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Biomedical subjects

N Howell

Publications and source records attributed to N Howell.

At least 19 recordsLinked to original sources
PubMed2000

Mitochondrial DNA haplogroups and susceptibility to AD and dementia with Lewy bodies.

The authors analyzed the relationship between nuclear genetic risk factors (apolipoprotein E genotype) and mitochondrial DNA (mtDNA) sequence variants in pathologically proved cases of AD (n = 185), dementia with Lewy bodies (DLB; n = 84), and control subjects (n = 179). Specific European mtDNA haplogroups and the A4336G mutation were not associated with an increased risk of AD. mtDNA haplogroup H was overrepresented in the DLB patients when compared with control subjects. Additional studies are needed to clarify the significance of the association.

Aged↗
PubMed2000

Persistent heteroplasmy of a mutation in the human mtDNA control region: hypermutation as an apparent consequence of simple-repeat expansion/contraction.

In the genealogical and phylogenetic analyses that are reported here, we obtained evidence for an unusual pattern of mutation/reversion in the human mitochondrial genome. The cumulative results indicate that, when there is a T-->C polymorphism at nt 16189 and a C-->T substitution at nt 16192, there is an extremely high rate of reversion (hypermutation) at the latter site. The apparent reversion rate is sufficiently high that there is persistent heteroplasmy at nt 16192 in maternal lineages and at the phylogenetic level, a situation that is similar to that observed for the rapid expansion/contraction of simple repeats within the control region. This is the first specific instance in which the mutation frequency at one site in the D-loop is markedly influenced by the local sequence "context." The 16189 T-->C polymorphism lengthens a (C:G)n simple repeat, which then undergoes expansion and contraction, probably through replication slippage. This proclivity toward expansion/contraction is more pronounced when there is a C residue, rather than a T, at nt 16192. The high T-->C reversion frequency at nt 16192 apparently is the result of polymerase misincorporation or slippage during replication, the same mechanism that also causes the expansion/contraction of this simple-repeat sequence. In addition to the first analysis of this mitochondrial hypermutation process, these results also yield mechanistic insights into the expansion/contraction of simple-repeat sequences in mtDNA.

Base Sequence↗
PubMed2000

Longitudinal analysis of the segregation of mtDNA mutations in heteroplasmic individuals.

The mutation load of the pathogenic LHON (Leber hereditary optic neuropathy) mtDNA mutation at nucleotide 3460 has been followed over time in the WBC/platelet fraction from members of a matrilineal pedigree. Longitudinal analysis over a sampling period of five to six years indicates that, in all five heteroplasmic family members, the mutation load decreases at a mean overall rate of approximately 1% per year. There was no change in mutation load in homoplasmic wildtype or in homoplasmic mutant individuals. For the purposes of comparison, a longitudinal analysis of a silent mtDNA polymorphism at nucleotide 14560 was also carried out for members of a second matrilineal pedigree. In contrast to the results for the pathogenic mtDNA mutation, there was no change in the proportion of the silent polymorphism in the WBC/platelet fraction of four family members over a period of seven years. These results indicate that the pathogenic 3460 LHON mutation segregates under negative selection in these cell populations. One possible mechanism through which selection may operate is that, in heteroplasmic individuals, the hematopoietic stem cells are generally homoplasmic, either for the wildtype or for the mutant allele. The homoplasmic mutant stem cells, because of their mitochondrial respiratory chain defect, produce fewer mature WBCs and platelets over time than do the wildtype stem cells. Alternatively, the stem cells may be heteroplasmic and selection may act to favor proliferation of mitochondria with lower levels of the pathogenic mutation in the WBC/platelet cell populations.

DNA Mutational Analysis↗
PubMed1999

Nonrandom tissue distribution of mutant mtDNA.

Heteroplasmic mitochondrial DNA (mtDNA) defects are an important cause of inherited human disease. On a cellular level, the percentage of mutant mtDNA is the principal factor behind the expression of the genetic defect. Marked variation in the level of mutant mtDNA among tissues is thought to be responsible for the diverse clinical phenotypes associated with the same pathogenic mtDNA mutation. This study was designed to determine whether the percentage level of a pathogenic mtDNA molecule is determined by a purely random process. The tissue distribution of the A3243G MELAS point mutation was analyzed in five individuals who were members of a family with maternally inherited diabetes and deafness. The level of mutant mtDNA was measured in four tissues in three individuals and three tissues in two individuals. The highest level of mutant mtDNA occurred in skeletal muscle, followed by hair follicles, and then buccal mucosa, with the lowest levels in blood (leucocyte/platelet fraction). The probability of observing any strict hierarchy in family is 4.82 x 10(-5). These results indicate that the distribution of the A3243G mutation is not solely determined by random processes.

Adult↗
PubMed1999

A novel mitochondrial DNA-like sequence in the human nuclear genome.

We describe here a nuclear mitochondrial DNA-like sequence (numtDNA) that is nearly identical in sequence to a continuous 5842 bp segment of human mitochondrial DNA (mtDNA) that spans nucleotide positions 3914 to 9755. On the basis of evolutionary divergence among modern primates, this numtDNA molecule appears to represent mtDNA from a hominid ancestor that has been translocated to the nuclear genome during the recent evolution of humans. This numtDNA sequence harbors synonymous and nonsynonymous nucleotide substitutions relative to the authentic human mtDNA sequence, including an array of substitutions that was previously found in the cytochrome c oxidase subunit 1 and 2 genes. These substitutions were previously reported to occur in human mtDNA, but subsequently contended to be present in a nuclear pseudogene sequence. We now demonstrate their exclusive association with this 5842-bp numtDNA, which we have characterized in its entirety. This numtDNA does not appear to be expressed as a mtDNA-encoded mRNA. It is present in nuclear DNA from human blood donors, in human SH-SY5Y and A431 cell lines, and in rho(0) SH-SY5Y and rho(0) A431 cell lines that were depleted of mtDNA. The existence of human numtDNA sequences with great similarities to human mtDNA renders the amplification of pure mtDNA from cellular DNA very difficult, thereby creating the potential for confounding studies of mitochondrial diseases and population genetics.

Cell Nucleus↗
PubMed1999

Human mitochondrial diseases: answering questions and questioning answers.

Since the first identification in 1988 of pathogenic mitochondrial DNA (mtDNA) mutations, the mitochondrial diseases have emerged as a major clinical entity. The most striking feature of these disorders is their marked heterogeneity, which extends to their clinical, biochemical, and genetic characteristics. The major mitochondrial encephalomyopathies include MELAS (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes), MERRF (myoclonic epilepsy with ragged red fibers), KSS/CPEO (Kearns-Sayre syndrome/chronic progressive external ophthalmoplegia), and NARP/MILS (neuropathy, ataxia, and retinitis pigmentosum/maternally inherited Leigh syndrome) and they typically present highly variable multisystem defects that usually involve abnormalities of skeletal muscle and/or the CNS. The primary emphasis here is to review recent investigations of these mitochondrial diseases from the standpoint of how the complexities of mitochondrial genetics and biogenesis might determine their varied features. In addition, the mitochondrial encephalomyopathies are compared and contrasted to Leber hereditary optic neuropathy, a mitochondrial disease in which the pathogenic mtDNA mutations produce a more uniform and focal neuropathology. All of these disorders involve, at some level, a mitochondrial respiratory chain dysfunction. Because mitochondrial genetics differs so strikingly from the Mendelian inheritance of chromosomes, recent research on the origin and subsequent segregation and transmission of mtDNA mutations is reviewed.

DNA Repair↗
PubMed1999

Mitochondrial DNA analysis: polymorphisms and pathogenicity.

The investigation of mtDNA disease can be relatively straightforward if a person has a recognisable phenotype and if it is possible to identify a known pathogenic mtDNA mutation. The difficulties arise when no known mtDNA defect can be found, or when the clinical abnormalities are complex and not easily matched to those of the more common mitochondrial disorders. We will describe here the difficulties that can be encountered during the identification of pathogenic mtDNA mutations and the approaches that can be used to confirm, or eliminate, a likely pathogenic role, in either single gene diseases or in multifactorial disorders.

Animals↗
PubMed1998

Leber hereditary optic neuropathy: respiratory chain dysfunction and degeneration of the optic nerve.

Leber hereditary optic neuropathy (LHON) is an inherited form of bilateral optic atrophy in which the primary etiological event is a mutation in the mitochondrial genome. The optic neuropathy involves a loss of central vision due to degeneration of the retinal ganglion cells and optic nerve axons that subserve central vision. The primary mitochondrial mutation is necessary, but not sufficient, for manifestation of the optic neuropathy and secondary genetic and/or epigenetic risk factors are also involved, although they are poorly defined at the present time. There is broad agreement that mutations at nucleotides 3460, 11,778 and 14,484 are primary LHON mutations, but there may also be other rare primary mutations. It appears that the three primary LHON mutations are associated with respiratory chain dysfunction, but the derangement may be relatively subtle. There is also debate on whether there are mitochondrial mutations that have a secondary etiological or pathogenic role in LHON. The specific pattern of neurodegeneration in LHON may arise from a 'chokepoint' in the optic nerve in the region of the nerve head and lamina cribosa and which may be more severe in those LHON family members who become visually affected. It is hypothesized that the respiratory chain dysfunction leads to axoplasmic stasis and swelling, thereby blocking ganglion cell function and causing loss of vision. In some LHON patients, this loss of function is reversible in a substantial number of ganglion cells, but in others, a cell death pathway (probably apoptotic) is activated with subsequent extensive degeneration of the retinal ganglion cell layer and optic nerve.

Cell Death↗
PubMed1998

MELAS and MERRF. The relationship between maternal mutation load and the frequency of clinically affected offspring.

The majority of pathogenic mitochondrial DNA (mtDNA) mutations are heteroplasmic, with both mutant and wild-type alleles present within the same individual. MtDNA is transmitted only from females to their offspring but a single female can bear offspring who harbour different levels of mutant mtDNA and have a variable phenotype. In single families, this complex genetic and phenotypic variability has confounded the identification of any relationship between the level of mutant mtDNA (mutation load) in the mother and the clinical features of her offspring. To obtain a more accurate description of the inheritance of pathogenic mtDNA mutations, we studied a large number of pedigrees that carried either the mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (A3243G MELAS) or the myoclonic epilepsy with ragged-red fibres (A8344G MERRF) mutations. We made two principal observations. First, for both mutations, higher levels of mutant mtDNA in the mothers' blood were associated with an increased frequency of affected offspring. Secondly, at any one level of maternal mutation load there was a greater frequency of affected offspring for the A3243G MELAS mutation than for the A8344G MERRF mutation. Although these results should not be used to give absolute risks to a female contemplating pregnancy, they suggest that the outcome of pregnancy is related to the level of mutant mtDNA in the mother and that the risks of having affected offspring may differ between different mtDNA mutations.

Adolescent↗
PubMed1997

The epidemiology of nontuberculous mycobacterial lymphadenitis affecting New Zealand children 1986-95.

AIMS: To study the epidemiological trends of nontuberculous mycobacterial lymphadenitis affecting New Zealand children from 1986-95. METHODS: Cases were identified from the records of the three regional reference laboratories in New Zealand. All children of less than 16 years with a positive culture of nontuberculous mycobacteria from a lymph node tissue sample were included. RESULTS: One hundred and sixty eight cases were identified, 43 in the first 5 years (no data available from Waikato) and 125 in the second 5 years of the study period. One hundred and fifty three (91%) of cases were in the 0-5 year age group and 101 (60%) were female. The head and neck was the most common site of infection accounting for 141 (84%) of all infection. In 161 (96%) of cases the causative organism was Mycobacterium avium intracellulare complex. CONCLUSION: Nontuberculous mycobacterial infections cause a subacute lymphadenitis in preschool children, usually affecting the lymph nodes of the head and neck. The annual number of microbiologically confirmed cases in New Zealand had increased substantially over recent years, most notably since 1992. The reason for the increase is unknown but possible explanations include increased awareness of mycobacterial disease, external factors causing either changes in the distribution or virulence of mycobacteria in the environment and alterations in the human immune response.

Adolescent↗
PubMed1997

Mutations in mitochondrial cytochrome c oxidase genes segregate with late-onset Alzheimer disease.

Mounting evidence suggests that defects in energy metabolism contribute to the pathogenesis of Alzheimer disease (AD). Cytochrome c oxidase (CO) is kinetically abnormal, and its activity is decreased in brain and peripheral tissue in late-onset AD. CO is encoded by both the mitochondrial and the nuclear genomes. Its catalytic centers, however, are encoded exclusively by two mitochondrial genes, CO1 and CO2 (encoding CO subunits I and II, respectively). We searched these genes, as well as other mitochondrial genes, for mutations that might alter CO activity and cosegregate with AD. In the present study, specific missense mutations in the mitochondrial CO1 and CO2 genes but not the CO3 gene were found to segregate at a higher frequency with AD compared with other neurodegenerative or metabolic diseases. These mutations appear together in the same mitochondrial DNA molecule and define a unique mutant mitochondrial genome. Asymptomatic offspring of AD mothers had higher levels of these mutations than offspring of AD fathers, suggesting that these mutations can be maternally inherited. Cell lines expressing these mutant mitochondrial DNA molecules exhibited a specific decrease in CO activity and increased production of reactive oxygen species. We suggest that specific point mutations in the CO1 and CO2 genes cause the CO defect in AD. A CO defect may represent a primary etiologic event, directly participating in a cascade of events that results in AD.

Aged↗