Showing papers by "Alison Goate published in 1998"

Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17

Abstract: Thirteen families have been described with an autosomal dominantly inherited dementia named frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17)(1-9), historically termed Pick's disease(10) Most FTDP-17 cases show neuronal and/or glial inclusions that stain positively with antibodies raised against the microtubule-associated protein Tau, although the Tau pathology varies considerably in both its quantity (or severity) and characteristics(1-8,12) Previous studies have mapped the FTDP-17 locus to a 2-centimorgan region on chromosome 17q2111; the tau gene also lies within this region We have now sequenced tau in FTDP-17 families and identified three missense mutations (G272V, P301L and R406W) and three mutations in the 5' splice site of exon in The splice-site mutations all destabilize a potential stem-loop structure which is probably involved in regulating the alternative splicing of exon10 (ref 13) This causes more frequent usage of the 5' splice site and an increased proportion of tan transcripts that include exon 10 The increase in exon 10(+) messenger RNA will increase the proportion of Tau containing four microtubule-binding repeats, which is consistent with the neuropathology described in several families with FTDP-17 (refs 12, 14)

Mutation-Specific Functional Impairments in Distinct Tau Isoforms of Hereditary FTDP-17

Abstract: Tau proteins aggregate as cytoplasmic inclusions in a number of neurodegenerative diseases, including Alzheimer's disease and hereditary frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Over 10 exonic and intronic mutations in the tau gene have been identified in about 20 FTDP-17 families. Analyses of soluble and insoluble tau proteins from brains of FTDP-17 patients indicated that different pathogenic mutations differentially altered distinct biochemical properties and stoichiometry of brain tau isoforms. Functional assays of recombinant tau proteins with different FTDP-17 missense mutations implicated all but one of these mutations in disease pathogenesis by reducing the ability of tau to bind microtubules and promote microtubule assembly.

Genome‐wide search for genes affecting the risk for alcohol dependence

Abstract: Alcohol dependence is a leading cause of morbidity and premature death. Several lines of evidence suggest a substantial genetic component to the risk for alcoholism: sibs of alcoholic probands have a 3-8 fold increased risk of also developing alcoholism, and twin heritability estimates of 50-60% are reported by contemporary studies of twins. We report on the results of a six-center collaborative study to identify susceptibility loci for alcohol dependence. A genome-wide screen examined 291 markers in 987 individuals from 105 families. Two-point and multipoint nonparametric linkage analyses were performed to detect susceptibility loci for alcohol dependence. Multipoint methods provided the strongest suggestions of linkage with susceptibility loci for alcohol dependence on chromosomes 1 and 7, and more modest evidence for a locus on chromosome 2. In addition, there was suggestive evidence for a protective locus on chromosome 4 near the alcohol dehydrogenase genes, for which protective effects have been reported in Asian populations.

Clinicopathologic studies in cognitively healthy aging and Alzheimer's disease: relation of histologic markers to dementia severity, age, sex, and apolipoprotein E genotype.

Abstract: Objective To study differences between subjects with Alzheimer disease (AD) and cognitively intact control subjects, with respect to brain histologic markers of AD, and the relationship of those markers in the AD group to severity of dementia, age at death, sex, and apolipoprotein E genotype. Setting Washington University Alzheimer's Disease Research Center, St Louis, Mo. Design and Subjects Consecutive neuropathologic series of 224 prospectively studied volunteer research subjects, 186 with dementia of the Alzheimer type (DAT) or "incipient" DAT and confirmed to have AD by postmortem examination and 13 cognitively intact subjects, confirmed to lack postmortem findings of AD. Main Outcome Measures Brain densities (number per square millimeter) of senile plaques and neurofibrillary tangles, extent of cerebral amyloid angiopathy, cortical Lewy bodies, and apolipoprotein E genotype. Results Neocortical neurofibrillary tangle densities were substantially correlated with dementia severity, and to a greater degree than was true for senile plaque densities. When infarcts, hemorrhages, and Parkinson disease changes coexisted with AD, neurofibrillary tangle and senile plaque densities were lower. Plaque-predominant AD was found in a greater proportion of subjects with milder than more severe dementia. Entorhinal cortical Lewy bodies were no more frequent in plaque-predominant AD than in the remaining AD cases. Increasing age at death was negatively correlated with dementia severity and densities of senile plaques and neurofibrillary tangles. The apolipoprotein E ϵ4 allele frequency was greater in AD than in control subjects but decreased with increasing age. After controlling for dementia severity, senile plaque densities were only weakly related to ϵ4 allele frequency, and only in hippocampus. However, the degree of cerebral amyloid angiopathy was clearly related to ϵ4 allele frequency. Among subjects diagnosed during life as having DAT or incipient DAT, only 7% were found to have a neuropathologic disorder other than AD causing their dementia. Conclusions (1) The order of the strength of relationships between densities of histologic markers and dementia severity in AD is neurofibrillary tangles greater than cored senile plaques greater than total senile plaques. (2) Advanced age at death is associated with somewhat less severe dementia and fewer senile plaques and neurofibrillary tangles. (3) Plaque-predominant AD may represent a developmental stage in AD. (4) Despite a substantial effect of apolipoprotein E ϵ4 as a risk factor for AD, on decreasing the age at AD onset, and increasing the amount of cerebral amyloid angiopathy, its effect on senile plaque densities is variable and complex, being confounded with age, dementia severity, and methodologic differences. (5) Stringent clinical diagnostic criteria for DAT, even in the very mild stage, and senile plaque–based neuropathologic criteria for AD are highly accurate.

A polymorphism in the regulatory region of APOE associated with risk for Alzheimer's dementia

Abstract: The epsilon4 allele of the apolipoprotein E gene (APOE) has been associated with an increased risk of developing Alzheimer's disease (AD; refs 1,2). However, it is apparent that the APOEepsilon4 allele alone is neither necessary nor sufficient to cause the disease. We have recently found three new polymorphisms within the APOE transcriptional regulatory region (M.J.A. et al., manuscript submitted) and now establish an association between one of these polymorphisms (-491A/T) and dementia as observed in Alzheimer's disease, in two independent clinical populations. The results suggest that homozygosity of a common variant (-491A) is associated with increased risk for AD, and that this association is independent of APOEepsilon4 status. In vitro studies suggest that the -491A/T polymorphism may increase risk for AD by altering the level of ApoE protein expression.

Hereditary dysphasic disinhibition dementia: a frontotemporal dementia linked to 17q21-22.

Abstract: OBJECTIVE: The clinical and pathologic features of hereditary dysphasic disinhibition dementia (HDDD) are described to determine whether it is a variant of known dementias. BACKGROUND: Several dementing disorders have clinical and pathologic similarities with AD, Pick's disease, and the "nonspecific" dementias. A detailed description of clinical and pathologic presentation will aid classification, but ultimately the discovery of causative gene(s) will define these disorders. METHODS: The authors performed a clinical assessment: gross and microscopic pathologic evaluation of brain tissue, genetic linkage studies, and sequence analyses. RESULTS: HDDD is an autosomal-dominant frontotemporal dementia with many similarities to Pick's disease. Salient clinical features are global dementia with disproportionate dysphasia and "frontotemporal" symptoms. A linkage between HDDD and 17q21-22 was shown, with a maximum lod score of 3.68 at zero recombination. CONCLUSIONS: Several dementias have been linked to the same region and have been termed frontotemporal dementia with parkinsonism linked to chromosome 17. These disorders may represent phenotypic variants arising from mutations within a common gene.

Risk for Alzheimer's disease correlates with transcriptional activity of the APOE gene

Abstract: While the straightepsilon4 allele of apolipoprotein E ( APOE, gene; ApoE, protein) is widely accepted as a major genetic risk factor for the late onset form of Alzheimer's disease (AD), recent evidence points to variations in ApoE levels as another important factor. We have previously reported that a common variant in the regulatory region of APOE (-491A) is associated with risk for late onset AD. In this report we analyze the association of another APOE promoter polymorphism (-427T/C) with AD in two case-control clinical samples and demonstrate a correlation between APOE promoter transcriptional activity and risk for AD. The association studies show that the allelic variant (-427C) and the haplotype [-491A-427C] of the APOE promoter are associated with increased risk for AD. Study of the transcriptional activity of the common haplotypes defined by combination of the -491 and -427 alleles indicated that the risk for late onset AD positively correlates with transcriptional activity of the APOE gene, suggesting that increases in the local expression of ApoE could be responsible for the association of APOE promoter polymorphism with AD.

Anxiety proneness linked to epistatic loci in genome scan of human personality traits.

Abstract: A genome-wide scan between normal human personality traits and a set of genetic markers at an average interval of 13 centimorgans was carried out in 758 pairs of siblings in 177 nuclear families of alcoholics. Personality traits were measured by the Tridimensional Personality Questionnaire. We detected significant linkage between the trait Harm Avoidance, a measure of anxiety proneness, and a locus on chromosome 8p21–23 that explained 38% of the trait variance. There was significant evidence of epistasis between the locus on 8p and others on chromosomes 18p, 20p, and 21q. These oligogenic interactions explained most of the variance in Harm Avoidance. There was suggestive evidence of epistasis in other personality traits. These results confirm the important influence of epistasis on human personality suggested by twin and adoption studies. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 81:313–317, 1998. © 1998 Wiley-Liss, Inc.

Amplitude of visual P3 event-related potential as a phenotypic marker for a predisposition to alcoholism : Preliminary results from the COGA project

Abstract: Recent data collected at six identical electrophysiological laboratories from the large national multisite Collaborative Study on the Genetics of Alcoholism provide evidence for considering the P3 amplitude of the event-related potential as a phenotypic marker for the risk of alcoholism. The distribution of P3 amplitude to target stimuli at the Pz electrode in individuals 16 years of age and over from 163 randomly ascertained control families (n = 687) was compared with those from 219 densely affected alcoholic families (n = 1276) in which three directly interviewed first-degree relatives met both DSM-III-R and Feighner criteria at the definite level for alcohol dependence (stage II). The control sample did not exclude individuals with psychiatric illness or alcoholism to obtain incidence rates of psychiatric disorders similar to those of the general population. P3 amplitude data from control families was converted to Z-scores, and a P3 amplitude beyond 2 SD's below the mean was considered an abnormal trait.' When age- and sex-matched distributions of P3 amplitude were compared, members of densely affected stage II families were more likely to manifest low P3 amplitudes (2 SD below the mean) than members of control families, comparing affected and unaffected offspring, and all individuals; all comparisons of these distributions between groups were significant (p < 0.00001). P3 amplitude means were also significantly lower in stage II family members, compared with control family members for all comparisons, namely probands, affected and unaffected individuals (p < 0.0001), and offspring (p < 0.01). Furthermore, affected individuals from stage II families, but not control families, had significantly lower P3 amplitudes than unaffected individuals (p < 0.001). Affected males from stage II families had significantly lower P3 amplitudes than affected females (p < 0.001). Recent linkage analyses indicate that visual P3 amplitude provides a biological phenotypic marker that has genetic underpinnings.

Interaction of Presenilins with the Filamin Family of Actin-Binding Proteins

Abstract: Mutations in presenilin genes PS1 and PS2 account for ∼50% of early-onset familial Alzheimer’s disease (FAD). The PS1 and PS2 genes encode highly homologous transmembrane proteins related to theCaenorhabditis elegans sel-12 and spe-4 gene products. A hydrophilic loop region facing the cytoplasmic compartment is likely to be functionally important because at least 14 mutations in FAD patients have been identified in this region. We report here that the loop regions of PS1 and PS2 interact with nonmuscle filamin (actin-binding protein 280, ABP280) and a structurally related protein (filamin homolog 1, Fh1). Overexpression of PS1 appears to modify the distribution of ABP280 and Fh1 proteins in cultured cells. A monoclonal antibody recognizing ABP280 and Fh1 binds to blood vessels, astrocytes, neurofibrillary tangles, neuropil threads, and dystrophic neurites in the AD brain. Detection of ABP280/Fh1 proteins in these structures suggests that these presenilin-interacting proteins may be involved in the development of AD and that interactions between presenilins and ABP280/Fh1 may be functionally significant. The ABP280 gene is located on the human X chromosome, whereas the newly identified Fh1 gene maps to human chromosome 3. These results provide a new basis for understanding the function of presenilin proteins and further implicate cytoskeletal elements in AD pathogenesis.

A Family-Based Analysis of the Association of the Dopamine D2 Receptor (DRD2) with Alcoholism

Abstract: The possible association of the OR02 locus, and in particular the Taql-A1 allele, with alcoholism remains controversial, in part because of differences in allele frequencies among populations. To avoid problems associated with differences in allele frequencies in different populations, we tested whether the OR02 locus is associated with alcohol dependence in a large family-based sample. Neither the transmission/disequilibrium test nor the Affected FarnilyBased Controls test provide any evidence of linkage or association between the OR02 locus and alcohol dependence. EVERAL LINES of evidence-including adoption, S half-sibling, twin, and family studies-point to a genetic component to the risk for alc~holism.’-~ Alcoholism is a complex disease, with no simple pattern of inheritance and with substantial environmental and social influences. The genes that affect the risk for alcoholism have been sought by several methods, including studies of candidate genes and searches of the whole genome. The DRD2 gene on chromosome llq22-q23 encodes the dopamine D2 receptor.s36 The dopamine system has been considered a candidate for involvement in alcoholism, with postulated links to novelty seeking and central nervous system An association between the TuqI-A1 polymorphism in the DRD2 gene and alcoholism was first reported by Blum et aL9 Shortly thereafter, the first nonreplication was reported.” This polymorphism has subsequently been examined by many groups, with differing results. There have been positive reports of the association of the TuqI-A1 allele with

A Family-Based Analysis of Whether the Functional Promoter Alleles of the Serotonin Transporter Gene HTT Affect the Risk for Alcohol Dependence

Abstract: A population association between a regulatory variation in the promoter of the serotonin transporter gene (HTT) and severe alcohol dependence was recently reported. We analyzed this potential association in a large number of systematically ascertained families in the United States; these families had at least three first-degree relatives who were alcohol-dependent. Analyses focused on individuals defined as alcohol-dependent by criteria from ICD-10 and on subsets of these individuals reporting withdrawal-related symptoms. Application of the transmission disequilibrium test did not provide support for either linkage or association between this functional polymorphism and alcohol dependence; there was no significant bias in the transmission of either allele to the alcohol-dependent offspring. We also report that African Americans differ from Caucasians in allele frequencies for this polymorphism.

Genetic Studies on Chromosome 12 in Late-Onset Alzheimer Disease

Abstract: CONTEXT: The only genetic locus universally accepted to be important as a risk factor for late-onset Alzheimer disease (AD) is the apolipoprotein E (APOE) locus on chromosome 19. However, this locus does not account for all the risk in late-onset disease, and a recent report has suggested a second locus on chromosome 12p11-12. OBJECTIVE: To look for evidence of linkage on chromosome 12 and to test for the presence of the new locus in an independent sample of familial late-onset AD cases. DESIGN: Retrospective cohort study. As part of a 20-centimorgan genome screen (approximately equal to 200 markers), we tested a series of 18 genetic markers on chromosome 12 and carried out multipoint, nonparametric lod score and exclusion analyses. SETTING: Clinic populations in the continental United States selected from the National Institute of Mental Health AD Genetics Consortium. PATIENTS: We selected samples for DNA analysis from affected sibling pairs, 497 subjects from 230 families with 2 or more affected individuals with probable or definite AD with onset ages older than 60 years (mean+/-SD, 75+/-6 years). Within the families, we used the 2 probable or definitely affected individuals. In families with more than 2 such cases available, we used all of them; in families with only 2 such cases in which unaffected individuals were available, we also sampled the oldest unaffected individual and used genotype data from this unaffected individual to check for nonpaternity and genotyping errors. MAIN OUTCOME MEASURE: Presence of linkage or locus on chromosome 12. RESULTS: Although linkage analyses confirmed the presence of a genetic susceptibility factor at the APOE locus in these families with late-onset AD, we were unable to confirm the presence of a locus close to the marker D12S1042. A moderate lod score (1.91) was found near D12S98 close to the alpha2-macroglobulin locus in the affected pairs in which both members did not possess an APOE epsilon4 allele. CONCLUSIONS: APOE remains the only locus established to be a risk factor for late-onset AD. We were unable to confirm that a locus on chromosome 12p11-12 has a major effect on risk for late-onset AD, although an effect smaller than that for APOE cannot be excluded.

Linkage of an alcoholism-related severity phenotype to chromosome 16

Abstract: There is substantial evidence for a significant genetic component to the risk for alcoholism. In searching for genes that contribute to this risk, the diagnostic criteria for alcohol dependence may not be the optimal phenotype; rather, creation of a more homogeneous phenotype will lead to a more homogeneous genetic etiology. Items from the Semi-Structured Assessment for the Genetics of Alcoholism collected from 830 individuals in 105 alcoholic families were used in a latent class analysis to identify a more homogeneous alcoholism-related phenotype. A four-class solution was chosen: class 1, unaffected group; class 2, mildly problematic group; class 3, moderately affected group; and class 4, severely affected group. Classes 3 and 4 had higher symptom endorsement probabilities than classes 1 and 2 for items reflecting severe alcohol dependence, and were combined to provide enough sibling pairs for genetic linkage analysis. A total of 291 markers distributed throughout the genome, with an average intermarker distance of 14 cM, were genotyped. Linkage analysis was performed to detect loci underlying classes 3 and 4, the moderately and severely affected alcoholics, of whom 88% met the Collaborative Study of the Genetics of Alcoholism, and >99% met ICD-10 criteria for alcohol dependence. Evidence for a locus on chromosome 16, near the marker D16S675, was found with a maximum multipoint lod score of 4.0. Analysis of additional markers on chromosome 16 yielded a lod score of 3.2, narrowed the critical region, and placed the gene between D16S475 and D16S675 in a 15 cM interval.

Monogenetic determinants of Alzheimer's disease: APP mutations

Abstract: Mutations within exons 16 and 17 of the beta-amyloid precursor protein (APP) gene were the first known cause of familial Alzheimer's disease. These mutations are rare and have been reported in a handful of families exhibiting autosomal dominant inheritance of Alzheimer's disease with age of onset around 50 years. In vitro and in vivo studies have demonstrated that each of these mutations alters proteolytic processing of APP, resulting in an increase in the production of A beta 42, a highly fibrillogenic peptide, that spontaneously aggregates and deposits in the brain. Transgenic mice carrying a mutant human APP gene also show age-dependent beta-amyloid (A beta) deposition in the brain. The rate of deposition in these mice can be modified by apolipoprotein E expression.

Genetics of alcoholism.

Abstract: One observation is relatively certain: Alcoholism runs in families. Medical experts seem to agree on this point more than any other. Any given alcoholic has a 50% chance of having at least one family member with alcoholism. A family that has at least one alcoholic is likely to have others, that is, 90% chance of having two or more family members with alcoholism. Furthermore, alcoholics with a family history of alcoholism tend to have a more severe course with greater adverse consequences from alcoholism. Alcoholic parents have alcoholic children about 4 to 5 times more often than do parents who are not alcoholics.1, 2, 3

Failure to replicate a protective effect of allele 2 of NACP/α‐synuclein polymorphism in Alzheimer's disease: An association study

Abstract: Recently, a dinucleotide repeat polymorphism was identified in the promoter of the nonamyloid component of plaques (NACP) gene, and it was shown that the NACP allele 2 was significantly associated with healthy elderly control individuals with at least one apolipoprotein E e4 allele, suggesting a protective role for this allele in Alzheimer's disease. We genotyped the same NACP polymorphism in a comparable number of individuals diagnosed with dementia of the Alzheimer's type and in healthy, elderly controls. In our analysis, however, no protective effect for NACP allele 2, or any of the other NACP alleles, was observed.

The NIK protein kinase and C17orf1 genes: chromosomal mapping, gene structures and mutational screening in frontotemporal dementia and parkinsonism linked to chromosome 17

Abstract: Full exon-intron structures are presented for the NIK serine/threonine protein kinase gene and a novel gene termed C17orf1. By in situ hybridisation and radiation hybrid mapping, a cosmid (cDD-Z) that contains regions of both of these genes has been localised between markers D17S800 and D17S791 at chromosome 17q21. The two genes are thus positional candidates for the mutant locus underlying frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), a disease for which NIK is also a good biological candidate. Using exon-intron maps, a genomic DNA sequencing based mutation screen has been performed for the NIK and C17orf1 genes in a chromosome 17-linked FTDP-17 pedigree. Two silent single-base variations were detected in C17orf1. No alterations were restricted to DNA samples from patients, thus excluding the C17orf1 and NIK genes as likely sites of mutation FTDP-17.

New diagnostic marker for splicing variety of gene related to neurological function

Abstract: PROBLEM TO BE SOLVED: To identify an individual subject to contraction of neurological diseases by detecting the presence of another splice site containing a specific sequence existing in a polyadenylated mRNAtransferred product or the like in a genetic specimen of an individual subject to contraction of neurological diseases. SOLUTION: A genetic specimen is prepared from an individual subject to contraction of neurological diseases including Alzheimer's disease; subsequently, the presence of another splice site containing an sequence VRXQ (V is valine; R is arginine; X is a hydrophobic amino acid residue; Q is glutamine) existing in a polyadenylated messenger RNA-transferred product or a protein coded thereby in the specimen is detected, thus identifying an individual subject to contraction of neurological diseases such as Alzheimer's disease by the subject diagnostic marker.

Amplitude of Visual P3 Phenotypic Marker for a Event-Related Potential as a Predisposition to Alcoholism: Preliminary Results from the COGA Project

Abstract: (n = 687) was compared with those from 219 densely affected alcoholic families (n = 1276) in which three directly interviewed first-degree relatives met both DSM-Ill-R and Feighner criteria at the definite level for alcohol dependence (stage 11). The control sample did not exclude individuals with psychiatric illness or alcoholism to obtain incidence rates of psychiatric disorders similar to those of the general population. P3 amplitude data from control families was converted to Z-scores, and a P3 amplitude beyond 2 SD's below the mean was considered an "abnormal trait." When age- and sex-matched distributions of P3 amplitude were compared, members of densely affected stage II families were more likely to manifest low P3 amplitudes (2 SD below the mean) than members of control families, comparing affected and unaffected offspring, and all individuals; all comparisons of these distributions between groups were significant (p c 0.oooOl). P3 amplitude means were also significantly lower in stage II family members, compared with control family members for all comparisons, namely probands, affected and unaffected individuals (p c O.OOOl), and offspring (p < 0.01). Furthermore, affected individuals