Biomedical subjects
Publications and source records attributed to A M Goate.
Deposition of beta-amyloid peptide in the brain is an early event in Alzheimer's disease, the most common cause of dementia. Studies of the beta-amyloid precursor protein (APP), which gives rise to beta-amyloid, are rapidly leading to a better understanding of the biochemical basis of the disease--a prerequisite for rational drug development.
The part that genetics plays in the origin of Alzheimer's disease (AD) is a complex problem that is only now, in the last few years, beginning to be understood. Progress in the study of the epidemiology of AD, discovery of multiple AD loci, and interpreting how mutations affect and produce the AD phenotype have been the initial keys to unlocking the mysteries of this disease. We now know of the existence of at least three AD loci on chromosomes 14, 19, and 21 and are beginning to understand the role that one of these loci, APP, and its mutations plays in the progression of AD. On future studies using animal modeling and the positional cloning of the other AD loci, a definite model for AD should become evident within the next few years.
Several point mutations within exons 16 and 17 of the amyloid precursor protein (APP) gene have been reported that are associated with Alzheimer's disease in a small number of familial cases. To determine the size of the APP gene and the organization of the exons within human genomic DNA, we have characterized 11 Yeast Artificial Chromosome (YAC) recombinants containing human APP gene sequences. The smallest YAC insert was 125 kb, and the largest was 1.4 Mb. The YACs were screened by polymerase chain reaction amplification of APP exons to determine which of the 18 exons coding for APP770 were present. Four of the YACs (D110G1, D110G6, D110E9, and B142F9) contain all 18 exons and at least part of the promoter. Construction of an overlapping map of the gene with all of the YACs demonstrated that 3 of the 11 YACs were chimeric. The orientation and position of the coding sequence on the map was determined by probing digests of the YAC DNA with exon PCR products and the vector arms. The coding region of the APP gene spans approximately 400 kb of genomic DNA.
Explore the source record for details and available documents.
Age of onset was examined for 139 members of 30 families affected by early-onset AD. Most (77%) of the variance of age of onset derived from differences between rather than within families. The constancy of age of onset within families was also observed in an analysis restricted to families derived from a population-based epidemiological study with complete ascertainment of early-onset AD. Furthermore, we observed clustering of age of onset within those families that support linkage to the predisposing locus on chromosome 21. Our data are compatible with the view that allelic heterogeneity at the AD locus may account for the similarity in age of onset within families. This finding may be of value for scientific studies of AD as well as for genetic counselling.
Explore the source record for details and available documents.
Evidence from linkage studies suggests that familial Alzheimer disease (AD) can be caused by a defect in a gene on the proximal long arm of chromosome 21. We have constructed a physical map spanning 10 megabases of this region of the chromosome by means of pulsed-field gel electrophoresis and analysis of somatic cell hybrids. Our data have allowed us to establish the order of chromosome 21 loci--cen-(S16,S48)-S13-S46-S4-(S52,S110)-(S1,S1 1)--and are thus of immediate relevance both to multipoint linkage analysis in families affected by AD and for moving from this linkage to the isolation of the genetic defect. We have also been able to identify several CpG-rich sequences close to the four most centromeric loci, suggesting the location of genes in this region. These probes, which are all within 1.5 megabases of one another, are currently the markers most tightly linked to the AD locus. Genes identified in this region can therefore be considered as candidates for the disease locus.
Explore the source record for details and available documents.
Linkage between Alzheimer's disease and markers on the long arm of chromosome 21 was investigated in six families affected by disease of early onset. Linkage was confirmed and the disease locus shown to be centromeric to the locus D21S1/S11 on the long arm of the chromosome. It is argued that the data are consistent with the notion that all patients with Alzheimer's disease of genetic aetiology have a predisposing locus on chromosome 21.
Explore the source record for details and available documents.
Translation in vitro of membrane-bound polyribosomal mRNAs from rat brain has shown several to be developmentally regulated [Hall & Lim (1981) Biochem. J. 196, 327-336]. Here we describe the isolation and characterization of cDNAs corresponding to two such brain mRNAs. One cDNA (M444) hybrid-selected a 0.95 kb mRNA directing the synthesis in vitro of a 21 kDa pI-6.3 polypeptide, which was processed in vitro by microsomal membranes. A second cDNA (M1622) hybridized to a 2.2 kb mRNA directing the synthesis of a 55 kDa pI-5.8 polypeptide. Both mRNAs were specific to membrane-bound polyribosomes. Restriction maps of the corresponding genomic DNA sequences are consistent with both being single copy. The two mRNAs were present in astrocytic and neuronal cultures, but not in liver or spleen or in neuroblastoma or glioma cells. The two mRNAs were differently regulated during brain development. In the developing forebrain there was a gradual and sustained increase in M444 mRNA during the first 3 weeks post partum, whereas M1622 mRNA appeared earlier and showed no further increase after day 10. In the cerebellum the developmental increase in M444 mRNA was biphasic. After a small initial increase there was a decrease in this mRNA at day 10, coincident with high amounts of M1622 mRNA. This was followed by a second, larger, increase in M444 mRNA, when amounts of M1622 mRNA were constant. The contrasting changes in these two mRNAs in the developing cerebellum are of particular interest, since they occur during an intensive period of cell proliferation, migration and altering neural connectivity. As these mRNAs are specific to differentiated neural tissue, they represent useful molecular markers for studying brain differentiation.
The human 70 kdalton heat-shock protein (HSP 70) is a member of a multigene family which is expressed in response to various physiological stresses including elevated temperatures. Using a cloned genomic HSP 70 DNA sequence we demonstrate by somatic cell hybrid and restriction fragment length polymorphism (RFLP) analyses that there are a minimum of three distinct HSP 70 loci in the human genome, one of which is located on chromosome 6.
A human genomic DNA fragment, pAM37 (HGM8; D21S22), was mapped to chromosome 21q2.1-q2.21 by in situ hybridization. This segment is therefore situated on the boundary of the "pathological region" of Down syndrome. A genomic restriction map encompassing 35 kb of chromosome 21 was derived and two restriction fragment length polymorphisms (RFLPs) were mapped and characterized. A homologous sequence was detected in the mouse genome but no homologous RNA was detected in a range of human tissues. This DNA segment will contribute to the linkage mapping of chromosome 21 and will facilitate delineation of the pathological region of Down syndrome.
Our work has confirmed that of St. George-Hyslop and colleagues, suggesting FAD linkage to the short arm of chromosome 21 in outbred families with a presenile onset of the disease. Future genetic studies should help clarify the current apparent discrepancies between certain laboratories and ultimately lead to a better understanding of the variables which predispose individuals to the disease.