Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0013421 (dystonia)
 8,418 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A five-generation Hispanic family expressing maternally transmitted Leber hereditary optic neuropathy and/or early-onset dystonia associated with bilateral basal ganglia lesions was studied. Buffy coat mitochondrial DNA (mtDNA) from a severely affected child was amplified by the polymerase chain reaction and greater than 90% sequenced. The mtDNA proved to be a Native American haplogroup D genotype and differed from the standard "Cambridge" sequence at 40 nucleotide positions. One of these variants, a G-to-A transition at nucleotide pair (np) 14459, changed a moderately conserved alanine to a valine at NADH dehydrogenase subunit 6 (ND6) residue 72. The np 14459 variant was not found in any of 38 Native American haplogroup D mtDNAs, nor was it detected in 108 Asian, 103 Caucasian, or 99 African mtDNAs. Six maternal relatives in three generations were tested and were found to harbor the mutation, with one female affected with Leber hereditary optic neuropathy being heteroplasmic. Thus, the np 14459 G-to-A missense mutation is specific to this family, alters a moderately conserved amino acid in a complex I gene, is a unique mtDNA variant in Native American haplogroup D, and is heteroplasmic, suggesting that it is the disease-causing mutation.
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PMID:A mitochondrial DNA mutation at nucleotide pair 14459 of the NADH dehydrogenase subunit 6 gene associated with maternally inherited Leber hereditary optic neuropathy and dystonia. 801 39

A heteroplasmic G-to-A transition at nucleotide pair (np) 14459 within the mitochondrial DNA (mtDNA)-encoded NADH dehydrogenase subunit 6 (ND6) gene has been identified as the cause of Leber hereditary optic neuropathy (LHON) and/or pediatric-onset dystonia in three unrelated families. This ND6 np 14459 mutation changes a moderately conserved alanine to a valine at amino acid position 72 of the ND6 protein. Enzymologic analysis of mitochondrial NADH dehydrogenase (complex I) with submitochondrial particles isolated from Epstein-Barr virus-transformed lymphoblasts revealed a 60% reduction (P < 0.005) of complex I-specific activity in patient cell lines compared with controls, with no differences in enzymatic activity for complexes II plus III, III and IV. This biochemical defect was assigned to the ND6 np 14459 mutation by using transmitochondrial cybrids in which patient Epstein-Barr virus-transformed lymphoblast cell lines were enucleated and the cytoplasts were fused to a mtDNA-deficient (p 0) lymphoblastoid recipient cell line. Cybrids harboring the np 14459 mutation exhibited a 39% reduction (p < 0.02) in complex I-specific activity relative to wild-type cybrid lines but normal activity for the other complexes. Kinetic analysis of the np 14459 mutant complex I revealed that the Vmax of the enzyme was reduced while the Km remained the same as that of wild type. Furthermore, specific activity was inhibited by increasing concentrations of the reduced coenzyme Q analog decylubiquinol. These observations suggest that the np 14459 mutation may alter the coenzyme Q-binding site of complex I.
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PMID:Use of transmitochondrial cybrids to assign a complex I defect to the mitochondrial DNA-encoded NADH dehydrogenase subunit 6 gene mutation at nucleotide pair 14459 that causes Leber hereditary optic neuropathy and dystonia. 862 78

We investigated a Japanese family with generalized dystonia attributed to striatal degeneration, which occurred in childhood, and late-onset optic neuropathy. We determined the entire nucleotide sequence of mitochondrial DNA (mtDNA) from the proband and compared our findings with the 2001 Revised Cambridge Reference Sequence. The mtDNA of the proband showed a total of 42 nucleotide changes. We identified two A3203G and G14459A mutations, which were completely absent in a population of 200 healthy Japanese, by estimating the frequency of each nucleotide change. The nucleotide G14459A mutation occurs in NADH dehydrogenase subunit 6, and has been suggested previously as the disease-causing mutation in Hispanic, African-American and Caucasian families of Leber's hereditary optic neuropathy (LHON) and/or dystonia. The significance of the A3203G mutation remains unknown. To our knowledge, this is the first case of LHON with dystonia that revealed a mtDNA mutation in a Japanese family.
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PMID:Leber's hereditary optic neuropathy with dystonia in a Japanese family. 1638 Jan 32

Bilateral striatal necrosis (BSN) has many causes and is characterized by unique clinical and neuroradiological features. Herein, we report a clinical and genetic analysis of three BSN cases from two independent Japanese families harboring a mitochondrial DNA (mtDNA) 14459G>A mutation located in a coding region of the NADH dehydrogenase subunit 6 gene. In the first family, two male siblings from non-consanguineous parents exhibited similar phenotypes, with infantile-onset generalized dystonia. A third sporadic case involved a male patient with a comparatively milder phenotype characterized by juvenile-onset mild truncal ataxia and parkinsonism. Cerebral magnetic resonance imaging of these cases revealed abnormal signal intensities along the bilateral putaminal area and enlarged lateral ventricle anterior horns caused by caudate nuclear atrophy, particularly in the sibling pair. The sibling-pair cases shared a homoplasmic 14459G>A mutation, and the sporadic case showed heteroplasmy of the same mutation. Additionally, all three cases harbored the 14605A>G single nucleotide polymorphism, which was previously reported as a rare synonymous variation (4.3%) in a Japanese population. Plasmid sequencing revealed a genetic linkage of these two DNA substitutions, suggesting that the three patients shared a genetic founder. Although our mtDNA analysis was only accessible using leukocytes, clinical severity might be associated with homoplasmy or heteroplasmy. In summary, it is important to evaluate potential mtDNA defects in BSN cases, regardless of familial occurrence.
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PMID:Bilateral striatal necrosis caused by a founder mitochondrial 14459G>A mutation in two independent Japanese families. 2870 90