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G D Schellenberg

Publications and source records attributed to G D Schellenberg.

At least 73 records · Page 4Linked to original sources
PubMed1997

Evidence for association of HLA-A2 allele with onset age of Alzheimer's disease.

Our earlier studies had suggested a possible association between the HLA-A2 allele and Alzheimer's disease (AD). In the present study we tested the hypothesis that A2 is associated with earlier AD onset. We performed two independent studies: a collaborative study with 111 patients and a confirmatory study with 96 patients. We found similar patterns of reduced age at onset as a function of A2 in both data sets. Overall, A2 was associated with a significant 3-year shift to earlier onset. The effects of A2 and epsilon 4 on age at onset appeared additive. Our results suggest A2, or a closely linked gene, modulates onset age of AD. Association with A2 would suggest an immune/inflammatory response mechanism for AD.

Age of Onset↗
PubMed1997

Mutations in the consensus helicase domains of the Werner syndrome gene. Werner's Syndrome Collaborative Group.

Werner syndrome (WS) is an autosomal recessive disease with a complex phenotype that is suggestive of accelerated aging. WS is caused by mutations in a gene, WRN, that encodes a predicted 1,432-amino-acid protein with homology to DNA and RNA helicases. Previous work identified four WS mutations in the 3' end of the gene, which resulted in predicted truncated protein products of 1,060-1,247 amino acids but did not disrupt the helicase domain region (amino acids 569-859). Here, additional WS subjects were screened for mutations, and the intron-exon structure of the gene was determined. A total of 35 exons were defined, with the coding sequences beginning in the second exon. Five new WS mutations were identified: two nonsense mutations at codons 369 and 889; a mutation at a splice-junction site, resulting in a predicted truncated protein of 760 amino acids; a 1-bp deletion causing a frameshift; and a predicted truncated protein of 391 amino acids. Another deletion is >15 kb of genomic DNA, including exons 19-23; the predicted protein is 1,186 amino acids long. Four of these new mutations either partially disrupt the helicase domain region or result in predicted protein products completely missing the helicase region. These results confirm that mutations in the WRN gene are responsible for WS. Also, the location of the mutations indicates that the presence or absence of the helicase domain does not influence the WS phenotype and suggests that WS is the result of complete loss of function of the WRN gene product.

Asian People↗
PubMed1997

Clinicopathologic correlations of soluble amyloid beta-protein precursor in cerebrospinal fluid in patients with Alzheimer disease and controls.

The authors compared concentrations of soluble beta-amyloid protein precursor (s beta PP) in cerebrospinal fluid (CSF) in 45 patients diagnosed with probable Alzheimer disease (AD) and 26 normal older control volunteers. Soluble beta-amyloid protein precursor concentrations were measured in 125 CSF samples using an enzyme-linked immunosorbent assay. All subjects had Mini-Mental State Examination (MMSE) and Clinical Dementia Rating Scale (CDRS) scores and assessment of disease duration. The s beta PP concentrations in CSF in the probable AD group (mean +/- SD = 493 +/- 268 micrograms/L) were decreased significantly compared with the age-matched control group (mean = 831 +/- 302 micrograms/L; p < 0.0001). In the probable AD group, MMSE scores correlated positively with s beta PP concentrations (correlation coefficient r = 0.53, p < 0.0001), and CDRS ratings and disease duration correlated inversely with s beta PP concentrations (r = -0.59, p < 0.0001 and r = -0.479, p = 0.0006, respectively). Although the decrease in CSF s beta PP from levels found in healthy elderly controls was significant in AD subjects, there was substantial overlap. In AD, CSF s beta PP was most reduced in patients in later stages of the disease. The s beta PP concentrations reflect disease severity, but utility in differential diagnosis has not been determined.

Aged↗
PubMed1996

Narrowing the position of the Werner syndrome locus by homozygosity analysis-extension of homozygosity analysis.

Werner syndrome (WS) is an autosomal recessive disorder characterized by the premature occurrence of many age-related features. Previously, the WS gene (WRN) was mapped between D8S131 and D8S87, in an 8.3-cM interval. In this study, regions of homozygosity in 36 WS patients from inbred families were searched for by genotyping for 35 dinucleotide repeat polymorphic markers to narrow down the WRN critical region. The region most consistently homozygous in these patients was between the D8S1219/D8S1220 cluster and D8S278, within a 4.4-cM interval. For 16 markers mapped in this interval, 24 WS patients (22 Japanese patients and 2 Caucasian patients) in whom consanguinity failed to be proved were also genotyped, under the assumption that some of these patients might still be from consanguineous marriages. The data were analyzed by Fisher's exact test with a 2 x 2 contingency table for the 22 Japanese patients, excluding the 2 Caucasian patients. The frequencies of homozygosity in the 22 patients at 10 of 16 markers tested were significantly higher than those detected in the general population. Analysis of homozygosity patterns indicated that the region most consistently homozygous was between D8S1445 and D8S278. Thus the WRN locus is most likely between the two markers D8S1445 and D8S278, in a 1.6-cM interval.

Asian People↗
PubMed1996

A YAC, P1, and cosmid contig and 17 new polymorphic markers for the Werner syndrome region at 8p12-p21.

A yeast artificial chromosome (YAC), P1, and cosmid clone contig was constructed for the Werner syndrome (WRN) region of chromosome 8p12-p21 and used to clone a candidate gene for WRN. This region also possibly contains a familial breast cancer locus. The contig was initiated by isolating YACs for the glutathione reductase (GSR) gene and extended in either direction by walking techniques. Sequence-tagged site (STS) markers were generated from subclones of 2 GSR YACs and used to identify P1 and cosmid clones. Additional STSs were generated from P1 and cosmid clones and from potential expressed sequences identified by cDNA selection and exon amplification methods. The final contig was assembled by typing 17 YACs, 20 P1 clones, and 109 cosmids for 54 STS markers. The WRN region could be spanned by 2 nonchimeric YACs covering approximately 1.4 Mb. A P1/cosmid contig was established covering the core 700-800 kb of the WRN region. Fifteen new short tandem repeat polymorphisms and 2 biallelic polymorphic markers were identified and included as STSs in the contig. Analysis of these markers in Werner syndrome subjects demonstrates that the candidate WRN gene is in a region of linkage disequilibrium.

Base Sequence↗
PubMed1996

Genomic structure and expression of STM2, the chromosome 1 familial Alzheimer disease gene.

Mutations in the gene STM2 result in autosomal dominant familial Alzheimer disease. To screen for mutations and to identify regulatory elements for this gene, the genomic DNA sequence and intron-exon structure were determined. Twelve exons including 10 coding exons were identified in a genomic region spanning 23,737 bp. The first 2 exons encode the 5'-untranslated region. Expression analysis of STM2 indicates that two transcripts of 2.4 and 2.8 kb are found in skeletal muscle, pancreas, and heart. In addition, a splice variant of the 2.4-kb transcript was identified that is the result of the use of an alternative splice acceptor site located in exon 10. The use of this site results in a transcript lacking a single glutamate. The promotor for this gene and the alternatively spliced exons leading to the 2.8-kb form of the gene remain to be identified. Expression of STM2 was high in skeletal muscle and pancreas, with comparatively low levels observed in brain. This expression pattern is intriguing since in Alzheimer disease, pathology and degeneration are observed only in the central nervous system.

Alternative Splicing↗
PubMed1996

Positional cloning of the Werner's syndrome gene.

Werner's syndrome (WS) is an inherited disease with clinical symptoms resembling premature aging. Early susceptibility to a number of major age-related diseases is a key feature of this disorder. The gene responsible for WS (known as WRN) was identified by positional cloning. The predicted protein is 1432 amino acids in length and shows significant similarity to DNA helicases. Four mutations in WS patients were identified. Two of the mutations are splice-junction mutations, with the predicted result being the exclusion of exons from the final messenger RNA. One of the these mutations, which results in a frameshift and a predicted truncated protein, was found in the homozygous state in 60 percent of Japanese WS patients examined. The other two mutations are nonsense mutations. The identification of a mutated putative helicase as the gene product of the WS gene suggests that defective DNA metabolism is involved in the complex process of aging in WS patients.

Aging↗
PubMed1996

Genetic factors for the development of Alzheimer disease in the Cherokee Indian.

OBJECTIVE: To study the relationship between the genetic degree of Cherokee ancestry, the apolipoprotein E *E4 (APOE*E4) allele type, and the development of Alzheimer disease (AD) in individuals from the Cherokee Nation who reside in northeastern Oklahoma. SETTING: Alzheimer disease center satellite clinic and university departments of neurology, psychiatry, and academic computing. DESIGN: Standardized dementia evaluations based on criteria from the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association were performed on 26 patients aged 65 years or older to establish a diagnosis of AD. Twenty-six control subjects were recruited and similarly assessed. The APOE allele type determinations were obtained on all patients and control subjects. Appropriate statistical analyses were used to compare the genetic degree of Cherokee ancestry, the APOE allele type, and the development of AD. RESULTS: The data indicated that as the genetic degree of Cherokee Indian ancestry increased, the representation of AD decreased. The 9 patients with AD with a greater than 50% genetic degree of Cherokee ancestry constituted 35% of the group with AD. The 17 remaining patients with AD who were less than 50% Cherokee constituted 65% of the group with AD. In contrast, 17 (65%) of the control subjects were more than 50% Cherokee; only 9 (35%) were less than 50% Cherokee. These percentages of AD were not changed by the *E4 allele. This inverse relationship between the genetic degree of Cherokee ancestry and AD, independent of the APOE*E4 allele status, diminished with increasing age, suggesting an age-related protective effect of being Cherokee. For a decrease of 10% in Cherokee ancestry, the odds of developing AD are estimated to be 9.00 times greater at age 65 years but only 1.34 times greater at age 80 years. CONCLUSIONS: A greater genetic degree of Cherokee ancestry reduces the risk of developing AD and, thus, seems protective. This protective genetic factor is independent of APOE allele type and diminishes with age.

Aged↗
PubMed1996

The clinical phenotype of two missense mutations in the presenilin I gene in Japanese patients.

We report the clinical and neuropathologic phenotypes associated with two different missense mutations in the presenilin 1 (PS-1) gene in Japanese patients with early-onset familial Alzheimer's disease (FAD). In the AM/JPN1 pedigree a missense mutation (C-->T) was found at nucleotide 1102, which is predicted to cause an alanine-to-valine missense substitution at codon 260. In this family, the disease had a mean age of onset of 40.3 years and an indolent course (range, 8-19 years). Neuropathologic studies in 3 members of this pedigree showed widespread senile plaques, neurofibrillary tangles, and neuronal loss, as well as abundant perivascular subpial amyloid deposits in the Virchow-Robin spaces and the presence of Pick-like intraneuronal inclusions in the dentate gyrus. In the second pedigree, transmitting a C-->T nucleotide substitution at position 1027, leading to the missense mutation of alanine to valine at codon 285, the disease had a later onset (mean, 51 years) but a more rapid course. Comparison of the disease phenotypes associated with other missense mutations in exon 9 of PS-1 reveals no clinical or pathological phenotype, which uniquely distinguishes Alzheimer's disease associated with PS-1 mutations from other forms of early-onset FAD, implying that direct mutation screening is required to identify these cases.

Adult↗
PubMed1996

Wide range in age of onset for chromosome 1--related familial Alzheimer's disease.

Mutations in three different genes on chromosomes 1, 14, and 21 cause autosomal dominant forms of familial Alzheimer's disease (FAD). Most result in an early-onset phenotype. However, several kindreds of Volga German ancestry have the same chromosome 1 gene mutation and demonstrate a relatively older mean age of onset and include individuals with late age of onset. In these families, the mean age of onset is 54.9 +/- 8.4 years (range, 40-75 years), mean age at death is 65.9 +/- 10.2 years (range, 43-88 years), and mean disease duration is 11.3 +/- 4.6 years (range, 5-23 years). This contrasts with a group of 7 families with chromosome 14 mutations in which the mean age of onset is 44.8 +/- 4.8 years (range, 30-55 years), mean age at death is 52.6 +/- 5.7 years (range, 39-65 years), and mean disease duration is 7.6 +/- 3.2 years (range, 2-17 years). (All means are significantly different in the 2 groups of families, p < 0.005.) In the chromosome 1 families, 7 persons (16%) had an age of onset at or older than 65 years and 22 (54%) survived to age 65 or older versus none in the chromosome 14 families. An example of probable nonpenetrance of disease at age 89 was also found in a chromosome 1 kindred. It is concluded that, unlike the chromosome 14 gene, mutations in the chromosome 1 FAD gene may result in individuals with a late age of onset overlapping with the more common sporadic form of the disease occurring in the general population. In light of the great variability in age of onset in persons with identical mutations, study of the genetic and environmental factors contributing to delayed onset of disease in chromosomal 1 FAD kindreds will be an important area for further investigation. Apolipoprotein E genotype may be one such factor that plays a partial role in this variability.

Adult↗
PubMed1996

Apolipoprotein E in Alzheimer's disease risk and case detection: a case-control study.

The objective of this study was to describe the association between the epsilon 4 allele of the apolipoprotein E gene (APOE E4) and Alzheimer's disease (AD) and to evaluate APOE E4 genotyping as a test for AD. The study base of this case-control study included about 23,000 persons 60 year of age or greater (a large health maintenance organization); the demographic characteristics of this group are similar to those of the surrounding area. Analysis focused on 234 Caucasian probable AD patients first identified between 1987 and 1993; and 304 cognitively intact controls of similar age, sex, and race who were randomly selected from the same study base. All cases were examined and diagnosed by study physicians using standard protocols. All subjects participate in continuing annual follow-up testing to verify their cognitive status. APOE genotypes were determined from blood samples using standard laboratory methods. Subject characteristics and diagnoses were obtained from interviews, diagnostic examination, or medical record review. Heterozygous E4 individuals had a crude odds ratio of 3.1 (2.1-4.5) for AD compared to those with no E4, while homozygous E4 subjects had an odds ratio of 34.3 (8.0-146.3) for AD. As an indicator of AD, having one E4 allele showed a sensitivity of 0.52 and a specificity of 0.74. Homozygous E4 genotype had a sensitivity of 0.23 and a specificity of 0.99 (when compared to non-E4 genotypes). Cardiovascular disease differed in cases and controls, but did not confound or modify the APOE E4-AI) association. In this study base, the APOE E4 allele was a significant risk factor. However, considering either homozygous or heterozygous E4 genotype as a screen or diagnostic marker for AD would miss many true cases and could misclassify many normals as AD.

Aged↗
PubMed1996

Homozygous and compound heterozygous mutations at the Werner syndrome locus.

The Werner syndrome (WS) is a rare autosomal recessive progeroid disorder. The Werner syndrome gene (WRN) has recently been identified as a member of the helicase family. Four distinct mutations were previously reported in three Japanese and one Syrian WS pedigrees. The latter mutation was originally described as a 4 bp deletion spanning a spliced junction. It is now shown that this mutation results in a 4 bp deletion at the beginning of an exon. Nine new WRN mutations in 10 additional WS patients, both Japanese and Caucasian, are described. These include three compound heterozygotes (one Japanese and two Caucasian). The new mutations are located all across the coding region.

Asian People↗
PubMed1996

Neuronal expression of STM2 mRNA in human brain is reduced in Alzheimer's disease.

Mutations in the STM2 gene cause familial Alzheimer's disease (AD) in Volga Germans. To understand the function of this protein and how mutations lead to AD, it is important to determine which cell types in the brain express this gene. In situ hybridization histochemistry indicates that STM2 expression in the human brain is widespread and is primarily neuronal. In addition, STM2 mRNA is expressed in a cell line with neuronal origins. Quantification of the level of expression of the STM2 message in the basal forebrain, frontal cortex, and hippocampus reveals a significant decrease in AD-affected subjects compared to normal age-matched controls. These data suggest that downregulation of neuronal STM2 gene expression may be involved in the progression of AD.

Aged↗
PubMed1996

Influence of apolipoprotein E genotype on the transmission of Alzheimer disease in a community-based sample.

The epsilon 4 allele of the apolipoprotein E locus (APOE) has been found to be an important predictor of Alzheimer disease (AD). However, linkage analysis has not clarified the role of APOE in the transmission of AD. The results of the current study provide evidence that the pattern of transmission of memory disorders differs in nuclear families in which the AD-affected proband did carry an epsilon 4 allele versus those families in which the AD-affected proband did not carry an epsilon allele. Further, risk of AD due to APOE genotype in the probands is modified by family history of memory disorders, suggesting gene-by-gene interactions. Family history remained a significant predictor of AD for affected probands with some, but not all, APOE genotypes in a logistic regression analysis. Though nonadditive in the prediction of AD, APOE genotype and family history acted additively in the prediction of age at AD onset. The results of complex segregation analysis were inconsistent with Mendelian segregation of memory disorders both in families of affected probands who did or did not carry an epsilon 4 allele, yet these two groups had significantly different parameter estimates for their transmission models. These results are consistent with gene-by-gene interactions, but also could result from common elements in the familial environment.

Age of Onset↗
PubMed1996

Gender difference in apolipoprotein E-associated risk for familial Alzheimer disease: a possible clue to the higher incidence of Alzheimer disease in women.

Late-onset Alzheimer disease (AD) is associated with the apolipoprotein E (APOE)-epsilon4 allele. In late-onset familial AD, women have a significantly higher risk of developing the disease than do men. The aim of this study was to determine whether the gender difference in familial AD is a function of APOE genotype. We studied 58 late-onset familial AD kindreds. Kaplan-Meier survival analysis was used to assess genotype-specific distributions of age at onset. Odds ratios were estimated by logistic regression with adjustment for age and by conditional logistic regression with stratification on families. All methods detected a significant gender difference for the epsilon4 heterozygous genotype. In women, epsilon4 heterozygotes had higher risk than those without epsilon4; there was no significant difference between epsilon4 heterozygotes and epsilon4 homozygotes. In men, epsilon4 heterozygotes had lower risk than epsilon4 homozygotes; there was not significant difference between epsilon4 heterozygotes and those without epsilon4. A direct comparison of epsilon4 heterozygous men and women revealed a significant twofold increased risk in women. We confirmed these results in 15 autopsy-confirmed AD kindreds from the National Cell Repository at Indiana University Alzheimer Disease Center. These observations are consistent with the increased incidence of familial AD in women and may be a critical clue to the role of gender in the pathogenesis of AD.

Age of Onset↗
PubMed1996

Toward localization of the Werner syndrome gene by linkage disequilibrium and ancestral haplotyping: lessons learned from analysis of 35 chromosome 8p11.1-21.1 markers.

Werner syndrome (WS) is an autosomal recessive disorder characterized by premature onset of a number of age-related diseases. The gene for WS, WRN, has been mapped to the 8p 11.1-21.1 region with further localization through linkage disequilibrium mapping. Here we present the results of linkage disequilibrium and ancestral haplotype analyses of 35 markers to further refine the location of WRN. We identified an interval in this region in which 14 of 18 markers tested show significant evidence of linkage disequilibrium in at least one of the two populations tested. Analysis of extended and partial haplotypes covering 21 of the markers studied supports the existence of both obligate and probable ancestral recombinant events which localize WRN almost certainly to the interval between D8S2196 and D8S2186, and most likely to the narrower interval between D8S2168 and D8S2186. These haplotype analyses also suggest that there are multiple WRN mutations in each of the two populations under study. We also present a comparison of approaches to performing disequilibrium tests with multiallelic markers, and show that some commonly used approximations for such tests perform poorly in comparison to exact probability tests. Finally, we discuss some of the difficulties introduced by the high mutation rate at microsatellite markers which influence our ability to use ancestral haplotype analysis to localize disease genes.

Age of Onset↗
PubMed1995

Genetic dissection of Alzheimer disease, a heterogeneous disorder.

The genetics of Alzheimer disease (AD) are complex and not completely understood. Mutations in the amyloid precursor protein gene (APP) can cause early-onset autosomal dominant AD. In vitro studies indicate that cells expressing mutant APPs overproduce pathogenic forms of the A beta peptide, the major component of AD amyloid. However, mutations in the APP gene are responsible for 5% or less of all early-onset familial AD. A locus on chromosome 14 is responsible for AD in other early-onset AD families and represents the most severe form of the disease in terms of age of onset and rate of decline. Attempts to identify the AD3 gene by positional cloning methods are underway. At least one additional early-onset AD locus remains to be located. In late-onset AD, the apolipoprotein E gene allele epsilon 4 is a risk factor for AD. This allele appears to act as a dose-dependent age-of-onset modifier. The epsilon 2 allele of this gene may be protective. Other late-onset susceptibility factors remain to be identified.

Alzheimer Disease↗