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Biomedical subjects

D C Wallace

Publications and source records attributed to D C Wallace.

At least 181 records · Page 10Linked to original sources
PubMed1989

A human muscle adenine nucleotide translocator gene has four exons, is located on chromosome 4, and is differentially expressed.

The human heart-skeletal muscle adenine nucleotide translocator (ANT1) gene was isolated and sequenced. It spans 5.8 kilobases and contains four exons. The 5'-nontranscribed region contains typical CCAAT and TATA sequences, a 22-nucleotide pair inverted repeat and a 13-nucleotide pair sequence homologous to a similar region in the ATP synthase beta subunit gene. The region surrounding the first exon and intron is G+C-region surrounding the first exon and intron is G+C-rich, and the intron contains three Sp1 binding motifs. ANT1 was assigned to chromosome 4 using both flow-sorted chromosomes and segregating human-mouse hybrid cells. Additional ANT sequences were found on at least two other chromosomes. ANT1 transcripts were present at high levels in human heart and skeletal muscle but were almost undetectable in liver, kidney, and brain. By contrast, fibroblast ANT (ANT2) mRNAs were present in all five tissues. The unique nature and arrangement of the ANT1 transcriptional control elements may account for this differential expression.

Adult↗
PubMed1989

A mitochondrial DNA mutation as a cause of Leber's hereditary optic neuropathy.

Leber's hereditary optic neuropathy is a maternally inherited disease associated with the late onset of bilateral loss of central vision and cardiac dysrhythmias. The maternal inheritance is explained by the mitochondrial origin of the disease. Analysis of the sequence of a mitochondrial DNA has indicated that a single nucleotide change at position 11778 is associated with this disease. This mutation converts the 340th amino acid of NADH dehydrogenase subunit 4 from an arginine to a histidine and eliminates an SfaNI endonuclease restriction site. A survey of restriction-fragment-length polymorphisms in the mitochondrial DNA of three independent families with this disease (an American black and two white European families) and 10 controls confirmed that this SfaNI site is associated with the disease. A phylogenetic tree for mitochondrial DNA polymorphism and sequence variants from three probands with Leber's disease and four controls was constructed, and the mutation at position 11778 was found to be associated with two mitochondrial DNA backgrounds--an American black mitochondrial DNA and a European mitochondrial DNA. Thus, this mutation must have arisen twice independently. Since the mutation correlated with symptoms of Leber's disease in both cases, these findings indicate that the mutation is a cause of the disease. This genetic analysis has identified the specific point mutation in the mitochondrial DNA that results in Leber's hereditary optic neuropathy.

Black People↗
PubMed1989

Mitochondrial DNA mutations and neuromuscular disease.

Mitochondrial DNA mutations have been identified in patients with certain neuromuscular diseases. Point mutations have been associated with maternally inherited diseases, while deletions have been identified in some 'spontaneous' cases.

Amino Acid Sequence↗
PubMed1989

Spontaneous Kearns-Sayre/chronic external ophthalmoplegia plus syndrome associated with a mitochondrial DNA deletion: a slip-replication model and metabolic therapy.

The muscle mitochondria of a patient with Kearns-Sayre/chronic external ophthalmoplegia plus syndrome were found to be completely deficient in respiratory complex I activity and partially deficient in complex IV and V activities. Treatment of the patient with coenzyme Q10 and succinate resulted in clinical improvement of respiratory function, consistent with the respiratory deficiencies. Restriction enzyme analysis of the muscle mtDNA revealed a 4.9-kilobase deletion in 50% of the mtDNA molecules. Polymerase chain reaction analysis demonstrated that the deletion was present in the patient's muscle but not in her lymphocytes or platelets. Furthermore, the deletion was not present in the muscle or platelets of two sisters. Hence, the mutation probably occurred in the patient's somatic cells. Direct sequencing of polymerase chain reaction-amplified DNA revealed a 4977-base-pair deletion removing four genes for subunits of complex I, one gene for complex IV, two genes for complex V, and five genes for tRNAs, which paralleled the respiratory enzymes affected in the disease. A 13-base-pair direct repeat was observed upstream from both breakpoints. Relative to the direction of heavy-strand replication, the first repeat was retained and the second repeat was deleted, suggesting a slip-replication mechanism. Sequence analysis of the human mtDNA revealed many direct repeats of 10 base pairs or greater, indicating that this mechanism could account for other reported deletions. We postulate that the prevalence of direct repeats in the mtDNA is a consequence of the guanine-cytosine bias of the heavy and light strands.

Base Sequence↗
PubMed1989

Evidence in a lethal infantile mitochondrial disease for a nuclear mutation affecting respiratory complexes I and IV.

A child died at 4 months of age of a lethal infantile mitochondrial disease associated with cardiomyopathy. Detailed pathologic evaluation of this patient revealed abnormalities in the striated muscle, smooth muscle, heart, and liver, but not the central nervous system. Biochemical analysis revealed a combined complex I and IV deficiency in skeletal muscle, heart, and liver, but not in kidney and brain. Analysis of mitochondrial translation products and mitochondrial DNA failed to detect any abnormality. Parallel studies on both parents were uniformly normal. These data support the hypothesis that this disease was the result of a nuclear DNA mutation in a developmental stage-specific and tissue-specific oxidative phosphorylation-gene.

Cardiomyopathies↗
PubMed1988

Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy.

Leber's hereditary optic neuropathy is a maternally inherited disease resulting in optic nerve degeneration and cardiac dysrhythmia. A mitochondrial DNA replacement mutation was identified that correlated with this disease in multiple families. This mutation converted a highly conserved arginine to a histidine at codon 340 in the NADH dehydrogenase subunit 4 gene and eliminated an Sfa NI site, thus providing a simple diagnostic test. This finding demonstrated that a nucleotide change in a mitochondrial DNA energy production gene can result in a neurological disease.

Animals↗
PubMed1988

Familial mitochondrial encephalomyopathy (MERRF): genetic, pathophysiological, and biochemical characterization of a mitochondrial DNA disease.

A large MERRF pedigree permitted the direct testing of the predictions for a mitochondrial DNA (mtDNA) mutation. A mtDNA mutation was demonstrated by proving maternal inheritance and by identifying specific deficiencies in muscle energetics and mitochondrial respiratory complexes I and IV. mtDNA heteroplasmy (a mixture of mutant and wild-type mtDNAs) was demonstrated by showing variation in the mitochondrial energetic capacity between family members. The phenotypic consequences of differential tissue-specific reliance on mitochondrial ATP was shown by correlating individual respiratory deficiency with the nature and severity of patients' clinical manifestations. The observed spectrum of clinical manifestations resulting from this heteroplasmic mtDNA mutation implies that mtDNA disease may be much more prevalent than previously anticipated.

Calorimetry, Indirect↗
PubMed1988

Mitochondrial DNA in anucleate human blood cells.

Homogeneous populations of human blood platelets or erythrocytes were lysed in alkaline EDTA, bound to nitrocellulose and hybridized to a radioactive mtDNA probe. By comparison to standards of known mtDNA concentration, we determined that platelets contained 4 mtDNA molecules per cell. Rhodamine 123 staining revealed an average of 4 mitochondria per platelet indicating that each mitochondrion contains a single mtDNA molecule. No detectable mtDNA was found in erythrocyte lysates. Using the same procedure, we found that in nucleated cells, mitochondria contained multiple mtDNAs per mitochondrion.

Blood Platelets↗
PubMed1988

Mitochondrial DNA polymorphisms in Italy. II. Molecular analysis of new and rare morphs from Sardinia and Rome.

A molecular analysis of morphs found in a previous survey of mtDNA restriction enzyme polymorphisms in Italy revealed that different site changes can give similar patterns and that the same mutation can yield variant morphs for apparently unrelated enzymes. 1. Alternative site variations were found to yield restriction fragment patterns resembling HpaI morph 4, HaeII morph 5 and AvaII morph 2. 2. A strong association was observed between the BamHI morph 3 (gain of site a) and the AvaII morph 9 and its derivatives (loss of site d). This association appears to result from an A to G transition at base pair (bp) 13,368 which simultaneously creates a new BamHI site and abolishes an AvaII site. On the other hand, the loss of the AvaII site d, which in Italy was only found in the above-mentioned association, does not always produce a new BamHI site, as observed in other Caucasian groups. Similarly, the BamHI morph 2 (gain of site b) was always found to be associated with AvaII morphs lacking site f. An A to G transition at bp 16,391 was shown to account for both changes. As in the previous case, the converse is not true. Hence, these data show that AvaII sites d and f were lost in more than one way and one of these seems to be typical of Caucasians. 3. The variation producing BamHI-3/AvaII-9 and derivatives is preferentially associated with MspI morph 4 but this is not a product of a shared mutation. Hence, this association must be the result of the linkage disequilibrium due to the maternal inheritance of mtDNA and lack of recombination. 4. The high frequency of the combination BamHI-3/AvaII-9 and derivatives with MspI-4 found in Italy (29 subjects out of 229 analysed) can best be explained by diffusion of the relevant haplotype rather than by repeated mutational events. 5. The phylogeny trees of all mtDNA morphs so far described and of mtDNA types in Caucasians have been revised taking into account both the inter- and the intra-morph heterogeneity detected by this analysis.

Child↗
PubMed1987

Sequence analysis of cDNAs for the human and bovine ATP synthase beta subunit: mitochondrial DNA genes sustain seventeen times more mutations.

We have cloned and sequenced human and bovine cDNAs for the beta subunit of the ATP synthase (ATP-syn beta), a nuclear DNA (nDNA) encoded oxidative phosphorylation (OXPHOS) gene. The two cDNAs were found to share 99% amino acid homology and 94% nucleotide homology. The evolutionary rate of ATPsyn beta was then compared with that of two mitochondrial DNA (mtDNA) ATP synthase genes (ATPase 6 and 8), seven other mtDNA OXPHOS genes, and a number of nuclear genes. The synonymous substitution rate for ATPsyn beta proved to be 1.9 x 10(-9) substitutions per site per year (substitutions x site-1 x year-1) (SSY). This is less than 1/2 that of the average nDNA gene, 1/12 the rate of ATPase 6 and 8, and 1/17 the rate of the average mtDNA gene. The synonymous and replacement substitution rates were used to calculate a new parameter, the "selective constraint ratio". This revealed that even the most variable mtDNA protein was more constrained than the average nDNA protein. Thus, the high substitution mutation rate and strong selective constraints of mammalian mtDNA proteins suggest that mtDNA mutations may result in a disproportionately large number of human hereditary diseases of OXPHOS.

Amino Acid Sequence↗
PubMed1987

cDNA sequence of a human skeletal muscle ADP/ATP translocator: lack of a leader peptide, divergence from a fibroblast translocator cDNA, and coevolution with mitochondrial DNA genes.

We have characterized a 1400-nucleotide cDNA for the human skeletal muscle ADP/ATP translocator. The deduced amino acid sequence is 94% homologous to the beef heart ADP/ATP translocator protein and contains only a single additional amino-terminal methionine. This implies that the human translocator lacks an amino-terminal targeting peptide, a conclusion substantiated by measuring the molecular weight of the protein synthesized in vitro. A 1400-nucleotide transcript encoding the skeletal muscle translocator was detected on blots of total RNA from human heart, kidney, skeletal muscle, and HeLa cells by hybridization with oligonucleotide probes homologous to the coding region and 3' noncoding region of the cDNA. However, the level of this mRNA varied substantially among tissues. Comparison of our skeletal muscle translocator sequence with that of a recently published human fibroblast translocator cognate revealed that the two proteins are 88% identical and diverged about 275 million years ago. Hence, tissues vary both in the level of expression of individual translocator genes and in differential expression of cognate translocator genes. Comparison of the base substitution rates of the ADP/ATP translocator and the oxidative phosphorylation genes encoded by mitochondrial DNA revealed that the mitochondrial DNA genes fix 10 times more synonymous substitutions and 12 times more replacement substitutions; yet, these nuclear and cytoplasmic respiration genes experience comparable evolutionary constraints. This suggests that the mitochondrial DNA genes are highly prone to deleterious mutations.

Base Sequence↗
PubMed1986

Mitotic segregation of mitochondrial DNAs in human cell hybrids and expression of chloramphenicol resistance.

The relationship between the chloramphenicol (CAP)-resistant phenotype and the mtDNA genotype was investigated in segregating human, HeLa X HT1080, somatic cell hybrids. The parental mtDNAs were quantitated in heteroplasmic cells by using restriction fragment length polymorphisms (RFLPs) detected in Southern blots. CAP-resistant (R) X CAP-sensitive (S) hybrids selected and grown in CAP for brief periods had as little as 25% CAP-R mtDNA. With prolonged selection, the CAP-R mtDNA increased to 90-95%. Hybrids selected and passaged without CAP either retained both mtDNAs or progressively lost one mtDNA (mitotic segregation). The CAP-resistance phenotype of these hybrids changed abruptly when the proportion of CAP-R mtDNAs fluctuated around approximately 10% (threshold effect). Hybrids with greater than 25% HT1080 mtDNA had an additional characteristic. They cloned better with CAP than without. The cloning efficiency in CAP of hybrids having 90% HT1080 mtDNA was more than fivefold greater than the control.

Cell Fusion↗
PubMed1986

Mitochondrial DNA polymorphisms in Italy. I. Population data from Sardinia and Rome.

The polymorphisms of human mitochondrial DNA were studied in about 150 Sardinians from Cagliari and 100 other Italians living in Rome, using total blood cell DNA and the following restriction enzymes: HpaI, BamHI, HaeII, MspI, AvaII and HincII. 1. Seven different new morphs have been identified, one for HaeII, four for AvaII and two for HincII. 2. 16 and 17 mtDNA types were observed in the Sardinian and Roman samples, respectively. Of these only seven were shared by both groups. The morphs BamHI-3, MspI-4 and AvaII-9 were found associated at a frequency (10.0%) much higher than expected (0.17%). 3. Sardinians can be differentiated from the other Italians for a higher frequency of both morph AvaII-1 (P less than 0.05) and type 1 (2-1-1-1-1) (P approximately less than 0.03), and for a lower intragroup heterogeneity (0.52 v. 0.61). 4. The Italian sample on the whole can also be differentiated from the Caucasian group previously examined for a lower frequency of BamHI morph 2 (P Yates less than 0.01), a higher frequency of HaeII morph 1 (P Yates less than 0.02) and for the presence at a non-negligible incidence (5 individuals out of 229) of the new type 57-2 (2-3-1-4-13-2). The data indicate that mtDNA polymorphisms have not only proved to be a useful tool in detecting differences among major human groups but they can also differentiate populations within the same major ethnic division.

Adult↗