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Biomedical subjects

M T Lott

Publications and source records attributed to M T Lott.

At least 19 recordsLinked to original sources
PubMed1999

Mitochondrial DNA variation in human evolution and disease.

Analysis of mitochondrial DNA (mtDNA) variation has permitted the reconstruction of the ancient migrations of women. This has provided evidence that our species arose in Africa about 150000 years before present (YBP), migrated out of Africa into Asia about 60000 to 70000 YBP and into Europe about 40000 to 50000 YBP, and migrated from Asia and possibly Europe to the Americas about 20000 to 30000 YBP. Although much of the mtDNA variation that exists in modern populations may be selectively neutral, studies of the mildly deleterious mtDNA mutations causing Leber's hereditary optic neuropathy (LHON) have demonstrated that some continent-specific mtDNA lineages are more prone to manifest the clinical symptoms of LHON than others. Hence, all mtDNA lineages are not equal, which may provide insights into the extreme environments that were encountered by our ancient ancestor, and which may be of great importance in understanding the pathophysiology of mitochondrial disease.

Biological Evolution↗
PubMed1998

MITOMAP: a human mitochondrial genome database--1998 update.

We have continued to develop MITOMAP (http://www.gen.emory. edu/MITOMAP ), a comprehensive database for the human mitochondrial DNA (mtDNA). MITOMAP uses the mtDNA sequence as the unifying element for bringing together information on mitochondrial genome structure and function, pathogenic mutations and their clinical characteristics, population associated variation, and gene-gene interactions. Over the past year we have increased the degree of interlinking of MITOMAP information available on the web page, by using our generalized information management system, GENOME. As increasingly larger regions of the human genome are sequenced and characterized, the need for integrating such information is growing. Consequently, MITOMAP and GENOME provide a valuable reference for the mitochondrial biologist, in addition to being a model for the development of comprehensive, information storage and retrieval systems for other components of the human genome. This paper documents the changes to MITOMAP which have been implemented over the past year.

Computer Communication Networks↗
PubMed1997

MITOMAP: an update on the status of the human mitochondrial genome database.

We have continued to develop MITOMAP, a comprehensive database for the human mitochondrial DNA (mtDNA). MITOMAP uses the mtDNA sequence as the unifying element for bringing together information on mitochondrial genome structure and function, pathogenic mutations and their clinical characteristics, population associated variation and gene-gene interactions. As increasingly larger regions of the human genome are sequenced and characterized, the need for integrating such information will grow. Consequently, MITOMAP not only provides a valuable reference for the mitochondrial biologist, it will also provide a model for the development of comprehensive, multi-media information storage and retrieval systems for other components of the human genome. This paper is an update of the changes which have occurred to MITOMAP over the past year.

Base Sequence↗
PubMed1996

MITOMAP: a human mitochondrial genome database.

We have developed a comprehensive database (MITOMAP) for the human mitochondrial DNA (mtDNA), the first component of the human genome to be completely sequenced [Anderson et al. (1981) Nature 290, 457-465]. MITOMAP uses the mtDNA sequence as the unifying element for bringing together information on mitochondrial genome structure and function, pathogenic mutations and their clinical characteristics, population associated variation, and gene- gene interactions. As increasingly larger regions of the human genome are sequenced and characterized, the need for integrating such information will grow. Consequently, MITOMAP not only provides a valuable reference for the mitochondrial biologist, it may also provide a model for the development of information storage and retrieval systems for other components of the human genome.

Amino Acid Sequence↗
PubMed1995

Mitochondrial DNA mutations in human degenerative diseases and aging.

A wide variety of mitochondrial DNA (mtDNA) mutations have recently been identified in degenerative diseases of the brain, heart, skeletal muscle, kidney and endocrine system. Generally, individuals inheriting these mitochondrial diseases are relatively normal in early life, develop symptoms during childhood, mid-life, or old age depending on the severity of the maternally-inherited mtDNA mutation; and then undergo a progressive decline. These novel features of mtDNA disease are proposed to be the product of the high dependence of the target organs on mitochondrial bioenergetics, and the cumulative oxidative phosphorylation (OXPHOS) defect caused by the inherited mtDNA mutation together with the age-related accumulation mtDNA mutations in post-mitotic tissues.

Adult↗
PubMed1995

African, Native American, and European mitochondrial DNAs in Cubans from Pinar del Rio Province and implications for the recent epidemic neuropathy in Cuba. Cuba Neuropathy Field Investigation Team.

Genetic predisposition, particularly specific mitochondrial DNA (mtDNA) backgrounds, has been proposed as a contributing factor in the expression of an epidemic of bilateral optic neuropathy that has affected residents of Cuba since 1991. To substantiate or refute the possibility that specific subsets of mtDNAs could participate in disease expression, we took advantage of the heterogeneous ethnic origin of the Cuban population and the recent identification of a number of mtDNA polymorphisms that appear to be specific for Africans, Native Americans, and Europeans. The screening of both carefully selected people with epidemic neuropathy and control subjects from the Pinar del Rio Province for these polymorphisms revealed that African, Native American, and European mtDNA haplotypes were equally represented among case and control subjects, and suggested that approximately 50% of Cuban mtDNAs originated from Europeans, 46% from Africans, and 4% from Native Americans. These findings demonstrate that mutations arising in specific mtDNAs are unlikely to play a role in the epidemic neuropathy and indicate that analysis of mtDNA haplotypes can be a valuable tool for assessing the relative maternal contribution of Africans, Native Americans, and Europeans in a mixed population.

Africa↗
PubMed1994

Marked changes in mitochondrial DNA deletion levels in Alzheimer brains.

Levels of the common 4977 nucleotide pair (np) mitochondrial DNA (mtDNA) deletion (mtDNA4977) were quantitated in the cortex, putamen, and cerebellum of patients with Alzheimer disease (AD) and compared to age-matched controls. Although cerebellum deletion levels were comparably low in AD patients and controls of all ages, cortical deletion levels were clearly different. The levels of mtDNA deletions in control brains started low, but rose markedly after age 75, while those of AD patients started high and declined to low levels by age 80. Choosing age 75 to arbitrarily delineate between younger and older subjects, younger patients had 15 times more mtDNA deletions than younger controls, while older patients had one-fifth the deletion level of older controls. Younger AD patients also had fourfold more deletions than older AD patients. These results support the hypothesis that OXPHOS defects resulting from somatic mtDNA mutations may play a role in AD pathophysiology.

Age Factors↗
PubMed1994

Epidemic neuropathy in Cuba not associated with mitochondrial DNA mutations found in Leber's hereditary optic neuropathy patients. Cuba Neuropathy Field Investigation Team.

An epidemic neuropathy in Cuba has caused bilateral optic neuropathies in more than 26,000 people during the past three years. Various pathogenetic factors have been proposed, including toxins, nutritional deficiencies, and an underlying genetic predisposition involving mitochondrial DNA. As part of a case-control collaborative investigation, 135 Cuban blood samples were analyzed for the most common mitochondrial DNA mutations associated with Leber's hereditary optic neuropathy. None of the participants tested were found to have the mitochondrial DNA mutations at nucleotide positions 11778, 3460, 14484, 7444, or 9804. Of 57 definite case subjects and 69 normal control subjects, three case and three control subjects had the mutation at nucleotide position 9438, three different case and three different control subjects had the mutation at position 13708, and one case and one control subject had the mutation at position 15257 in association with the mutation at position 13708. The most common mitochondrial DNA mutations associated with Leber's hereditary optic neuropathy do not appear to be contributing factors in the epidemic neuropathy in Cuba. We also identified a large Cuban family with maternally related members who experienced visual loss consistent with the diagnosis of Leber's hereditary optic neuropathy. Maternal family members harbored the highly pathogenetic mutation at nucleotide position 11778.

Adolescent↗
PubMed1994

Mitochondrial DNA mutations in epilepsy and neurological disease.

Recent discoveries in mitochondrial clinical genetics have revealed that a broad spectrum of clinical phenotypes are associated with mutations in mitochondrial DNA. Diseases caused by mutations in mitochondrial DNA are by nature quantitative. Myoclonic epilepsy and ragged-red fiber disease are caused by a mutation in the transfer RNA gene lysine. Although everyone in a maternal lineage will harbor the same mutation, the nature and severity of the symptoms vary markedly among individuals. This variability correlates with the inherited percentage of mutations in the individual's mitochondrial DNA and the individual's age. Age-related expression of mitochondrial disease has also been demonstrated for mitochondrial DNA deletions. Although deletions that retain both origins of replication result in late-onset disease because of the progressive enrichment of the deleted mitochondrial DNA, a 10.4-kb deletion that lacks the light-strand replication origin and maintains a stable mutant percentage in both tissues and cultured cells has been discovered. This deletion is associated with adult-onset diabetes and deafness, but not with ophthalmoplegia, ptosis, or mitochondrial myopathy. Biochemically, it causes a generalized defect in mitochondrial protein synthesis and oxidative phosphorylation. The age-related decline in oxidative phosphorylation could reflect the accumulation of somatic mitochondrial DNA mutations. Inhibition of oxidative phosphorylation stimulates this accumulation. The general paradigm for mitochondrial DNA diseases may be that inherited mutations inhibit the electron transport chain. This damages the mitochondrial DNA, further reducing oxidative phosphorylation. Ultimately, oxidative phosphorylation drops below the expression threshold of cells and tissues, and clinical symptoms appear.

Adult↗
PubMed1994

mtDNA and the origin of Caucasians: identification of ancient Caucasian-specific haplogroups, one of which is prone to a recurrent somatic duplication in the D-loop region.

mtDNA sequence variation was examined in 175 Caucasians from the United States and Canada by PCR amplification and high-resolution restriction-endonuclease analysis. The majority of the Caucasian mtDNAs were subsumed within four mtDNA lineages (haplogroups) defined by mutations that are rarely seen in Africans and Mongoloids. The sequence divergence of these haplogroups indicates that they arose early in Caucasian radiation and gave raise to modern European mtDNAs. Although ancient, none of these haplogroups is old enough to be compatible with a Neanderthal origin, suggesting that Homo sapiens sapiens displaced H. s. neanderthaliensis, rather than mixed with it. The mtDNAs of one of these haplogroups have a unique homoplasmic insertion between nucleotide pair (np) 573 and np 574, within the D-loop control region. This insertion makes these mtDNAs prone to a somatic mutation that duplicates a 270-bp portion of the D-loop region between np 309 and np 572. This finding suggests that certain nonpathogenic mtDNA mutations could predispose individuals to mtDNA rearrangements.

Animals↗
PubMed1994

mtDNA and Y-chromosome polymorphisms in four Native American populations from southern Mexico.

mtDNA sequence variation was examined in 60 Native Americans (Mixtecs from the Alta, Mixtecs from the Baja, Valley Zapotecs, and Highland Mixe) from southern Mexico by PCR amplification and high-resolution restriction endonuclease analysis. Four groups of mtDNA haplotypes (haplogroups A, B, C, and D) characterize Amerind populations, but only three (haplogroups A, B, and C) were observed in these Mexican populations. The comparison of their mtDNA variation with that observed in other populations from Mexico and Central America permits a clear distinction among the different Middle American tribes and raises questions about some of their linguistic affiliations. The males of these population samples were also analyzed for Y-chromosome RFLPs with the probes 49a, 49f, and 12f2. This analysis suggests that certain Y-chromosome haplotypes were brought from Asia during the colonization of the Americas, and a differential gene flow was introduced into Native American populations from European males and females.

DNA, Mitochondrial↗
PubMed1993

Atypical Leber's hereditary optic neuropathy with molecular confirmation.

OBJECTIVE: Leber's hereditary optic neuropathy (LHON) is typically a familial disease of primarily young, male adults. Analysis of mitochondrial DNA has identified point mutations associated with LHON and allowed us to identify cases of LHON not consistent with traditional descriptions of the disease. DATA SOURCES: The collective experience of three tertiary referral centers contributed to this report. STUDY SELECTION: Patients with bilateral optic neuropathies who were positive for the 11778 LHON mutation were included in this study if they were female and there was no family history of visual loss. DATA EXTRACTION: Six case histories are presented. DATA SYNTHESIS: The diagnosis of LHON remained unknown in six female patients with bilateral optic neuropathies until molecular analysis revealed the 11778 mitochondrial DNA mutation. None of the patients had a family history of visual loss, and five were initially diagnosed as having factitious visual loss. Other individual features atypical for LHON included lack of the characteristic LHON funduscopic appearance, bitemporal hemianopia, optic disc cupping, and premonitory episodes of transient visual loss. In one patient the correct diagnosis was delayed 17 years. CONCLUSIONS: The diagnosis of LHON should be considered in all cases of unexplained optic neuropathy, including those with negative family history, late or early age at onset, female gender, or normal funduscopic appearance.

Adult↗
PubMed1993

Mitochondrial DNA variants observed in Alzheimer disease and Parkinson disease patients.

Mitochondrial DNA (mtDNA) variants associated with Alzheimer disease (AD) and Parkinson disease (PD) were sought by restriction endonuclease analysis in a cohort of 71 late-onset Caucasian patients. A tRNA(Gln) gene variant at nucleotide pair (np) 4336 that altered a moderately conserved nucleotide was present in 9/173 (5.2%) of the patients surveyed but in only 0.7% of the general Caucasian controls. One of these patients harbored an additional novel 12S rRNA 5-nucleotide insertion at np 956-965, while a second had a missense variant at np 3397 that converted a highly conserved methionine to a valine. This latter mutation was also found in an independent AD + PD patient, as was a heteroplasmic 16S rRNA variant at np 3196. Additional studies will be required to determine the significance, if any, of these mutations.

Aged↗
PubMed1992

Optic disk cupping and electrocardiographic abnormalities in an American pedigree with Leber's hereditary optic neuropathy.

We examined the clinical characteristics of affected and unaffected members of an American black family with the 11778 mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Thirty-six individuals from four generations were included. All maternally related subjects were shown to be essentially homoplasmic for the 11778 mitochondrial DNA mutation in blood. Paternally related subjects did not carry this mutation. Patients affected with optic neuropathy had optic nerve head cupping. Loss of unmyelinated axons from the prelaminar optic nerve may be responsible for cupping in these patients. Electrocardiographic analysis of subjects carrying the 11778 mitochondrial DNA mutation disclosed statistically significant (P = .02) prolongation of the corrected OT interval as compared to control subjects. While the clinical significance of this magnitude of corrected QT prolongation is unknown, it may represent a systemic manifestation of the 11778 mutation. No electrocardiographic evidence of preexcitation syndromes was seen.

Adolescent↗
PubMed1992

Diseases resulting from mitochondrial DNA point mutations.

A number of mitochondrial DNA (mtDNA) mutations have been identified which cause familial, late onset neuromuscular degenerative diseases. These include missense mutations in most of the mtDNA polypeptide genes as well as base substitutions in several tRNA genes. Missense mutations in the mitochondrial electron-transport genes cause Leber hereditary optic neuropathy. Ten mutations have been associated with this disease, but four at nps 11,178, 3460, 4160 and 15,257 appear sufficient in themselves to cause the disease. One missense mutation in the ATPase 6 gene at np 8993 causes a second phenotype, neurogenic muscle weakness, ataxia and retinitis pigmentosum. Transfer RNA mutations have been identified for myoclonic epilepsy and ragged-red fibre disease in the tRNA(Lys) gene at np 8344 and for the mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome and for maternal mitochondrial myopathy and cardiomyopathy syndrome in the tRNA(Leu)(UUR) gene at nps 3234 and 3260, respectively. Deficiencies in mitochondrial oxidative phosphorylation enzymes have been observed in several common neurodegenerative diseases such as Alzheimer and Parkinson diseases. Perhaps mtDNA mutations play a role in these as well.

Base Sequence↗
PubMed1992

Association of mitochondrial DNA damage with aging and coronary atherosclerotic heart disease.

The role of somatic mitochondrial DNA (mtDNA) damage in human aging and progressive diseases of oxidative phosphorylation (OXPHOS) was examined by quantitating the accumulation of mtDNA deletions in normal hearts and hearts with coronary atherosclerotic disease. In normal hearts, mtDNA deletions appeared after 40 and subsequently accumulated with age. The common 4977 nucleotide pair (np) deletion (mtDNA4977) reached a maximum of 0.007%, with the mtDNA7436 and mtDNA10,422 deletions appearing at the same time. In hearts deprived of mitochondrial substrates due to coronary artery disease, the level of the mtDNA4977 deletion was elevated 7-220-fold over age-matched controls, with the mtDNA7436 and mtDNA10,422 deletions increasing in parallel. This cumulative mtDNA damage was associated with a compensatory 3.5-fold induction of nuclear OXPHOS gene mRNA and regions of ischemic hearts subjected to the greatest work load (left ventricle) showed the greatest accumulation of mtDNA damage and OXPHOS gene induction. These observations support the hypothesis that mtDNA damage does accumulate with age and indicates that respiratory stress greatly elevates mitochondrial damage.

Adult↗