Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease

@article{Goate1991SegregationOA,
  title={Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease},
  author={Alison M. Goate and Marie Christine Chartier-Harlin and Mike Mullan and Jeremy S. Brown and Fiona Crawford and Liana Fidani and LuisA. Giuffra and Andrew R. Haynes and Nicholas G. Irving and L. A. James and Rebecca Mant and P. J. Newton and Karen Rooke and Penelope Roques and Chris J. Talbot and Margaret A. Pericak-Vance and A. D. Roses and R. Williamson and Martin N. Rossor and Mike J. Owen and John Hardy},
  journal={Nature},
  year={1991},
  volume={349},
  pages={704-706}
}
A LOCUS segregating with familial Alzheimer's disease (AD) has been mapped to chromosome 21 (ref. 1), close to the amyloid precursor protein (APP) gene2–5. Recombinants between the APP gene and the AD locus have been reported6–8 which seemed to exclude it as the site of the mutation causing familial AD. But recent genetic analysis of a large number of AD families has demonstrated that the disease is heterogeneous9. Families with late-onset AD do not show linkage to chromosome 21 markers9,10… Expand
Clinical features of early onset, familial Alzheimer's disease linked to chromosome 14.
TLDR
The clinical features and genetic analysis of a British pedigree with early onset AD in which neither the beta APP locus nor any other chromosome 21 locus segregates with the disease, but in which good evidence is seen for linkage on the long arm of chromosome 14. Expand
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The emerging picture is that AD is a genetically complex, heterogeneous disorder and how these genetic factors interact with each other and with other yet-to-be-identified genetic and nongenetic factors to produce the clinical and pathologic findings in AD remains to be elucidated. Expand
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TLDR
Recent genome-wide scanning studies have revealed the existence of a new locus on chromosome 12, which, together with inheritance of the epsilon4 allele of apolipoprotein E gene, represent the most important genetic factors associated with an increased risk of developing the disease in late onset FAD families. Expand
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TLDR
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Genetic dissection of Alzheimer disease, a heterogeneous disorder.
  • G. Schellenberg
  • Biology, Medicine
  • Proceedings of the National Academy of Sciences of the United States of America
  • 1995
TLDR
In late-onset AD, the apolipoprotein E gene allele epsilon 4 is a risk factor for AD and appears to act as a dose-dependent age-of-onsett modifier. Expand
Genetic heterogeneity of gene defects responsible for familial Alzheimer disease
TLDR
This review provides a historical perspective of the search for FAD gene defects and summarizes the progress made in world-wide attempts to isolate and characterize the genes responsible for this disorder. Expand
Molecular genetics of Alzheimer's disease
  • J. Hardy
  • Biology, Medicine
  • Biochemical Society transactions
  • 1989
TLDR
The occurrence and effects of the mutations in APP and the fact that the ε4 allele of ApoE are genetic risk factors point to the hypothesis that the extracellular deposition of β‐amyloid is the key initiating event in the pathogenesis of AD. Expand
Genetic Defects in Early Onset Alzheimer’s Disease and Related Disorders
There is sufficient evidence that genes play an important role in the aetiology of Alzheimer’s disease (AD). In families with patients with an early onset of AD (EOAD) before the age of 65 years, theExpand
The amyloid precursor protein locus and very-late-onset Alzheimer disease.
TLDR
It is concluded that the APP locus may predispose to AD in the very elderly. Expand
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The genetic defect in familial Alzheimer's disease is not tightly linked to the amyloid β-protein gene
TLDR
The detection of several recombination events with FAD suggests that the AP gene is not the site of the inherited defect underlying this disorder, and the pattern of segregation of theAP gene in FAD pedigrees is determined using restriction fragment length polymorphisms. Expand
Failure of familial Alzheimer's disease to segregate with the A4-amyloid gene in several European families
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It is demonstrated that the gene for plaque core A4-amyloid cannot be the locus of a defect causing Alzheimer's disease in these families, and alterations in the plaque core amyloid gene cannot explain the molecular pathology for all cases of Alzheimer's Disease. Expand
Absence of linkage of chromosome 21q21 markers to familial Alzheimer's disease.
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No evidence for linkage was found between familial Alzheimer's disease (FAD) and chromosome 21q21 markers (D 21S1/D21S72 and the amyloid beta gene) and data indicate that FAD is genetically heterogeneous. Expand
Genetic linkage studies suggest that Alzheimer's disease is not a single homogeneous disorder
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The inheritance of five polymorphic DNA markers from the proximal long arm of chromosome 21 in a large unselected series of pedi-grees with familial Alzheimer's disease suggests that Alzheimer's Disease is not a single entity, but rather results from genetic defects on chromosome 21 and from other genetic or nongenetic factors. Expand
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Linkage studies undertaken to test the localization of both early onset and late onset Alzheimer's disease families to chromosome 21 failed to establish linkage and excluded linkage from a large portion of the region where the early onset Alzheimer't disease gene was localized. Expand
The genetic defect causing familial Alzheimer's disease maps on chromosome 21.
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The chromosomal location of this defective gene has been discovered by using genetic linkage to DNA markers on chromosome 21 and provides an explanation for the occurrence of Alzheimer's disease-like pathology in Down syndrome. Expand
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The data indicate that the APP gene is tightly linked to HCHWA-D and therefore, in contrast to familial Alzheimer's disease, cannot be excluded as the site of mutation in HCH WA-D. Expand
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Definition of the linkage relationships for these chromosome 21 markers will help refine the map position of the familial Alzheimer's disease gene and facilitate investigation of the role of recombination in nondisjunction associated with Down syndrome. Expand
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Overexpression of the gene in brain tissue from fetuses with Down syndrome (trisomy 21) can be explained by dosage since the locus encoding the beta protein maps to chromosome 21. Expand
PREDISPOSING LOCUS FOR ALZHEIMER'S DISEASE ON CHROMOSOME 21
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Data from six families affected by disease of early onset are argued to be consistent with the notion that all patients with Alzheimer's disease of genetic aetiology have a predisposing locus on chromosome 21. Expand
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