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Gerard D Schellenberg

Publications and source records attributed to Gerard D Schellenberg.

52 records · Page 3Linked to original sources
PubMed2004

ADLAPH: A molecular haplotyping method based on allele-discriminating long-range PCR.

We present a method, called Allele-Discriminating Long and Accurate PCR Haplotyping (ADLAPH), for directly determining haplotypes from an extended genomic region. This method uses allele-discriminating primers in long-range PCR to amplify only one of the two chromosome homologues for the region of interest. Haplotypes are then determined from these phase-separated PCR fragments by conventional single nucleotide polymorphism (SNP) genotyping methods. This simple robust procedure makes it practical for high-throughput haplotyping of unrelated individuals, and potentially allows direct observation of haplotype information for up to 40 kb or more. We demonstrate the feasibility of this molecular haplotyping procedure by generating apolipoprotein E (APOE) haplotypes from 100 unrelated subjects.

Alleles↗
PubMed2003

Neurodegeneration and defective neurotransmission in a Caenorhabditis elegans model of tauopathy.

Frontotemporal dementia with parkinsonism chromosome 17 type (FTDP-17) is caused by mutations in MAPT, the gene encoding tau. FTDP-17 begins with executive function deficits and other abnormal behaviors, which progress to dementia. Neurodegenerative changes include accumulation of aggregated tau as neuronal and glial fibrillary tangles. Aggregated tau is seen in numerous other neurodegenerative diseases, including Alzheimer's disease (AD). We expressed normal and FTDP-17 mutant human tau (mutations P301L and V337M) in Caenorhabditis elegans to model tauopathy disorders. Tau pan-neuronal expression caused progressive uncoordinated locomotion (Unc), characteristic of nervous system defects in worms. Subsequently, insoluble tau accumulates and both soluble and insoluble tau is phosphorylated at many of the sites hyperphosphorylated in FTDP-17, AD, and other tauopathies. Substantial neurodegeneration, seen as bulges and gaps in nerve cords followed by loss of neurons, occurs after insoluble tau begins to accumulate. Axons show vacuoles, membranous infoldings, and whorls with associated amorphous tau accumulations and abnormal tau-positive aggregates. FTDP-17 mutation lines had a more severe Unc phenotype, accumulated more insoluble tau at a younger age, were more resistant to cholinergic inhibitors, and had more severe axonal degeneration when compared with lines expressing normal tau. The Unc phenotype is caused by a presynaptic defect. Postsynaptic transmission is intact. This transgenic model will enable mechanistic dissection of tau-induced neurodegeneration and identification of genes and compounds that inhibit pathological tau formation.

Animals↗
PubMed2003

Paraoxonase activity, but not haplotype utilizing the linkage disequilibrium structure, predicts vascular disease.

OBJECTIVE: The effects of paraoxonase (PON1) activity and of genetic variation in the PON1 promoter and coding region on carotid artery disease (CAAD) were investigated. METHODS AND RESULTS: We identified functional promoter polymorphisms and examined their effects in a cohort with and without CAAD. We used the full sequences in 23 white subjects to determine the linkage disequilibrium (LD) structure of the PON1 region and to direct the grouping of haplotypes for disease association testing. There are several discrete regions of the PON1 gene with strong local LD, but the useful levels of LD do not extend across the entire gene. Indeed, PON1-162/-108/55/192 haplotype did not predict additional variation in PON1 activities compared with the 4 genotypes separately. PON1 hydrolysis activity predicted CAAD status, but this was not attributable to the promoter or coding region polymorphisms or haplotype or to the effects of smoking or statin use on PON1 activity. CONCLUSIONS: PON1 does not have LD across the gene, and use of haplotypes in association studies should consider the LD structure. PON1 activity predicts CAAD, yet 4 functional polymorphisms do not. Additional investigations of genetic and environmental factors that influence PON1 activity as a risk factor for vascular disease are warranted.

Adult↗
PubMed2003

Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer's disease is associated with the apolipoprotein E-epsilon4 allele.

Abeta is the major component of amyloid plaques characterizing Alzheimer's disease (AD). Abeta accumulation can be affected by numerous factors including increased rates of production and/or impaired clearance. Insulin-degrading enzyme (IDE) has been implicated as a candidate enzyme responsible for the degradation and clearance of Abeta in the brain. We have previously shown that AD patients exhibit abnormalities in insulin metabolism that are associated with apoliprotein E (APOE) status. The possible association of IDE with AD, as well as the link between APOE status and insulin metabolism, led us to examine the expression of IDE in AD. We report that hippocampal IDE protein is reduced by approximately 50% in epsilon4+ AD patients compared to epsilon4- patients and controls. The allele-specific decrease of IDE in epsilon4+ AD patients is not associated with neuronal loss since neuron-specific enolase levels were comparable between the AD groups, regardless of APOE status. Hippocampal IDE mRNA levels were also reduced in AD patients with the epsilon4 allele compared to AD and normal subjects without the epsilon4 allele. These findings show that reduced IDE expression is associated with a significant risk factor for AD and suggest that IDE may interact with APOE status to affect Abeta metabolism.

Aged↗
PubMed2003

Insulin dose-response effects on memory and plasma amyloid precursor protein in Alzheimer's disease: interactions with apolipoprotein E genotype.

In previous studies, adults with Alzheimer's disease (AD) showed memory enhancement when plasma insulin levels were raised to 85 microU/ml, whereas normal adults' memory was unchanged. Degree of memory enhancement was also related to apolipoprotein E (apoE) genotype status for AD patients. Response differences between normal and AD groups could reflect dose-response differences for insulin. To examine this question, 22 adults with AD and 15 normal adults received five doses of insulin on separate days in counterbalanced order, resulting in five plasma insulin levels (10, 25, 35, 85 and 135 microU/ml), while plasma glucose levels of ~100 mg/dl were maintained. Cognitive performance and plasma APP levels were measured after 120 min of infusion. Relative to baseline, AD patients who were not apoE- epsilon 4 homozygotes had improved memory at higher insulin levels of 35 and 85 microuU/ml, whereas normal adults and AD patients who were epsilon 4 homozygotes showed improved memory at insulin levels of 25 microU/ml. Normal adults' memory was also improved at insulin levels of 85 microU/ml. Plasma APP was lowered for adults with AD without the epsilon 4 allele at higher levels (85 microU/ml) than for normal adults and epsilon 4 homozygotes, who showed decreased APP at the 35 microU/ml level. AD patients with a single epsilon 4 allele showed a different pattern of insulin effects on APP than did other subjects. In general, few effects of insulin were seen at the highest dose for any subject group. These results support a role for insulin in normal memory and APP modulation that follows a curvilinear response pattern, and suggest that AD patients who are not epsilon 4 homozygotes have reduced sensitivity to insulin that may interfere with such modulation.

Aged↗
PubMed2003

Alteration in calcium channel properties is responsible for the neurotoxic action of a familial frontotemporal dementia tau mutation.

Tau, a microtubule binding protein, is not only a major component of neurofibrillary tangles in Alzheimer's disease, but also a causative gene for hereditary frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). We show here that an FTDP-17 tau mutation (V337M) in SH-SY5Y cells reduces microtubule polymerization, increases voltage-dependent calcium current (ICa) density, and decreases ICa rundown. The reduced rundown of ICa by V337M was significantly inhibited by nifedipine (L-type Ca channel blocker), whereas omega-conotoxin GVIA (N-type Ca channel blocker) showed smaller effects, indicating that tau mutations affect L-type calcium channel activity. The depolarization-induced increase in intracellular calcium was also significantly augmented by the V337M tau mutation. Treatment with a microtubule polymerizing agent (taxol), an adenylyl cyclase inhibitor, or a protein kinase A (PKA) inhibitor, counteracted the effects of mutant tau on ICa. Taxol also attenuated the Ca2+ response to depolarization in cells expressing mutant tau. Apoptosis in SH-SY5Y cells induced by serum deprivation was exacerbated by the V337M mutation, and nifedipine, taxol, and a PKA inhibitor significantly protected cells against apoptosis. Our results indicate that a tau mutation which decreases its microtubule-binding ability augments calcium influx by depolymerizing microtubules and activating adenylyl cyclase and PKA.

Calcium↗
PubMed2002

No evidence for linkage of liability to autism to HOXA1 in a sample from the CPEA network.

A recent study by Ingram et al. [2000b: Teratology 62:393-405] suggests a (His)73(Arg) polymorphism (A:G) in HOXA1 contributes substantially to a liability for autism. Using 68 individuals diagnosed with Autism Spectrum Disorders, they found a significant dearth of G homozygotes and biased transmission of G alleles from parents to affected offspring, especially from mothers. Because the connection between HOXA1 and liability to autism is compelling, we attempted to replicate their finding using a larger, independent sample from the Collaborative Programs of Excellence in Autism (CPEA) network. In our data, genotype frequencies conform to Hardy-Weinberg equilibrium; allele transmissions meet Mendelian expectations; and there is no obvious sex-biased allele transmission. Based on our sample size, calculations suggest that we would have at least 95% power to detect linkage and association even if the A:G polymorphism were to account for only 1% of the heritability of autism. Therefore, although we cannot exclude the possibility that the samples in the two studies are intrinsically different, our data from our sample argue against a major role for HOXA1 (His)73(Arg) in liability to autism.

Asperger Syndrome↗
PubMed2002

Vitamin C and E intake is associated with increased paraoxonase activity.

OBJECTIVE: Paraoxonase (PON1), an esterase physically associated with high density lipoprotein, has been shown to inhibit atherogenic low density lipoprotein and high density lipoprotein oxidation. PON1 activity appears to be primarily under genetic control with some environmental modification and is a predictor of vascular disease. Vitamins C and E, dietary antioxidants, scavenge free-oxygen radical products that may depress PON1 activity. Therefore, we evaluated the relationship between dietary vitamin C and E intake and PON1 activity. METHODS AND RESULTS: The vitamin C and E intakes of male white subjects (n=189) were estimated by using a standardized food frequency survey. With covariates, vitamin C or E intakes were found to be significant positive predictors of PON1 activity for the hydrolysis of paraoxon and diazoxon with the use of linear regression. Smoking and use of statins were independent predictors of PON1 activity. CONCLUSIONS: PON1 activity, which is primarily genotype dependent, varies with antioxidant vitamins, cigarette smoking, and statin drug use. Because PON1 activity is a better predictor of vascular disease than is the currently described genetic variation in PON1, further studies of the environmental influences on PON1 activity and additional PON1 genetic variants are warranted.

Aged↗
PubMed2002

Presence of large deletions in kindreds with autism.

Autism is caused, in part, by inheritance of multiple interacting susceptibility alleles. To identify these inherited factors, linkage analysis of multiplex families is being performed on a sample of 105 families with two or more affected sibs. Segregation patterns of short tandem repeat polymorphic markers from four chromosomes revealed null alleles at four marker sites in 12 families that were the result of deletions ranging in size from 5 to >260 kb. In one family, a deletion at marker D7S630 was complex, with two segments deleted (37 kb and 18 kb) and two retained (2,836 bp and 38 bp). Three families had deletions at D7S517, with each family having a different deletion (96 kb, 183 kb, and >69 kb). Another three families had deletions at D8S264, again with each family having a different deletion, ranging in size from <5.9 kb to >260 kb. At a fourth marker, D8S272, a 192-kb deletion was found in five families. Unrelated subjects and additional families without autism were screened for deletions at these four sites. Families screened included 40 families from Centre d'Etude du Polymorphisme Humaine and 28 families affected with learning disabilities. Unrelated samples were 299 elderly control subjects, 121 younger control subjects, and 248 subjects with Alzheimer disease. The deletion allele at D8S272 was found in all populations screened. For the other three sites, no additional deletions were identified in any of the groups without autism. Thus, these deletions appear to be specific to autism kindreds and are potential autism-susceptibility alleles. An alternative hypothesis is that autism-susceptibility alleles elsewhere cause the deletions detected here, possibly by inducing errors during meiosis.

Adult↗
PubMed2002

tau Exon 10 expression involves a bipartite intron 10 regulatory sequence and weak 5' and 3' splice sites.

tau mutations that deregulate alternative exon 10 (E10) splicing cause frontotemporal dementia with parkinsonism chromosome 17-type by several mechanisms. Previously we showed that E10 splicing involved exon splicing enhancer sequences at the 5' and 3' ends of E10, an exon splicing silencer, a weak 5' splice site, and an intron splicing silencer (ISS) within intron 10 (I10). Here, we identify additional regulatory sequences in I10 using both non-neuronal and neuronal cells. The ISS sequence extends from I10 nucleotides 11-18, which is sufficient to inhibit use of a weakened 5' splice site of a heterologous exon. Furthermore, ISS function is location-independent but requires proximity to a weak 5' splice site. Thus, the ISS functions as a linear sequence. A new cis-acting element, the intron splicing modulator (ISM), was identified immediately downstream of the ISS at I10 positions 19-26. The ISM and ISS form a bipartite regulatory element, within which the ISM functions when the ISS is present, mitigating E10 repression by the ISS. Additionally, the 3' splice site of E10 is weak and requires exon splicing enhancer elements for efficient E10 inclusion. Thus far, tau FTDP-17 splicing mutations affect six predicted cis-regulatory sequences.

Alternative Splicing↗
PubMed2002

Dementia and Alzheimer disease incidence: a prospective cohort study.

CONTEXT: Age-specific incidence rates for dementia and Alzheimer disease (AD) are important for research and clinical practice. Incidence estimates for the United States are few and vary with the population sampled and study design; we present data that will contribute to a consensus of these rates. OBJECTIVES: To provide age-specific incidence estimates for dementia and AD and to estimate the association of sex, educational level, and apolipoprotein E genotype with onset. DESIGN: Prospective cohort study; begun in 1994 with follow-up interviews every 2 years. SETTING: Members of community-based, large health maintenance organization with demographics consistent with the surrounding base population; diagnostic evaluation by university-based study clinicians. SUBJECTS: Random sample of subjects aged 65 years or older from the base population; dementia free, nonnursing home residents. Of 5422 who were eligible, 2581 were enrolled, and 2356 had at least 1 follow-up evaluation (10 591 person-years of observation). MAIN OUTCOME MEASURE: Dementia and Alzheimer disease diagnoses were based on standard criteria. Age-specific incidence rates were calculated using a person-years approach with Poisson distribution confidence intervals. Cox proportional hazards model analysis was used to examine other factors. RESULTS: Two hundred fifteen cases of dementia and 151 cases of AD were diagnosed. Incidence rates for dementia and AD increase across the 5-year age groups; AD rates rise from 2.8 per 1000 person-years (age group, 65-69 years) to 56.1 per 1000 person-years in the older than 90-year age group. The rates nearly triple from the 75-to-79-year and 80-to-84-year age groups, but the relative increase is much less thereafter. Sex was not associated with AD onset. Educational level (>15 years vs <12 years) was associated with a decreased risk of AD; however, the association was also dependent on the baseline cognitive screening test score. CONCLUSIONS: Our dementia and AD incidence rates are consistent with recent US and European cohort studies, providing clinicians and researchers new information concerning the reproducibility of incidence estimates across settings. Increased risk was associated with age and the apolipoprotein E genotype; also with a low baseline cognitive screening test score. Educational level was inversely associated with the risk of dementia and positively associated with the baseline cognitive test score; thus, detection of AD by the screening test could also be influenced by educational level.

Age Factors↗
PubMed2002

An R5L tau mutation in a subject with a progressive supranuclear palsy phenotype.

MAPT, the gene encoding tau, was screened for mutations in 96 progressive supranuclear palsy subjects. A point mutation (R5L) was identified in a single progressive supranuclear palsy subject that was not in the other progressive supranuclear palsy subjects or in 96 controls. Functionally, this mutation alters the ability of tau to promote microtubule assembly. Analysis of soluble tau from different brain regions indicates that the mutation does not affect the ratio of tau isoforms synthesized. Aggregated insoluble tau from subcortical regions was predominantly four-repeat tau with no or one amino terminal insert (0N4R and 1N4R). Insoluble tau from cortical regions also contained 1N3R tau. Thus, the R5L mutation causes a progressive supranuclear palsy phenotype, presumably by a gain-of-function mechanism.

Amino Acid Sequence↗
PubMed2002

Identification of a novel gene on chromosome 7q11.2 interrupted by a translocation breakpoint in a pair of autistic twins.

We report here the identification and characterization of a novel gene (AUTS2) that spans the 7q11.2 breakpoint in a monozygotic twin pair concordant for autism and a t(7;20) (q11.2; p11.2) translocation. AUTS2 is 1.2 Mb and has 19 exons. The predicted protein is 1295 amino acids and does not correspond to any known protein. DNA sequence analysis of autism subjects and controls revealed 22 biallelic polymorphic sites. For all sites, both alleles were observed in both cases and controls. Thus no autism-specific mutation was observed. Association analysis with two exonic polymorphic sites and linkage analysis of four dinucleotide repeat markers, two within and two flanking AUTS2, was negative. Thus, although it is unlikely that AUTS2 is an autism susceptibility gene for idiopathic autism, it may be the gene responsible for the disorder in the twins studied here.

Amino Acid Sequence↗
PubMed2002

Defining the broader phenotype of autism: genetic, brain, and behavioral perspectives.

Achieving progress in understanding the cause, nature, and treatment of autism requires an integration of concepts, approaches, and empirical findings from genetic, cognitive neuroscience, animal, and clinical studies. The need for such integration has been a fundamental tenet of the discipline of developmental psychopathology from its inception. It is likely that the discovery of autism susceptibility genes will depend on the development of dimensional measures of broader phenotype autism traits. It is argued that knowledge of the cognitive neuroscience of social and language behavior will provide a useful framework for defining such measures. In this article, the current state of knowledge of the cognitive neuroscience of social and language impairments in autism is reviewed. Following from this, six candidate broader phenotype autism traits are proposed: (a) face processing, including structural encoding of facial features and face movements, such as eye gaze; (b) social affiliation or sensitivity to social reward, pertaining to the social motivational impairments found in autism; (c) motor imitation ability, particularly imitation of body actions; (d) memory, specifically those aspects of memory mediated by the medial temporal lobe-prefrontal circuits; (e) executive function, especially planning and flexibility; and (f) Language ability, particularly those aspects of language that overlap with specific language impairment, namely, phonological processing.

Autistic Disorder↗
PubMedDate not supplied

Mitochondrial genetic variants and Alzheimer disease: a case-control study of the T4336C and G5460A variants.

The T4336C mitochondrial genetic variant was associated with Alzheimer disease in several previous studies. Recent investigations, however, failed to confirm this association. We tested this association in newly diagnosed Alzheimer disease cases and controls of similar age and gender recruited from an established HMO serving Seattle, Washington and surrounding areas. In this, the largest case-control study reported to date, the T4336C variant was not associated with Alzheimer disease overall (present in 6 of 236 cases and 7 of 328 controls; odds ratio = 1.20, 95% CI 0.33 to 4.22). There was evidence of effect modification by Apolipoprotein E (APOE) status--among subjects with an APOE epsilon 4 allele, the T4336C variant was associated with disease (present in 5 of 139 cases and none of 82 controls; odds ratio = infinity, 95% CI 0.73 to infinity). APOE may be an important modifier of the T4336C effect, potentially explaining variable findings across previous studies. Alternatively, the positive findings reported to date may simply reflect the problem of "type I" error inherent in genetic association studies. Substantially larger samples than are currently available would be required to resolve this question. G5460(A/T) variants were also investigated and found not to be associated with Alzheimer disease.

Aged↗