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ABSTRACT: We performed whole-exome sequencing in two autopsy-confirmed cases and an elderly unaffected control from a multigenerational family with autosomal dominant neuronal ceroid lipofuscinosis (ANCL). A novel single-nucleotide variation (c.344T>G) in the DNAJC5 gene was identified. Mutational screening in an independent family with autosomal dominant ANCL found an in-frame single codon deletion (c.346_348 delCTC) resulting in a deletion of p.Leu116del. These variants fulfill all genetic criteria for disease-causing mutations: they are found in unrelated families with the same disease, exhibit complete segregation between the mutation and the disease, and are absent in healthy controls. In addition, the associated amino acid substitutions are located in evolutionarily highly conserved residues and are predicted to functionally affect the encoded protein (CSPα). The mutations are located in a cysteine-string domain, which is required for membrane targeting/binding, palmitoylation, and oligomerization of CSPα. We performed a comprehensive in silico analysis of the functional and structural impact of both mutations on CSPα. We found that these mutations dramatically decrease the affinity of CSPα for the membrane. We did not identify any significant effect on palmitoylation status of CSPα. However, a reduction of CSPα membrane affinity may change its palmitoylation and affect proper intracellular sorting. We confirm that CSPα has a strong intrinsic aggregation propensity; however, it is not modified by the mutations. A complementary disease-network analysis suggests a potential interaction with other NCLs genes/pathways. This is the first replication study of the identification of DNAJC5 as the disease-causing gene for autosomal dominant ANCL. The identification of the novel gene in ANCL will allow us to gain a better understanding of the pathological mechanism of ANCLs and constitutes a great advance toward the development of new molecular diagnostic tests and may lead to the development of potential therapies.
PLoS ONE 01/2011; 6(11):e26741. · 4.09 Impact Factor
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Odity Mukherjee,
Jun Wang,
Michael Gitcho,
Sumi Chakraverty,
Lisa Taylor-Reinwald,
Shantia Shears,
John S K Kauwe, Joanne Norton,
Denise Levitch,
Eileen H Bigio,
Kimmo J Hatanpaa,
Charles L White,
John C Morris,
Nigel J Cairns,
Alison Goate
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ABSTRACT: Frontotemporal dementia (FTD) is a clinical term encompassing dementia characterized by the presence of two major phenotypes: 1) behavioral and personality disorder, and 2) language disorder, which includes primary progressive aphasia and semantic dementia. Recently, the gene for familial frontotemporal lobar degeneration (FTLD) with ubiquitin-positive, tau-negative inclusions (FTLD-U) linked to chromosome 17 was cloned. In the present study, 62 unrelated patients from the Washington University Alzheimer's Disease Research Center and the Midwest Consortium for FTD with clinically diagnosed FTD and/or neuropathologically characterized cases of FTLD-U with or without motor neuron disease (MND) were screened for mutations in the progranulin gene (GRN; also PGRN). We discovered two pathogenic mutations in four families: 1) a single-base substitution within the 3' splice acceptor site of intron 6/exon 7 (g.5913A>G [IVS6-2A>G]) causing skipping of exon 7 and premature termination of the coding sequence (PTC); and 2) a missense mutation in exon 1 (g.4068C>A) introducing a charged amino acid in the hydrophobic core of the signal peptide at residue 9 (p.A9D). Functional analysis in mutation carriers for the splice acceptor site mutation revealed a 50% decrease in GRN mRNA and protein levels, supporting haploinsufficiency. In contrast, there was no significant difference in the total GRN mRNA between cases and controls carrying the p.A9D mutation. Further, subcellular fractionation and confocal microscopy indicate that although the mutant protein is expressed, it is not secreted, and appears to be trapped within an intracellular compartment, possibly resulting in a functional haploinsufficiency.
Human Mutation 04/2008; 29(4):512-21. · 5.69 Impact Factor
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Odity Mukherjee,
Pau Pastor,
Nigel J Cairns,
Sumi Chakraverty,
John S K Kauwe,
Shantia Shears,
Maria I Behrens,
John Budde,
Anthony L Hinrichs, Joanne Norton,
Denise Levitch,
Lisa Taylor-Reinwald,
Michael Gitcho,
P-H Tu,
Lea Tenenholz Grinberg,
Rajka M Liscic,
Javier Armendariz,
John C Morris,
Alison M Goate
[show abstract]
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ABSTRACT: Familial autosomal dominant frontotemporal dementia with ubiquitin-positive, tau-negative inclusions in the brain linked to 17q21-22 recently has been reported to carry null mutations in the progranulin gene (PGRN). Hereditary dysphasic disinhibition dementia (HDDD) is a frontotemporal dementia with prominent changes in behavior and language deficits. A previous study found significant linkage to chromosome 17 in a HDDD family (HDDD2), but no mutation in the MAPT gene. Longitudinal follow-up has enabled us to identify new cases and to further characterize the dementia in this family. The goals of this study were to develop research criteria to classify the different clinical expressions of dementia observed in this large kindred, to identify the causal mutation in affected individuals and correlate this with phenotypic characteristics in this pedigree, and to assess the neuropathological characteristics using immunohistochemical techniques.
In this study we describe a detailed clinical, pathological and mutation analysis of the HDDD2 kindred.
Neuropathologically, HDDD2 represents a familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions (FTLD-U). We developed research classification criteria and identified three distinct diagnostic thresholds, which helped localize the disease locus. The chromosomal region with the strongest evidence of linkage lies within the minimum critical region for FTLD-U. Sequencing of each exon of the PGRN gene led to the identification of a novel missense mutation, Ala-9 Asp, within the signal peptide.
HDDD2 is an FTLD-U caused by a missense mutation in the PGRN gene that cosegregates with the disease and with the disease haplotype in at-risk individuals. This mutation is the first reported pathogenic missense mutation in the signal peptide of the PGRN gene causing FTLD-U. In light of the previous reports of null mutations and its position in the gene, two possible pathological mechanisms are proposed: (1) the protein may accumulate within the endoplasmic reticulum due to inefficient secretion; and (2) mutant RNA may have a lower expression because of degradation via nonsense-mediated decay.
Annals of Neurology 10/2006; 60(3):314-22. · 11.09 Impact Factor
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ABSTRACT: Cases of early-onset Alzheimer disease (AD) with an autosomal dominant inheritance pattern (familial AD [FAD]) are rare but have greatly advanced our understanding of the molecular pathogenesis of AD. We describe herein a kindred with very early-onset FAD (age, <40 years) with unusual pathological features and a novel mutation in the presenilin 1 (PSEN1) gene (S170F) and review the existing literature on very early-onset FAD.
To analyze the neuropathological and genetic features of a family with onset of AD in the third decade of life.
The proband underwent full clinical assessment and postmortem examination at the Washington University Alzheimer's Disease Research Center, St Louis, Mo. Limited pathological samples and autopsy records of 2 affected family members were available. The proband underwent screening for mutations in genes linked with FAD.
Dementia developed in 3 family members in this kindred at a mean age of 27 years; the proband had myoclonus, seizures, and rigidity, similar to findings in previously described kindreds with PSEN1 mutations. All 3 family members were confirmed to have AD by neuropathological examination. The proband also had widespread Lewy body pathology in the brainstem, limbic areas, and neocortex; specific staining for Lewy bodies was not performed in the other 2 family members. The proband had a single mutation (S170F) in exon 6 of the PSEN1 gene, which segregates with disease.
A novel PSEN1 mutation causes very-early-onset FAD with associated Lewy bodies. To our knowledge, this kindred has the earliest reported onset of pathologically confirmed FAD and dementia with Lewy bodies.
Archives of Neurology 12/2005; 62(12):1821-30. · 7.58 Impact Factor
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ABSTRACT: Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are sporadic neurodegenerative diseases presenting as atypical parkinsonian disorders, characterized by the presence of tau-positive neurofibrillary tangles. Recently, an extended haplotype (H1E) of 787.6 kb that comprises several genes including MAPT showed increased association with PSP. The objective of this study was to determine the size of the H1E haplotype associated with PSP and CBD in different populations and to identify specific subhaplotypes in the background of H1E haplotype. Nineteen single nucleotide polymorphisms (SNPs) in the 17q21 region were genotyped in two case-control samples. The SNPs that were associated with higher risk for the disease in the homozygous state delimit a region of more that 1 Mb. Haplotype analyses in the Spanish sample showed that the most frequent haplotype found among the patients (H1E'), which extends 1.04 Mb and contains several genes such as MAPT, CRHR1, IMP5, Saitohin, WTN3, and NSF. A specific subhaplotype (H1E'A) was present in 16% of PSP patients but was not observed in the controls. Furthermore, the H2E'A haplotype, was rarely present in the disease group suggesting that it plays a protective role. The identification of these specific subhaplotypes that modify risk for PSP/CBD supports the hypothesis that a pathogenic allele exists in a subgroup of PSP patients.
Annals of Neurology 09/2004; 56(2):249-58. · 11.09 Impact Factor
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Janel Johnson,
Jovanka Ostojic,
Lars Lannfelt,
Anna Glaser,
Hans Basun,
Ekaterina Rogaeva,
Toshitaka Kawarai,
Amalia Bruni,
Peter H St George Hyslop,
Alison Goate,
Pau Pastor,
Sumi Chakraverty, Joanne Norton,
John C Morris,
John Hardy,
Andrew Singleton
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ABSTRACT: Given the remarkable similarities between the genetics of tau diseases and the genetics of alpha-synuclein diseases, and given the fact that we have recently found a triplication of the alpha-synuclein locus in a family in which we had shown linkage to the alpha-synuclein locus, we determined to test whether some of the several families with autosomal dominant frontal temporal dementia which show genetic linkage to the tau locus but in which tau mutations have not been found could be caused by similar structural mutations. We did not find any such mutations.
Neuroscience Letters 07/2004; 363(2):99-101. · 2.11 Impact Factor
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Victoria Busby,
Steven Goossens,
Petra Nowotny,
Gillian Hamilton,
Scott Smemo,
Denise Harold,
Dragana Turic,
Luke Jehu,
Amanda Myers,
Meredith Womick, [......],
Lesley Jones,
Julie Williams,
Peter Holmans,
Michael J. Owen,
Andrew Grupe,
John Powell,
Jolanda van Hengel,
Alison Goate,
Frans Van Roy,
Simon Lovestone
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ABSTRACT: The gene encoding α-T-catenin, CTNNA3, is positioned within a region on chromosome 10, showing strong evidence of linkage to Alzheimer’s disease (AD), and is therefore
a good positional candidate gene for this disorder. We have demonstrated that α-T-catenin is expressed in human brain, and
like other α-catenins, it inhibits Wnt signaling and is therefore also a functional candidate. We initially genotyped two
single-nucleotide polymorphisms (SNPs) in the gene, in four independent samples comprising over 1200 cases and controls but
failed to detect an association with either SNP. Similarly, we found no evidence for association between CTNNA3 and AD in a sample of subjects showing linkage to chromosome 10, nor were these SNPs associated with Aβ deposition in brain.
To comprehensively screen the gene, we genotyped 30 additional SNPs in a subset of the cases and controls (n>700). None of these SNPs was associated with disease. Although an excellent candidate, we conclude that CTNNA3 is unlikely to account for the AD susceptibility locus on chromosome 10.
NeuroMolecular Medicine 03/2004; 5(2):133-146. · 5.00 Impact Factor
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Amanda J Myers,
Helen Marshall,
Peter Holmans,
Danielle Compton,
Richard J P Crook,
Adrian P Mander,
Petra Nowotny,
Scott Smemo,
Melanie Dunstan,
Luke Jehu, [......],
Sumi Chakraventy,
Nigel Tunstall,
Simon Lovestone,
Ronald Petersen,
Michael O'Donovan,
Lesley Jones,
Julie Williams,
Michael J Owen,
John Hardy,
Alison Goate
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ABSTRACT: Linkage studies indicate that the same region of chromosome 10 contains a risk locus for late onset Alzheimer disease (LOAD) and a QTL for plasma Abeta42 levels suggesting that a single locus may influence risk for AD by elevating plasma Abeta42 [Ertekin-Taner et al., 2000; Myers et al., 2000]. A strong positional and biological candidate is the urokinase-plasminogen activator (PLAU) gene. Eight polymorphisms spanning the entire gene were examined using case control (CC) and family-based association methods. No association was observed by any method making it unlikely that variation in PLAU explains our linkage data.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 02/2004; 124B(1):29-37. · 3.70 Impact Factor
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Victoria Busby,
Steven Goossens,
Petra Nowotny,
Gillian Hamilton,
Scott Smemo,
Denise Harold,
Dragana Turic,
Luke Jehu,
Amanda Myers,
Meredith Womick, [......],
Lesley Jones,
Julie Williams,
Peter Holmans,
Michael J Owen,
Andrew Grupe,
John Powell,
Jolanda van Hengel,
Alison Goate,
Frans Van Roy,
Simon Lovestone
[show abstract]
[hide abstract]
ABSTRACT: The gene encoding alpha-T-catenin, CTNNA3, is positioned within a region on chromosome 10, showing strong evidence of linkage to Alzheimer's disease (AD), and is therefore a good positional candidate gene for this disorder. We have demonstrated that alpha-T-catenin is expressed in human brain, and like other alpha-catenins, it inhibits Wnt signaling and is therefore also a functional candidate. We initially genotyped two single-nucleotide polymorphisms (SNPs) in the gene, in four independent samples comprising over 1200 cases and controls but failed to detect an association with either SNP. Similarly, we found no evidence for association between CTNNA3 and AD in a sample of subjects showing linkage to chromosome 10, nor were these SNPs associated with Abeta deposition in brain. To comprehensively screen the gene, we genotyped 30 additional SNPs in a subset of the cases and controls (n > 700). None of these SNPs was associated with disease. Although an excellent candidate, we conclude that CTNNA3 is unlikely to account for the AD susceptibility locus on chromosome 10.
NeuroMolecular Medicine 01/2004; 5(2):133-46. · 5.00 Impact Factor
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Pau Pastor,
Catherine M Roe,
Andrés Villegas,
Gabriel Bedoya,
Sumi Chakraverty,
Gloria García,
Victoria Tirado, Joanne Norton,
Silvia Ríos,
Maribel Martínez,
Kenneth S Kosik,
Francisco Lopera,
Alison M Goate
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ABSTRACT: We previously have identified a large kindred from Colombia in which Alzheimer's disease (AD) is caused by the E280A presenilin 1 (PS1) mutation. The objective of this study was to examine whether environmental and genetic factors are responsible for variation in the phenotypic expression of the E280A PS1 mutation. We genotyped coding and promoter polymorphisms of the APOE gene in carriers of the E280A PS1 mutation. Kaplan-Meier product-limit and Cox proportional hazard models were used in the statistical analyses. DNA was available from 114 carriers of the E280A PS1 mutation, including 52 subjects with AD. APOE epsilon 4 allele carriers were more likely to develop AD at an earlier age than subjects without the epsilon 4 allele (hazard ratio, 2.07; 95% confidence interval, 1.07-3.99; p = 0.030). Subjects with low education were more likely to develop AD later than those with higher education (hazard ratio, 0.476; 95% confidence interval, 0.26-0.87). Low educational level was associated with rural residence (p < 0.001). Promoter APOE variants did not influence either the onset or the duration of the disease. This study is the first to our knowledge to demonstrate that genetic and environmental factors influence age of onset in a kindred with a familial AD mutation.
Annals of Neurology 08/2003; 54(2):163-9. · 11.09 Impact Factor
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Richard Abraham,
Amanda Myers,
Fabienne Wavrant-DeVrieze,
Marian L. Hamshere,
Hollie V. Thomas,
Helen Marshall,
Danielle Compton,
Gillian Spurlock,
Dragana Turic,
Bastiaan Hoogendoorn, [......],
John C. Morris,
Roger Bullock,
Danae Liolitsa,
Simon Lovestone,
John Hardy,
Alison Goate,
Michael O'Donovan,
Julie Williams,
Michael J. Owen,
Lesley Jones
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ABSTRACT: Insulin-degrading enzyme (IDE; insulysin; EC 3.4.24.56) is a 110-kDa neutral metallopeptidase that can degrade a number of peptides including #-amyloid. The gene encoding IDE is located on chromosome 10 close to a region of linkage for late-onset Alzheimer's disease (LOAD) and thus is a functional and positional candidate for this disorder. We analysed all of the coding exons, untranslated regions and 1000 bp of 5'-flanking sequence of IDE by using denaturing high-performance liquid chromatography and sequencing. We detected eight single nucleotide polymorphisms (SNPs), three in the 5' flanking sequence and five in the coding sequence, of which three were found at lower than 5% frequency. None of them changed the amino acid sequence. We genotyped the five SNPs with allele frequencies of more than 5% in 133 Caucasian LOAD cases and 135 controls collected in the UK and 95 cases and 117 controls collected at the Mayo Clinic, Rochester, USA. Two of the SNPs were analysed in a further independent case-control sample (Washington University, St. Louis: 86 cases, 94 controls). No significant association was found with any individual SNP in any of the samples or with any haplotypes. Analysis of the marker D10S583, which maps 36 kb upstream of IDE, also failed to show association in 134 cases and 111 matched controls from the UK (P=0.63). Strong linkage disequilibrium was detected between the five SNPs that spanned the whole of the 120-kb genomic region of IDE and one major and a number of minor haplotypes were detected in the populations studied. We conclude that IDE does not make a substantial contribution to the aetiology of LOAD and therefore cannot account for the linkage between LOAD and 10q.
Human Genetics 11/2001; 109(6):646-652. · 5.07 Impact Factor
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Mike Hutton,
Corinne L. Lendon,
Patrizia Rizzu,
Matt Baker,
Susanne Froelich,
Henry Houlden,
Stuart Pickering-Brown,
Sumi Chakraverty,
Adrian Isaacs,
Andrew Grover, [......],
David Craufurd,
David Neary,
Frank Owen,
Ben A. Oostra,
John Hardy,
Alison Goate,
John van Swieten,
David Mann,
Timothy Lynch,
Peter Heutink
[show abstract]
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ABSTRACT: Thirteen families have been described with an autosomal dominantly inherited
dementia named frontotemporal dementia and parkinsonism linked to chromosome
17 (FTDP-17)
Nature 06/1998; 393(6686):702-705. · 36.28 Impact Factor
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Leonard Berg,
Daniel W McKeel,
J Philip Miller,
Martha Storandt,
Eugene H Rubin,
John C Morris,
Jack Baty,
Mary Coats, Joanne Norton,
Alison M Goate,
Joseph L Price,
Marla Gearing,
Suzanne S Mirra,
Ann M Saunders
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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.Arch Neurol. 1998;55:326-335-->
Archives of neurology 03/1998; 55(3):326-335. · 6.31 Impact Factor
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Corinne L. Lendon,
Alonso Martinez,
Isabel Maria Behrens,
Kenneth S. Kosik,
Lucia Madrigal, Joanne Norton,
Rosalind Neuman,
Amanda Myers,
Frances Busfield,
Michelle Wragg,
Mauricio Arcos,
Juan Carlos Arango Viana,
Jorge Ossa,
Andres Ruiz,
Alison M. Goate,
Francisco Lopera
[show abstract]
[hide abstract]
ABSTRACT: A single base substitution of a glutamic acid to an alanine codon 280 was found in the presenilin-1 (PS-1) gene on chromosome 14 in affected individuals in each of seven Colombian early-onset Alzheimer's disease (AD) kindreds. The mutation segregated with disease in kindreds tested. In the largest kindred (C2), the maximum two-point lod score between the mutation and AD was Z = 8.14 at θ = 0. The presence of a single mutation and the common geographic origin, with all families from the state of Antioquia, suggest a founder effect in this population. This finding is supported by the observation of a rare haplotype inherited with AD in all kindreds. These kindreds form the largest collection of AD cases with the same PS-1 mutation and the same educational, environmental, and ethnic background in which to study the phenotypic effect of putative risk factors, such as the ϵ4 allele of apolipoprotein E (ApoE) or head trauma. Of the few AD cases having a history of head trauma, the age of onset was not lowered. No effect of ApoE genotype on the age of onset was detected. Previous investigations of the effect of ApoE genotype on the age of onset were confounded by small patient numbers, familial clustering of ApoE genotypes, and combining data from unrelated families with different mutations. Hum Mutat 10:186–195, 1997. © 1997 Wiley-Liss, Inc.
Human Mutation 12/1996; 10(3):186 - 195. · 5.69 Impact Factor
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[show abstract]
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ABSTRACT: We have identified more than 20 nuclear Alzheimer's disease (AD) families in Colombia that carry a single point mutation,
E280A, in the presenilin 1 (PSEN1) gene. Genealogical and genetic studies have demonstrated that these families share a common founder more than 400 years
ago. The mean age of onset of AD in these families is 45.2 years but the range is almost 30 years (35–62 years). The wide
range in age of onset suggests that genetic and/or environmental risk factors modify the age of onset. We are using two complementary
approaches to the identification of genetic modifiers: candidate gene analyses and a whole genome screen analysis.
We have genotyped polymorphisms in each of the known AD genes: ß-amyloid protein precursor gene (APP), presenilin 1 (PSEN1) gene, presenilin 2 (PSEN2) gene and apolipoprotein E gene (APOE). Several polymorphisms in these genes have previously been associated with risk for AD in some but not all studies. To determine
whether these polymorphisms modify the age of onset in the Colombian kindreds, we initially used survival curve analysis.
The only gene that modified age of onset with this methodology was APOE. The APOE4 allele was associated with an earlier age of onset whereas the presence of the APOE2 allele was associated with later age of onset. This result is consistent with the observations of the effect of APOE alleles on sporadic AD and suggests that genes that influence the risk for late onset AD may also modify age of onset in
familial early onset Alzheimer's disease (FAD).
We have also used survival analysis to examine several putative environmental risk factors. These studies demonstrated that
both years of education and urban dwelling were associated with an earlier age of onset. Since these two factors were highly
correlated in this study, it was not possible to determine which one was primarily the responsible risk factor.
To identify novel genetic risk factors for AD, we have used two complementary approaches: genetic analysis of a large series
of late onset AD sibling pairs and a search for genes that modify age of onset in the Colombian families. Our genome screen
in AD sibling pairs has provided evidence of AD susceptibility genes on chromosomes 9, 10, and 12 and suggestive evidence
of an age of onset modifier gene on chromosome 12.
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