Biomedical subjects
Publications and source records attributed to A D Roses.
Familial Alzheimer diseases is a neurological disorder of adult onset. Three research centers have each contributed their families and genetic linkage data for combined analyses. The data from the Duke and Boston centers, comprising 73 pedigrees for whom numerous markers on chromosomes 19 and 21 were typed are described.
The senile plaque and congophilic angiopathy in brains of patients with Alzheimer's disease contain abnormal extracellular depositions. These depositions have very complex molecular structure, some elements of which have been identified. The most abundant protein in these structures is beta A amyloid peptide, which is produced by proteolytic processing of a larger protein, the amyloid precursor protein. It is not known how plaques and angiopathy are formed. Binding of proteins with the beta A peptide may be critical in this process. Using synthetic beta A peptides we show that the amyloid precursor protein found in cerebrospinal fluid binds beta A peptide with high avidity. Analysis of recombinant amyloid precursor proteins containing deletions of various domains demonstrate that the beta A peptide binds to the amino terminus of its own precursor. A model of plaque assembly is presented.
Charcot-Marie-Tooth (CMT) disease type 2 (CMT2) is an inherited peripheral neuropathy characterized by variable age of onset and normal or slightly diminished nerve conduction velocity. CMT2 is pathologically and genetically distinct from CMT type 1 (CMT1). While CMT1 has been shown to be genetically heterogeneous, no chromosomal localization has been established for CMT2. We have performed pedigree linkage analysis in six large autosomal dominant CMT2 families and have demonstrated linkage and heterogeneity to a series of microsatellites (D1S160, D1S170, D1S244, D1S228 and D1S199) in the distal region of the short arm of chromosome 1. Significant evidence for heterogeneity was found using admixture analysis and the two-point lod scores. Admixture analyses using the multipoint results for the markers D1S244, D1S228, and D1S199 supported the two-point findings. Three families, DUK662, DUK1241, and 1523 gave posterior probabilities of 1.0, 0.98, and 0.88 of being of the linked type. Multipoint analysis examining the "linked" families showed that the most favored location for the CMT2A gene is within the interval flanked by D1S244 and D1S228 (odds approximately 70:1 of lying within versus outside that interval). These findings suggest that the CMT2 phenotype is secondary to at least two different genes and demonstrate further heterogeneity in the CMT phenotype.
Four related genes, Shaker, Shab, Shaw, and Shal, encode voltage-gated K+ channels in Drosophila. Multigene subfamilies corresponding to each of these Drosophila genes have been identified in rodents and primates; this suggests that the four genes are older than the common ancestor of present-day insects and mammals and that the expansion of each into a family occurred before the divergence of rodents and primates. In order to define these evolutionary relationships more precisely and to facilitate the search for mammalian candidate K+ channel gene mutations, we have mapped members of the Shaw-homologous gene family in humans and mice. Fluorescence in situ hybridization analysis of human metaphase chromosomes mapped KCNC2 (KShIIIA, KV3.2) and KCNC3 (KShIIID, KV3.3) to Chromosome (Chr) 19q13.3-q13.4. Inheritance patterns of DNA restriction fragment length variants in recombinant inbred strains of mice placed the homologous mouse genes on distal Chr 10 near Ms15-8 and Mdm-1. The mouse Kcnc1 (KShIIIB, NGK2-KV4, KV3.1) gene mapped to Chr7 near Tam-1. These results are consistent with the hypothesis that the generation of the mammalian KCNC gene family included both duplication events to generate family members in tandem arrays (KCNC2, KCNC3) and dispersion of family members to unlinked chromosomal sites (KCNC1). The KNCN2 and KCNC3 genes define a new synteny group between humans and mice.
Autosomal recessive Charcot-Marie-Tooth (CMT) disease (CMT4) is a complex group of severe childhood motor and sensory neuropathies, characterized by an early age of onset with rapidly progressive distal limb weakness and atrophy. One subgroup designated CMT4 type A (CMT4A) was selected from a series of Tunisian CMT4 families according to the following electrophysiological and pathological criteria: slow motor nerve conduction velocity (MCV), severe hypomyelination upon nerve biopsy with basal lamina onion bulbs and no myelin outfolding. In an attempt to localize the CMT4A locus, we studied four inbred families with 13 affected patients. Significant evidence for linkage was found for several markers from chromosome 8q13-21.1 (D8S279, D8S164, D8S286, D8S84, D8S275 and D8S167). An overall two point peak lod score of z(theta) = 9.19 at theta = 0.00 (95% confidence limit 0.00-0.08) was obtained for D8S164. No evidence of genetic heterogeneity was found. The chromosomal localization of one form of CMT4 will have important implications in clarifying the nosology of this complex group of disorders.
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Familial Alzheimer's disease (FAD) has been shown to be associated with three distinct point mutations within the same codon of the amyloid precursor protein (APP) gene. The mutation identified in the Indiana kindred is a G-->T transversion at the first position of the codon for amino acid 717, resulting in a substitution of phenylalanine for valine in the APP protein. Screening of persons at risk for the APP Phe-717 mutation using a variation of the polymerase chain reaction identified nine positives among 34 tested. In addition, DNA from 145 FAD subjects were tested for the three known APP 717 mutations.
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We found a novel polymorphism in the amyloid precursor protein (APP) gene in a patient with ischemic cerebrovascular disease who had no evidence of Alzheimer's disease (AD). This polymorphism deletes a Fok I restriction enzyme site and causes the substitution of threonine for alanine at codon 673. This is adjacent to the site at which APP is thought to undergo cleavage in AD. Analysis of this polymorphism may provide insight into the basis of APP processing.
Recent progress in human neurogenetics has led to the discovery of new modes of inheritance and disease expression, including 1) stably inherited duplications in Charcot-Marie-Tooth disease type 1a, 2) dynamic mutations in fragile X syndrome and myotonic dystrophy, and 3) identical mutations with different phenotypes in fatal familial insomnia and Creutzfeldt-Jakob disease. The mechanisms by which known mutations of the amyloid precursor protein lead to early-onset Alzheimer's disease remain unexplained, despite hundreds of recent studies of beta-amyloid.
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Golden retriever muscular dystrophy (GRMD) is a spontaneous, X-linked, progressively fatal disease of dogs and is also a homologue of Duchenne muscular dystrophy (DMD). Two-thirds of DMD patients carry detectable deletions in their dystrophin gene. The defect underlying the remaining one-third of DMD patients is undetermined. Analysis of the canine dystrophin gene in normal and GRMD dogs has failed to demonstrate any detectable loss of exons. Here, we have demonstrated a RNA processing error in GRMD that results from a single base change in the 3' consensus splice site of intron 6. The seventh exon is then skipped, which predicts a termination of the dystrophin reading frame within its N-terminal domain in exon 8. This is the first example of dystrophin deficiency caused by a splice-site mutation.
The zinc finger motif is a highly conserved tandemly repeated sequence of 28-30 amino acids that was first identified in transcription factor TFIIIA from Xenopus laevis. Subsequently, similar motifs were found and characterized in many genes from mammalian genomes and the genomes of lower eukaryotes such as Drosophila and yeast, thereby defining a large superfamily of genes. Non-finger-coding modules conserved among members of subfamilies of zinc finger genes have been described in the murine genome (finger-associated boxes, or FAX domain) and the human genome (Krüppel-associated boxes, or KRAB domain). Here we report the identification and partial characterization of more members of the human KRAB-containing subfamily of genes. Based on Southern blot hybridization experiments, they also are zinc-finger-coding genes. All members share a highly homologous 42-amino-acid-long A element of the described KRAB domain. The conservation extends to the murine developmentally expressed zinc finger gene, mKr2. The homologous sequences, however, are part of the 5'-untranslated region. In all cases for which there is adequate information, the KRAB domain is found at the NH2-terminus of the respective protein. In one zinc-finger-encoding cDNA clone that we characterized further in this work, BRc1744 (ZNF45), the KRAB domain most probably constitutes the entire second exon of the gene. Based on the data, it is tempting to speculate that the FAX- and KRAB-containing zinc finger genes define subfamilies of genes with overlapping functions that participate in the regulation of common or similar developmental programs.
Autosomal recessive Duchenne-like muscular dystrophy (DLMD) is a severe dystrophic myopathy. The incidence is unknown because of its clinical similarity to Duchenne muscular dystrophy (DMD). Three highly inbred DLMD families from Tunisia were analysed for chromosomal linkage using 135 polymorphic microsatellite markers. A significant lod score of z = 9.15 at theta = 0.03 was found with the 13q12 locus D13S115. Two additional 13q12 markers, D13S143 and D13S120, also gave significant lod scores. Therefore, the primary DLMD defect gene lies in the pericentrometric region of chromosome 13q.
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