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PubMed1997

Studies in a large family with late-onset Alzheimer disease (LOAD).

A large 10-generation family with late-onset Alzheimer disease (LOAD) inherited as an autosomal dominant trait was evaluated historically, clinically, and genetically. The family origin was traced to a founder couple of French ancestry with approximately 3,000 descendants. Although the transmission of a genetic predisposition to LOAD is demonstrated through male individuals, a predominance of affected women is observed. Currently, 14 individuals, 12 of whom are women, are classified as affected with Alzheimer disease (AD). Among the affected, the age of onset ranged from 55 to 78 years. Genotyping of the apolipoprotein E (APOE) locus demonstrated that homozygotes for the E4 allele (APOE4) developed signs of AD in their late 60s, whereas affected heterozygotes presented with the disease in their 70s. A significantly higher APOE4 frequency was observed in affected family members than in those unaffected (0.79 vs. 0.25, chi 2 = 9.919, p = 0.0016, df = 1). Survival for more than 15 years after diagnosed onset was observed in a number of those affected and can be attributed to an improved environment, including excellent care and management during the disabling phase of illness. Alternatively, it may be an example of the genetic heterogeneity in AD. Complete documentation of large families such as the one presented will facilitate the discovery of the multiple genetic factors involved in the pathogenesis of AD.

Aged↗
PubMed2002

Mechanotransduction in bone: genetic effects on mechanosensitivity in mice.

Bone formation is enhanced by mechanical loading, but human exercise intervention studies have shown that the response to mechanical loading is variable, with some individuals exhibiting robust osteogenic responses while others respond modestly. Thus, mechanosensitivity - the ability of bone tissue to detect mechanical loads - could be under genetic control. We applied controlled mechanical loading to the ulnae of 20-week-old (adult) female mice derived from three different inbred strains (C3H/He, C57BL/6, and DBA/2), and measured the bone formation response with fluorochrome labels. Mechanical properties, including mechanical strain, second moments of area, and cortical bone material properties, were measured in a group of calibration animals not subjected to in vivo loading. The C3H/He mice were significantly less responsive to mechanical loading than the other two biological strains. Material properties (flexural elastic modulus, ultimate stress) were greatest in the C3H/He cortical tissue. Geometric and areal properties at the midshaft ulna were also greatest in the C3H/He mice. Based on the presumed role of osteocytes in strain detection, we measured osteocyte lacuna population densities in decalcified midshaft ulna sections. Osteocyte lacuna density was not related to mechanosensitivity. Our data suggest that bone mechanosensitivity has a significant genetic component. Identification of the genes that exert their influence on mechanosensitivity could ultimately lead to therapies that enhance bone mass and reduce fracture susceptibility.

Animals↗
PubMed2005

The impact of including tRNA content on the optimality of the genetic code.

Statistical and biochemical studies have revealed nonrandom patterns in codon assignments. The canonical genetic code is known to be highly efficient in minimizing the effects of mistranslational errors and point mutations, since it is known that, when an amino acid is converted to another due to error, the biochemical properties of the resulted amino acid are usually very similar to those of the original one. In this study, we have taken into consideration both relative frequencies of amino acids and relative gene copy frequencies of tRNAs in genomic sequences in order to introduce a fitness function which models the mistranslational probabilities more accurately in modern organisms. The relative gene copy frequencies of tRNAs are used as estimates of the tRNA content. We also altered the rule previously used for the calculation of the probabilities of single base mutation occurrences. Our model signifies higher optimality of the genetic code towards load minimization and suggests the presence of a coevolution of tRNA frequency and the genetic code.

Amino Acids↗
PubMed2002

The genetic abnormality in the beta cell determines the response to an oral glucose load.

AIMS/HYPOTHESIS: We assessed how the role of genes genetic causation in causing maturity-onset diabetes of the young (MODY) alters the response to an oral glucose tolerance test (OGTT). METHODS: We studied OGTT in 362 MODY subjects, from seven European centres; 245 had glucokinase gene mutations and 117 had Hepatocyte Nuclear Factor -1 alpha ( HNF-1alpha) gene mutations. RESULTS: BMI and age were similar in the genetically defined groups. Fasting plasma glucose (FPG) was less than 5.5 mmol/l in 2 % glucokinase subjects and 46 % HNF-1 alpha subjects ( p < 0.0001). Glucokinase subjects had a higher FPG than HNF-1 alpha subjects ([means +/- SD] 6.8 +/- 0.8 vs 6.0 +/- 1.9 mmol/l, p < 0.0001), a lower 2-h value (8.9 +/- 2.3 vs 11.2 +/- 5.2 mmol/l, p < 0.0001) and a lower OGTT increment (2-h - fasting) (2.1 +/- 2.3 vs 5.2 +/- 3.9 mmol/l, p < 0.0001). The relative proportions classified as diabetic depended on whether fasting (38 % vs 22 %, glucokinase vs HNF-1 alpha) or 2-h values (19 % vs 44 %) were used. Fasting and 2-h glucose values were not correlated in the glucokinase subjects ( r = -0.047, p = 0.65) but were strongly correlated in HNF-1 alpha subjects ( r = 0.8, p < 0.001). Insulin concentrations were higher in the glucokinase subjects throughout the OGTT. CONCLUSION/INTERPRETATION: The genetic cause of the beta-cell defect results in clear differences in both the fasting glucose and the response to an oral glucose load and this can help diagnostic genetic testing in MODY. OGTT results reflect not only the degree of hyperglycaemia but also the underlying cause.

Adult↗
PubMed2002

Is skeletal mechanotransduction under genetic control?

Studies of twins have established that peak bone mass is about 70% heritable. The skeletal response to exercise contributes to peak bone mass, as mechanical loading increases skeletal mass during growth and development. It is possible that the skeletal responsiveness to mechanical loading is under genetic control, so that some individuals will build stronger bones with exercise. This appears to be the case in mice. Long bones in mice of the C3H/He strain are largely unresponsive to mechanical loading. Ironically, this strain of mice has very high bone density. Perhaps the genes that regulate BMD are not the same as those that regulate mechanical loading response. Studies of recombinant inbred and congenic strains derived from C3H mice will help to identify genes influencing bone size, density and responsiveness to mechanical loading.

Journal Article↗
PubMed2006

Protein misfolding and human disease.

Protein misfolding is a common event in living cells. In young and healthy cells, the misfolded protein load is disposed of by protein quality control (PQC) systems. In aging cells and in cells from certain individuals with genetic diseases, the load may overwhelm the PQC capacity, resulting in accumulation of misfolded proteins. Dependent on the properties of the protein and the efficiency of the PQC systems, the accumulated protein may be degraded or assembled into toxic oligomers and aggregates. To illustrate this concept, we discuss a number of very different protein misfolding diseases including phenylketonuria, Parkinson's disease, alpha-1-antitrypsin deficiency, familial neurohypophyseal diabetes insipidus, and short-chain acyl-CoA dehydrogenase deficiency. Despite the differences, an emerging paradigm suggests that the cellular effects of protein misfolding provide a common framework that may contribute to the elucidation of the cell pathology and guide intervention and treatment strategies of many genetic and age-dependent diseases.

Aging↗
PubMed2006

Association analysis of peroxisome proliferator-activated receptor gamma polymorphisms and late onset Alzheimer's disease in the Finnish population.

Alzheimer's disease (AD), especially late-onset AD (LOAD), is a complex disease. To date, the only established genetic risk factor for LOAD is apolipoprotein E (APOE) epsilon4, which explains partially the risk of the disease and modifies the age of onset. Peroxisome proliferator-activated receptor gamma (PPARgamma) regulates the transcription of BACE1 as well as inflammatory responses in the brain and atherosclerotic risk factors known to be involved also in AD. Based on these findings, the gene encoding PPARgamma can be viewed as an interesting candidate in AD. We examined the effect of the two previously reported variants of PPARgamma polymorphisms, the Pro12Ala and exon 6 C478T, on the risk of LOAD and age of onset in a population-based follow-up sample of aged subjects (125 LOAD patients and 462 non-demented controls). The genetic risk of AD was not significantly associated with the studied polymorphisms, but the PPARgamma Ala12-478T genotype carriers were significantly younger at the onset of dementia than the non-carriers (p = 0.026). These results suggest that the PPARgamma gene may modify the age of onset in LOAD.

Age of Onset↗
PubMed1984

Body sodium level in hypertensive and normotensive rats: effects of dietary sodium levels and sodium loads.

Rats of the genetically hypertensive (GH) strain do not have an increased body sodium content or increased natriuresis of hypertension. Spontaneously hypertensive rats (SHR), on the other hand, have an increased body sodium content and an increased rate of excretion of a sodium load. They also have an increased appetite for salt. In a study on three groups of normotensive rats with high normal, low normal, and very low sodium intakes, respectively, body sodium content was highest with the highest intake and lowest with the lowest intake. At the age of 22 weeks, after being on these intakes for 6 weeks, all three groups were put on a low sodium intake. Body sodium content of the two groups with the previous higher intakes failed to fall to the level of the group with the previous lowest intake. Thus there may be a prolonged carryover effect of salt intake in rats. The results are discussed in terms of the set point theory for sodium homeostasis.

Animals↗
PubMed1994

Mutation load and mutation-selection-balance in quantitative genetic traits.

Haldane (1937) showed that the reduction of equilibrium mean fitness in an infinite population due to recurrent deleterious mutations depends only on the mutation rate but not on the harmfulness of mutants. His analysis, as well as more recent ones (cf. Crow 1970), ignored back mutation. The purpose of the present paper is to extend these results to arbitrary mutation patterns among alleles and to quantitative genetic traits. We derive first-order approximations for the equilibrium mean fitness (and the mutation load) and determine the order of the error term. For a metric trait under mutation-stabilizing-selection balance our result differs qualitatively from that of Crow and Kimura (1964), whose analysis is based on a Gaussian assumption. Our general approach also yields a mathematical proof that the variance under the usual mutation-stabilizing-selection model is, to first order, micro/s (the house-of cards approximation) as micro/s tends to zero. This holds for arbitrary mutant distributions and does not require that the population mean coincide with the optimum. We show how the mutant distribution determines the order of the error term, and thus the accuracy of the house-of-cards approximation. Upper and lower bounds to the equilibrium variance are derived that deviate only to second order as micro/s tends to zero. The multilocus case is treated under the assumption of global linkage equilibrium.

Alleles↗
PubMed1992

Genetic variability and rodent models of human aging.

Inbred strains, outbred strains, and natural populations of rodents differ greatly in the amount and nature of the genetic variability they possess. Consequently, as models of human aging they vary with respect to the areas of research to which they are best suited. Inbred strains, in which all individuals are genetically identical, are best suited as models of specific disease processes and for manipulations involving tissue transplantation. Their lack of genetic variability, however, and the disruption of genetic linkage groups that occurs during inbreeding limit their value as models of more general aging processes. Outbred strains exhibit large interindividual genetic variation--a result of ongoing random accumulation of deleterious alleles with late ages of action. This makes them ideal models for studying the diversity of pathologic lesions, connections between pathologies, and susceptibility to pathologic lesions that collectively produce the reductions in reproductive capacity, physiological efficiency, and viability that are characteristic of aging. Natural populations also may exhibit relatively large amounts of interindividual genetic variability. However, difficulties with husbandry, variable parasite loads, and complex population genetics can compromise their suitability as models of human aging. Ultimately, a consideration of the range of animal models available and a more careful matching of the goals of a study with the genetic system of the model will prove fruitful to gerontology.

Aging↗
PubMed2003

Drug-inducible, dendritic cell-based genetic immunization.

Determining the mechanism of Ag loading of Langerhans cells (LC) for genetic immunization (GI) is complicated by the inability to distinguish between the response generated by direct transfection of LC from that due to exogenous uptake. To unravel this mechanism, we examined the impact of gene gun treatment on LC with respect to their activation and migration from skin, transgene expression, and ability to initiate humoral and cellular immune responses upon transfer to naive mice. To assess responses generated by direct LC transfection, an RU486-inducible expression system was used as a GI vector. In vitro skin organ cultures were developed from gene gun immunized mouse ear specimens to obtain LC. Gene gun treatment markedly augmented (3-fold) LC migration from ear skin, and these LC expressed the transgene at RNA and protein levels. Transfer of 2 x 10(5) migratory cells resulted in identical cellular responses to, but 10-fold lower humoral responses than, standard GI. Using an RU486-inducible system, we were able to measure responses generated by directly transfected LC. Our results indicate that direct transfection is a predominant pathway for LC Ag loading. The ability to regulate transgene expression with inducible DC-based vaccines demonstrates a new level of immunological control.

Adoptive Transfer↗
PubMed2004

Sexual abuse prevention for individuals with mental retardation: considerations for genetic counselors.

It is now widely recognized that children, adolescents, and adults with mental retardation are especially vulnerable to sexual abuse. Because at least 10% of genetic conditions are reported to include mental retardation as a feature, the provision of services to individuals with mental retardation represents a substantial portion of the case load for many genetic counselors. Our objective is to educate genetic counselors and other health professionals about this vulnerable population in order to enhance the frequency and efficacy of inquiry into sexual education and sexual abuse prevention training for patients with mental retardation. The following review article is intended to assist genetic counselors by increasing their knowledge of factors that lead to sexual abuse and provides recommendations for integrating this information into the counseling interaction.

Adolescent↗
PubMed1991

Host genetic factors do not account for variation in parasite loads in Strongyloides fuelleborni kellyi.

Previous work in Papua New Guinea has shown considerable variation in egg counts between different people infected with Strongyloides fuelleborni kellyi, although individual egg loads remained relatively constant over a 14-month period. Possible explanations include genetic predisposition, a surprising longevity of the worms, or external auto-infection. We have now analysed the pedigrees of 177 individuals for whom egg counts were available, and find no evidence for polygenic inheritance of factors related to egg counts. The use of genetic models postulating the segregation of a single unknown susceptibility gene did not enable us, using the data available, to distinguish between this hypothesis and environmental determination of egg counts; nor did we find any association between egg load and the class 1 HLA genotype of the host.

Animals↗
PubMed1998

Effect of Insertion Site and Metabolic Load on the Environmental Fitness of a Genetically Modified Pseudomonas fluorescens Isolate.

An isolate of Pseudomonas fluorescens (SBW25) was modified with different marker genes (lacZY, aph-1, and xylE). These marker genes were inserted singly or in combination into two separate (1 Mbp apart) and presumably nonessential sites (-6- and Ee) on the chromosome of SBW25. This allowed the production of a range of genetically modified SBW25 variants that differed with respect to insertion site of the marker genes and metabolic burden. The environmental fitness of the different SBW25 variants was tested in soil, in the rhizosphere of wheat and pea, and on the phylloplane of wheat. Reduced environmental fitness of the different variants was mainly attributed to the extra metabolic burden of novel gene expression, whereas choice of insertion site was of little significance. Changes in environmental fitness were dependent on the environmental conditions; an environment, such as soil, with a low microbial carrying capacity had a negative effect on the environmental fitness of variants with a large metabolic load. In environments with a larger carrying capacity, such as the rhizosphere of pea, environmental fitness of variants with a large metabolic load was not significantly different from that of variants with a smaller metabolic burden.

Journal Article↗
PubMed2005

Structural correlates of early and late onset Alzheimer's disease: voxel based morphometric study.

OBJECTIVE: To examine the brain structural correlates of age at onset in patients with Alzheimer's disease. METHODS: We studied nine patients with early onset (age < or =65 years), nine with late onset (age > 65) Alzheimer's disease (EOAD and LOAD, respectively) of mild-moderate severity, and 26 controls who were stratified into younger (YC, age < or =65, n = 9) and older (OC, age > 65, n = 17) subjects. The patients were closely matched for clinical severity: 3/2/3/1 patients had clinical dementia rating of 0.5/1/2/3, respectively, in both the groups. High resolution magnetic resonance images of the brain of the EOAD and YC groups and the LOAD and OC groups were compared on a voxel by voxel basis with statistical parametric mapping to detect areas specifically atrophic. RESULTS: The patients with EOAD showed greater neocortical atrophy at the temporoparietal junction while the patients with LOAD showed greater hippocampal atrophy. The results could not be accounted for by the apolipoprotein E genotype. CONCLUSIONS: Since genetic factors are believed to play a relevant pathogenetic role in EOAD and environmental factors in LOAD, genetic and environmental factors may differentially predispose the neocortical and limbic areas to the development of Alzheimer's neuropathology.

Age of Onset↗
PubMed1990

Isolation of high frequency of recombination donors from Tn5 chromosomal mutants of Pseudomonas putida PPN and recalibration of the genetic map.

A Tn5 loaded derivative of the IncP-10 plasmid R91-5 (pMO75) was used as a suicide vector to generate random chromosomal insertion mutations in Pseudomonas putida PPN. Reintroduction of pMO75 into such mutants resulted in integration of the plasmid at the site of Tn5 insertion, giving rise to two classes of high frequency of donors recombination (Hfr) donors, transferring chromosome at high frequency (greater than 10(-1) per donor cell) in opposite directions. Consequently, Tn5 induced auxotrophic mutations could be equated with or distinguished from previously mapped mutations, and closely linked markers ordered, on the basis of marker recovery using the two classes of Hfr donor. The isolation of many new transfer origins allowed more accurate time-of-entry analysis than previously possible and resulted in the reduction of the genetic map from 103 min to 88 min.

Blotting, Southern↗