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- Bruder, CEG, et al.
(författare)
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High resolution deletion analysis of constitutional DNA from neurofibromatosis type 2 (NF2) patients using microarray-CGH
- 2001
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Ingår i: Human Molecular Genetics. - Oxford, United Kingdom : Oxford University Press. - 0964-6906 .- 1460-2083. ; 1, s. 271-
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Tidskriftsartikel (refereegranskat)abstract
- Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder whose hallmark is bilateral vestibular schwannoma. It displays a pronounced clinical heterogeneity with mild to severe forms. The NF2 tumor suppressor (merlin/schwannomin) has been cloned and extensively analyzed for mutations in patients with different clinical variants of the disease. Correlation between the type of the NF2 gene mutation and the patient phenotype has been suggested to exist. However, several independent studies have shown that a fraction of NF2 patients with various phenotypes have constitutional deletions that partly or entirely remove one copy of the NF2 gene. The purpose of this study was to examine a 7 Mb interval in the vicinity of the NF2 gene in a large series of NF2 patients in order to determine the frequency and extent of deletions. A total of 116 NF2 patients were analyzed using high-resolution array-comparative genomic hybridization (CGH) on an array covering at least 90% of this region of 22q around the NF2 locus. Deletions, which remove one copy of the entire gene or are predicted to truncate the schwannomin protein, were detected in 8 severe, 10 moderate and 6 mild patients. This result does not support the correlation between the type of mutation affecting the NF2 gene and the disease phenotype. This work also demonstrates the general usefulness of the array-CON methodology for rapid and comprehensive detection of small (down to 40 kb) heterozygous and/or homozygous deletions occurring in constitutional or tumor-derived DNA.
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| 4. |
- Li, Wei, et al.
(författare)
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3-Aminopropanal, formed during cerebral ischaemia, is a potent lysosomotropic neurotoxin
- 2003
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Ingår i: Biochemical Journal. - 0264-6021 .- 1470-8728. ; 371:2, s. 429-436
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Tidskriftsartikel (refereegranskat)abstract
- Cytotoxic polyamine-derived amino aldehydes, formed during cerebral ischaemia, damage adjacent tissue (the so-called 'penumbra') not subject to the initial ischaemic insult. One such product is 3-aminopropanal (3-AP), a potent cytotoxin that accumulates in ischaemic brain, although the precise mechanisms responsible for its formation are still unclear. More relevant to the present investigations, the mechanisms by which such a small aldehydic compound might be cytotoxic are also not known, but we hypothesized that 3-AP, having the structure of a weak lysosomotropic base, might concentrate within lysosomes, making these organelles a probable focus of initial toxicity. Indeed, 3-AP leads to lysosomal rupture of D384 glioma cells, a process which clearly precedes caspase activation and apoptotic cell death. Immunohistochemistry reveals that 3-AP concentrates in the lysosomal compartment and prevention of this accumulation by the lysosomotropic base ammonia, NH3, protects against 3-AP cytotoxicity by increasing lysosomal pH. A thiol compound, N-(2-mercaptopropionyl)glycine, reacts with and neutralizes 3-AP and significantly inhibits cytoxocity. Both amino and aldehyde functions of 3-AP are necessary for toxicity: the amino group confers lysosomotropism and the aldehyde is important for additional, presently unknown, reactions. We conclude that 3-AP exerts its toxic effects by accumulating intralysosomally, causing rupture of these organelles and releasing lysosomal enzymes which initiate caspase activation and apoptosis (or necrosis if the lysosomal rupture is extensive). These results may have implications for the development of new therapeutics designed to lessen secondary damage arising from focal cerebral ischaemia.
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- Telang, S, et al.
(författare)
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Strain-specific iron-dependent virulence in Escherichia coli
- 2001
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Ingår i: Journal of Infectious Diseases. - 0022-1899 .- 1537-6613. ; 184:2, s. 159-165
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Tidskriftsartikel (refereegranskat)abstract
- For reasons unknown, certain Escherichia coli strains become highly virulent when injected with hemoglobin or other soluble iron sources. Two clinical isolates (virulent and nonvirulent) showed equivalent hemoglobin-mediated growth acceleration in vitro. However, when injected intraperitoneally into mice without hemoglobin, the virulent strain was cleared more slowly (t(1/2), >4 h vs. <30 min). The virulent E. coli strain had a polysialic acid-containing capsule, whereas the nonvirulent strain did not. Virulent E. coli grown at 20C (which blocks polysialylation) were cleared as rapidly as nonvirulent organisms. In another virulent E. coli strain having abundant outer membrane polysialic acid, targeted deletion of the polysialyltransferase accelerated host clearance and blocked iron-dependent virulence. The iron-dependent virulence of certain E. coli strains may represent the combined effect of slow in vivo clearance-associated, in this case, with outer membrane polysialylation coupled with accelerated growth permitted by iron compounds.
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