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Biomedical subjects

A D Roses

Publications and source records attributed to A D Roses.

At least 163 records · Page 9Linked to original sources
PubMed1995

Mutation analysis of the TSC2 gene in an African-American family.

Tuberous sclerosis complex is an autosomal dominant disorder with loci on chromosome 9q34 (TSC1) and chromosome 16p13.3 (TSC2). The TSC2 gene has been isolated. To date, only a small number of intragenic deletional and point mutations have been detected, almost exclusively in sporadic (no family history) cases. With the exception of a single parent/offspring pair, there have been no published reports of mutations in extended multigenerational chromosome 16-linked TSC2 families. For our TSC studies we ascertained and sampled a four-generation African-American TSC family that shows a high likelihood for linkage to chromosome 16 (z=1.53). Using single-strand conformation polymorphism analysis we identified a 4590/4591delC mutation in exon 34. The 4590/4591delC causes a frameshift mutation resulting in the creation of a premature stop codon. In addition, we have detected a 542del4 polymorphism in the two partially overlapping polyadenylation signals in exon 40 that segregates in the family. The polymorphism has been detected in six of 72 African-American control chromosomes examined, and has not been detected in 80 Caucasian control chromosomes examined.

Amino Acid Sequence↗
PubMed1995

Cystatin C mutation in an elderly man with sporadic amyloid angiopathy and intracerebral hemorrhage.

BACKGROUND: Cerebral amyloid angiopathy (CAA) with intracerebral hemorrhage (ICH) occurs both sporadically and as a result of mutations in either cystatin C or the amyloid precursor protein. ICH due to cystatin C mutations typically occurs in young people of Icelandic origin. CASE DESCRIPTION: We report a case of sporadic CAA with ICH in an elderly Croatian man with a mutation in cystatin C identical to that found in Icelandic hereditary cerebral hemorrhage with amyloidosis. CONCLUSIONS: This is the first case report of sporadic CAA associated with the same mutation causing hereditary cerebral hemorrhage with amyloidosis of the Icelandic type. Sporadic CAA may thus be associated with genetic mutations in some patients. The frequency of these mutations is yet to be determined.

Cerebral Amyloid Angiopathy↗
PubMed1995

Modulation of skeletal muscle sodium channels by human myotonin protein kinase.

In myotonic muscular dystrophy, abnormal muscle Na currents underlie myotonic discharges. Since the myotonic muscular dystrophy gene encodes a product, human myotonin protein kinase, with structural similarity to protein kinases, we tested the idea that human myotonin protein kinase modulates skeletal muscle Na channels. Coexpression of human myotonin protein kinase with rat skeletal muscle Na channels in Xenopus oocytes reduced the amplitude of Na currents and accelerated current decay. The effect required the presence of a potential phosphorylation site in the inactivation mechanism of the channel. The mutation responsible for human disease, trinucleotide repeats in the 3' untranslated region, did not prevent the effect. The consequence of an abnormal amount of the kinase would be altered muscle cell excitability, consistent with the clinical finding of myotonia in myotonic dystrophy.

Animals↗
PubMed1995

Apolipoprotein E genotype and Lewy body disease.

To determine whether apolipoprotein E (APOE) genotype affects neuropathology in Lewy body disease (LBD), we examined 18 cases of LBD that did not have concurrent Alzheimer's disease by the CERAD criteria. We obtained APOE genotypes, determined diffuse beta-amyloid plaque (A beta P) and Lewy body densities in multiple brain regions, and graded the intensity of CA2-3 ubiquitin-positive neurites, vacuolar change, nigral pathology, amyloid angiopathy, and subpial amyloid deposition. The APOE allele frequencies were as follows: epsilon 2, 0.14 +/- 0.07; epsilon 3, 0.64 +/- 0.08; and epsilon 4, 0.22 +/- 0.03. The mean A beta P density was lower in APOE epsilon 3/3 cases (14.5 A beta Ps per mm2) than in the groups with the APOE epsilon 2 (67.0) or APOE epsilon 4 (46.6) alleles. This difference was due largely to the difference between A beta P density in the APOE epsilon 2 group and the APOE epsilon 3/3 group (F = 5.525, p < 0.02). CA2-3 neuritic degeneration was greater in those with the APOE epsilon 4 allele than in those with the APOE epsilon 3/3 genotype (grade = 1.9 +/- 1.3 versus 0.938 +/- 0.9; Kruskal-Wallis test statistic = 6.962, p < 0.05). These data are consistent with the hypothesis that APOE genotype may affect neuropathology in LBD.

Aged↗
PubMed1995

Influence of the susceptibility genes apolipoprotein E-epsilon 4 and apolipoprotein E-epsilon 2 on the rate of disease expressivity of late-onset Alzheimer's disease.

Apolipoprotein E-epsilon 4 (APOE4, gene; apoE4, protein) is a susceptibility gene or risk factor for Alzheimer's disease. The genetic relevance of APOE4 has been widely confirmed. The APOE gene is not a disease locus, with specific mutations causing Alzheimer disease. Allelic variations at the APOE locus affect the rate of disease progression. The association of specific inherited APOE alleles with age of onset distributions describes biological effects based on genotype. The inheritance of polymorphic genes with single amino acid differences between apoE4 and apoE3 (and between apoE3 and apoE2) at the protein level is associated with differences in the mean age of disease onset spanning almost two decades. The isoform-specific metabolism of apoE resulting in a faster rate of disease expression can now be studied with the expectation that genetically relevant processes are being investigated. There is now an opportunity to develop theories directed at the genetically relevant apoE metabolism that can significantly delay disease expression.

Age of Onset↗
PubMed1994

Isoform-specific interactions of apolipoprotein E with the microtubule-associated protein MAP2c: implications for Alzheimer's disease.

The apolipoprotein E type 4 allele is a susceptibility gene for late-onset Alzheimer's disease. Apolipoprotein E is found in neurons, some of which contain paired helical filaments made of the microtubule-associated protein tau. Previous studies have demonstrated that the apoE3 isoform, but not the apoE4 isoform, binds tau with high avidity. Because the microtubule-associated protein MAP2c also effects microtubule assembly and stability, we examined interactions between apoE isoforms and MAP2c. Similar to the tau-binding results, apoE3, but not apoE4, bound MAP2c. Binding was detectable down to 10(-9) M MAP2c and 10(-8) M apoE3. Isoform-specific interactions of apoE with the microtubule-associated proteins MAP2c and tau might affect intracellular maintenance of microtubules and could contribute to a time-dependent pathogenesis of Alzheimer's disease.

Alzheimer Disease↗
PubMed1994

Isoform-specific interactions of apolipoprotein E with microtubule-associated protein tau: implications for Alzheimer disease.

The apolipoprotein E (apoE) type 4 allele (APOE4) is a susceptibility gene for late-onset familial and sporadic Alzheimer disease. ApoE is found in some neurofibrillary tangle-bearing neurons, one of the major pathologic hallmarks of the disease. Neurofibrillary tangles contain paired helical filaments formed from hyperphosphorylated microtubule-associated protein tau. In vitro, tau binds avidly to apoE3, but not to apoE4, forming a bimolecular complex. Tau phosphorylated with a brain extract does not bind either isoform. ApoE3 binds to the microtubule-binding repeat region of tau, which is also the region that is thought to cause self-assembly into the paired helical filament. Binding studies with fragments of ApoE demonstrate that the tau-binding region of apoE3 corresponds to its receptor-binding domain and is distinct from the region that binds lipoprotein particles or beta/A4 peptide. Isoform-specific interactions of apoE with tau may regulate intraneuronal tau metabolism in Alzheimer disease and alter the rate of formation of paired helical filaments and neurofibrillary tangles.

Alzheimer Disease↗
PubMed1994

Apolipoprotein E uptake and degradation via chloroquine-sensitive pathway in cultivated monkey cells overexpressing low density lipoprotein receptor.

Alzheimer's disease with late onset is associated with inheritance of isoform 4 of the polymorphic apolipoprotein E (ApoE). We describe an experimental model where intracellular interaction between ApoE isoforms and cellular proteins may be studied. Internalization and intracellular fate of ApoE from fresh normal cerebrospinal fluid is followed in COS cells (an SV40 transformed Simian kidney cell line) overexpressing the low density lipoprotein receptor. Chase and chloroquine experiments strongly suggest that internalized ApoE travels through the endosomal-lysosomal pathway after dissociation from the receptor in early endosome.

Alzheimer Disease↗
PubMed1994

Relative abundance of Alzheimer A beta amyloid peptide variants in Alzheimer disease and normal aging.

The Alzheimer A beta amyloid peptide (A beta) is the principal proteinaceous component of amyloid associated with Alzheimer disease (AD). We have determined the relative abundance of A beta structural variants present in amyloid from brains of 10 individuals with sporadic AD, 2 individuals with familial AD carrying specific mutations in the Alzheimer amyloid precursor protein gene, and 5 nondemented elderly controls. A procedure of isolation based on the extreme insolubility of A beta amyloid was used. The purified, nondigested A beta was analyzed by N-terminal sequencing and electrospray-ionization mass spectrometry. Three principal A beta variants were detected--A beta-(1-40), A beta-(1-42), and A beta-(11-42)--in all brains analyzed. The predominant variant in sporadic AD was A beta-(1-40), whereas the principal A beta variant in nondemented elderly controls was A beta-(1-42). The ratio A beta-(1-40)/A beta-(1-42) differed by 10-fold between brains from nondemented controls and those with sporadic AD.

Aged↗
PubMed1994

A new human slow skeletal troponin T (TnTs) mRNA isoform derived from alternative splicing of a single gene.

A human muscle cDNA library was screened for slow skeletal troponin T (TnTs). Sequence analysis revealed that one of the selected clones had a cDNA coding sequence different from the two previously described. RNase protection assays confirmed the expression of this new isoform in adult skeletal muscle. In addition, results of the RNase protection assays strongly suggested the expression of a fourth isoform. These isoforms for human slow TnT most likely result from combinatorial alternative splicing of a single gene.

Adult↗
PubMed1994

A molecular genetic study of intracerebral hemorrhage.

BACKGROUND: Two forms of inherited intracerebral hemorrhage (ICH) are associated with an amyloid angiopathy caused by mutations in the genes for the amyloid precursor protein or cystatin C. The purpose of this study was to determine whether patients with sporadic ICH have mutations in the amyloid precursor protein or cystatin C genes. METHODS: Consecutive patients with ICH admitted to the neurology or neurosurgery services at Duke University Hospital, Durham, NC, were studied. Using the polymerase chain reaction, we amplified exons 16 and 17 of the amyloid precursor protein and exon 2 of cystatin C and sequenced the products. Twenty-six men and 22 women were studied. The ICH location was deep in 29 patients, lobar in 16, cerebellar in two, and brain stem in one. There were 30 patients (63%) with a positive family history of stroke; seven of them (15%) had a family history of ICH. CONCLUSIONS: Mutations previously reported to cause familial forms of ICH were not found in this group of patients.

Adult↗
PubMed1994

Novel amyloid precursor protein gene mutation (codon 665Asp) in a patient with late-onset Alzheimer's disease.

Amyloid plaques in Alzheimer's disease contain beta-amyloid, encoded by portions of exons 16 and 17 of the amyloid precursor protein. The specific association of rare amyloid precursor protein mutations with some kindreds with early-onset familial Alzheimer's disease suggests that specific abnormalities in amyloid precursor protein may contribute to the pathogenesis of Alzheimer's disease. Until now, there has been no evidence suggesting that amyloid precursor protein mutations could be involved in late-onset or sporadic Alzheimer's disease. We used reverse transcription-polymerase chain reaction, denaturing gradient gel electrophoresis, and direct DNA sequencing to analyze amyloid precursor protein exons 16 and 17 from postmortem cerebellar samples from patients with histologically confirmed Alzheimer's disease and control subjects. We found a novel point mutation, substitution of cytosine for guanine, at nucleotide 2119 (amyloid precursor protein 770 messenger RNA transcript) in a patient with late-onset Alzheimer's disease. This substitution deletes a BglII site and substitutes aspartate for glutamine at codon 665. Denaturing gradient gel electrophoresis analysis showed that this mutation was absent in 40 control subjects and 127 dementia patients. Whether this mutation is a rare but normal variant or contributes to the development of Alzheimer's disease is not known. The BglII restriction fragment length polymorphism enables investigators to determine the frequency of this polymorphism in normal subjects and Alzheimer's disease patients.

Aged↗
PubMed1994

Detecting prion protein gene mutations by denaturing gradient gel electrophoresis.

Mutations of the prion protein (PrP) gene are present in patients with Gerstmann-Sträussler-Scheinker syndrome (GSS), familial Creutzfeldt-Jakob disease (CJD), and fatal familial insomnia (FFI). We developed a denaturing gradient gel electrophoresis (DGGE) strategy that readily identifies point mutations in the PrP coding sequence. By comparison with appropriate controls, haplotypes often may be deduced. This method permits samples from many patients with GSS, CJD, as well as patients with unusual degenerative neurologic disorders, to be screened rapidly, sensitively, and inexpensively for the presence of known and novel PrP mutations. We illustrate the sensitivity of this approach by reporting 2 novel polymorphisms in the PrP coding sequence.

Base Sequence↗