosymptomatic myopathy with recurrent myoglobinuria is a rare phenotype of mitochondrial myopathies. We report this phenotype in a family affected by a novel homoplasmic mutation in MT-ND1. It is the first time such a phenotype has been associated with complex I gene mutations and a homoplasmic mutation of mtDNA.

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“…More than 95 % of patients with LHON have 1 of 3 mutations: m.11778 G > A, m.3460 G > A, or m.144484 T > C. Over multiple age ranges, mutations in complex I, more specifically in the gene encoding the ND1 subunit, are the most common, but mutations are spread thoughout the mtDNA genes encoding other complex I subunits [106]. Several interesting mechanisms that modify phenotype are also found in LHON.…”

Section: Lhonmentioning

confidence: 99%

“…Most are case/family reports and have been noted to be associated with genes encoding complex I, III, and IV subunits. For a review, the reader is referred to an article by Wong [106].…”

Section: Other Mitochondrial Diseases Expressed During Infancy and Chmentioning

confidence: 99%

Mitochondrial Disease in Childhood: mtDNA Encoded

Saneto

Sedensky

2013

Neurotherapeutics

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Since the first description of a mitochondrial DNA (mtDNA)-associated disease in the late 1980s, there have been more than 275 mutations within the mtDNA genome described causing human disease. The phenotypic expression of these disorders is vast, as disturbances of the unique physiology of mitochondria can create a wide range of clinical heterogeneity. Features of heteroplasmy, threshold effect, genetic bottleneck, mtDNA depletion, mitotic segregation, and maternal inheritance have been identified and described as a result of novel biochemical and genetic controls of mitochondrial function. We hope that as we unfold this fascinating part of clinical medicine, the reader will see how alterations in the tapestry of mitochondrial biochemistry and genetics can give rise to human illness.

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Pathogenic mitochondrial DNA mutations in protein‐coding genes

Cited by 109 publications

References 115 publications

Role of mitochondrial DNA variants and copy number in diabetic atherogenesis

Role of mitochondrial DNA variants and copy number in diabetic atherogenesis

Exercise Intolerance and Myoglobinuria Associated with a Novel Maternally Inherited MT-ND1 Mutation

Mitochondrial Disease in Childhood: mtDNA Encoded

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