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921.
Isolation of a candidate gene for Norrie disease by positional cloning. 总被引:17,自引:0,他引:17
W Berger A Meindl T J van de Pol F P Cremers H H Ropers C D?erner A Monaco A A Bergen R Lebo M Warburg 《Nature genetics》1992,1(3):199-203
The gene for Norrie disease, an X-linked disorder characterized by progressive atrophy of the eyes, mental disturbances and deafness, has been mapped to chromosome Xp11.4 close to DXS7 and the monoamine oxidase (MAO) genes. By subcloning a YAC with a 640 kilobases (kb) insert which spans the DXS7-MAOB interval we have generated a cosmid contig which extends 250 kb beyond the MAOB gene. With one of these cosmids, microdeletions were detected in several patients with Norrie disease. Screening of cDNA libraries has enabled us to isolate and sequence a likely candidate gene for Norrie disease which is expressed in retina, choroid and fetal brain. No homologous sequences were found in DNA and protein databases indicating that this cDNA is part of a gene encoding a 'pioneer' protein. 相似文献
922.
Telomere-associated chromosome fragmentation (TACF) is a new approach for chromosome mapping based on the non-targeted introduction of cloned telomeres into mammalian cells. TACF has been used to generate a panel of somatic cell hybrids with nested terminal deletions of the long arm of the human X chromosome, extending from Xq26 to the centromere. This panel has been characterized using a series of X chromosome loci. Recovery of the end clones by plasmid rescue produces a telomeric marker for each cell line and partial sequencing will allow the generation of sequence tagged sites (STSs). TACF provides a powerful and widely applicable method for genome analysis, a general way of manipulating mammalian chromosomes and a first step towards constructing artificial mammalian chromosomes. 相似文献
923.
D Sidransky T Mikkelsen K Schwechheimer M L Rosenblum W Cavanee B Vogelstein 《Nature》1992,355(6363):846-847
Tumour progression is a fundamental feature of the biology of cancer. Cancers do not arise de novo in their final form, but begin as small, indolent growths, which gradually acquire characteristics associated with malignancy. In the brain, for example, low-grade tumours (astrocytomas) evolve into faster growing, more dysplastic and invasive high-grade tumours (glioblastomas). To define the genetic events underlying brain tumour progression, we analysed the p53 gene in ten primary brain tumour pairs. Seven pairs consisted of tumours that were high grade both at presentation and recurrence (group A) and three pairs consisted of low-grade tumours that had progressed to higher grade tumours (group B). In group A pairs, four of the recurrent tumours contained a p53 gene mutation; in three of them, the same mutation was found in the primary tumour. In group B pairs, progression to high grade was associated with a p53 gene mutation. A subpopulation of cells were present in the low-grade tumours that contained the same p53 gene mutation predominant in the cells of the recurrent tumours that had progressed to glioblastoma. Thus, the histological progression of brain tumours was associated with a clonal expansion of cells that had previously acquired a mutation in the p53 gene, endowing them with a selective growth advantage. These experimental observations strongly support Nowell's clonal evolution model of tumour progression. 相似文献
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925.
926.
A Schneider P Montague I Griffiths M Fanarraga P Kennedy P Brophy K A Nave 《Nature》1992,358(6389):758-761
Proteolipid protein (PLP; M(r) 30,000) is a highly conserved major polytopic membrane protein in myelin but its cellular function remains obscure. Neurological mutant mice can often provide model systems for human genetic disorders. Mutations of the X-chromosome-linked PLP gene are lethal, identified first in the jimpy mouse and subsequently in patients with Pelizaeus-Merzbacher disease. The unexplained phenotype of these mutations includes degeneration and premature cell death of oligodendrocytes with associated hypomyelination. Here we show that a new mouse mutant rumpshaker is defined by the amino-acid substitution Ile-to-Thr at residue 186 in a membrane-embedded domain of PLP. Surprisingly, rumpshaker mice, although myelin-deficient, have normal longevity and a full complement of morphologically normal oligodendrocytes. Hypomyelination can thus be genetically separated from the PLP-dependent oligodendrocyte degeneration. We suggest that PLP has a vital function in glial cell development, distinct from its later role in myelin assembly, and that this dichotomy of action may explain the clinical spectrum of Pelizaeus-Merzbacher disease. 相似文献
927.
Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production. 总被引:41,自引:0,他引:41
M Citron T Oltersdorf C Haass L McConlogue A Y Hung P Seubert C Vigo-Pelfrey I Lieberburg D J Selkoe 《Nature》1992,360(6405):672-674
Progressive cerebral deposition of the 39-43-amino-acid amyloid beta-protein (A beta) is an invariant feature of Alzheimer's disease which precedes symptoms of dementia by years or decades. The only specific molecular defects that cause Alzheimer's disease which have been identified so far are missense mutations in the gene encoding the beta-amyloid precursor protein (beta-APP) in certain families with an autosomal dominant form of the disease (familial Alzheimer's disease, or FAD). These mutations are located within or immediately flanking the A beta region of beta-APP, but the mechanism by which they cause the pathological phenotype of early and accelerated A beta deposition is unknown. Here we report that cultured cells which express a beta-APP complementary DNA bearing a double mutation (Lys to Asn at residue 595 plus Met to Leu at position 596) found in a Swedish FAD family produce approximately 6-8-fold more A beta than cells expressing normal beta-APP. The Met 596 to Leu mutation is principally responsible for the increase. These data establish a direct link between a FAD genotype and the clinicopathological phenotype. Further, they confirm the relevance of the continuous A beta production by cultured cells for elucidating the fundamental mechanism of Alzheimer's disease. 相似文献
928.
The thymus positively selects thymocytes that bear T-cell receptors which recognize antigen presented by self major histocompatibility complex (MHC) proteins. Positive selection is usually driven by MHC products on radiation-resistant cortical epithelial cells. It is unknown whether positive selection is mediated by all thymic epithelial cells or by some specialized subsets. Here we introduce an H-2b-expressing thymic epithelial cell line into the thymuses of lethally irradiated H-2k animals reconstituted with H-2b/k F1 BM or fetal liver cells. I-Ab-restricted T cells are found in these animals, demonstrating that selection occurs on the introduced epithelial cells. 相似文献
929.
Optical imaging of animal somatosensory, olfactory and visual cortices has revealed maps of functional activity. In non-human primates, high-resolution maps of the visual cortex have been obtained using only an intrinsic reflection signal. Although the time course of the signal is slower than membrane potential changes, the maximum optical changes correspond to the maximal neuronal activity. The intrinsic optical signal may represent the flow of ionic currents, oxygen delivery, changes in blood volume, potassium accumulation or glial swelling. Here we use similar techniques to obtain maps from human cortex during stimulation-evoked epileptiform afterdischarges and cognitively evoked functional activity. Optical changes increased in magnitude as the intensity and duration of the afterdischarges increased. In areas surrounding the afterdischarge activity, optical changes were in the opposite direction and possibly represent an inhibitory surround. Large optical changes were found in the sensory cortex during tongue movement and in Broca's and Wernicke's language areas during naming exercises. The adaptation of high-resolution optical imaging for use on human cortex provides a new technique for investigation of the organization of the sensory and motor cortices, language, and other cognitive processes. 相似文献
930.
Tyrosine phosphorylation of vav proto-oncogene product containing SH2 domain and transcription factor motifs. 总被引:30,自引:0,他引:30
B Margolis P Hu S Katzav W Li J M Oliver A Ullrich A Weiss J Schlessinger 《Nature》1992,356(6364):71-74