排序方式: 共有29条查询结果,搜索用时 218 毫秒
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Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome 总被引:36,自引:0,他引:36
Eriksson M Brown WT Gordon LB Glynn MW Singer J Scott L Erdos MR Robbins CM Moses TY Berglund P Dutra A Pak E Durkin S Csoka AB Boehnke M Glover TW Collins FS 《Nature》2003,423(6937):293-298
Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by features reminiscent of marked premature ageing. Here, we present evidence of mutations in lamin A (LMNA) as the cause of this disorder. The HGPS gene was initially localized to chromosome 1q by observing two cases of uniparental isodisomy of 1q-the inheritance of both copies of this material from one parent-and one case with a 6-megabase paternal interstitial deletion. Sequencing of LMNA, located in this interval and previously implicated in several other heritable disorders, revealed that 18 out of 20 classical cases of HGPS harboured an identical de novo (that is, newly arisen and not inherited) single-base substitution, G608G(GGC > GGT), within exon 11. One additional case was identified with a different substitution within the same codon. Both of these mutations result in activation of a cryptic splice site within exon 11, resulting in production of a protein product that deletes 50 amino acids near the carboxy terminus. Immunofluorescence of HGPS fibroblasts with antibodies directed against lamin A revealed that many cells show visible abnormalities of the nuclear membrane. The discovery of the molecular basis of this disease may shed light on the general phenomenon of human ageing. 相似文献
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Carpten JD Robbins CM Villablanca A Forsberg L Presciuttini S Bailey-Wilson J Simonds WF Gillanders EM Kennedy AM Chen JD Agarwal SK Sood R Jones MP Moses TY Haven C Petillo D Leotlela PD Harding B Cameron D Pannett AA Höög A Heath H James-Newton LA Robinson B Zarbo RJ Cavaco BM Wassif W Perrier ND Rosen IB Kristoffersson U Turnpenny PD Farnebo LO Besser GM Jackson CE Morreau H Trent JM Thakker RV Marx SJ Teh BT Larsson C Hobbs MR 《Nature genetics》2002,32(4):676-680
We report here the identification of a gene associated with the hyperparathyroidism-jaw tumor (HPT-JT) syndrome. A single locus associated with HPT-JT (HRPT2) was previously mapped to chromosomal region 1q25-q32. We refined this region to a critical interval of 12 cM by genotyping in 26 affected kindreds. Using a positional candidate approach, we identified thirteen different heterozygous, germline, inactivating mutations in a single gene in fourteen families with HPT-JT. The proposed role of HRPT2 as a tumor suppressor was supported by mutation screening in 48 parathyroid adenomas with cystic features, which identified three somatic inactivating mutations, all located in exon 1. None of these mutations were detected in normal controls, and all were predicted to cause deficient or impaired protein function. HRPT2 is a ubiquitously expressed, evolutionarily conserved gene encoding a predicted protein of 531 amino acids, for which we propose the name parafibromin. Our findings suggest that HRPT2 is a tumor-suppressor gene, the inactivation of which is directly involved in predisposition to HPT-JT and in development of some sporadic parathyroid tumors. 相似文献
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Production and auto-induction of transforming growth factor-alpha in human keratinocytes 总被引:8,自引:0,他引:8
R J Coffey R Derynck J N Wilcox T S Bringman A S Goustin H L Moses M R Pittelkow 《Nature》1987,328(6133):817-820
Transforming growth factor-alpha (TGF-alpha) is a polypeptide which is structurally related to epidermal growth factor (EGF) and binds to the EGF receptor. TGF-alpha synthesis occurs in a variety of neoplastic cells and during early fetal development but has not been reported in normal cells of the adult organisms. TGF-alpha has therefore been regarded as an embryonic growth factor which is inappropriately expressed during neoplasia. Here we report that primary cultures of normal human keratinocytes synthesize TGF-alpha. Furthermore, we show that addition of EGF or TGF-alpha to these cultures induces TGF-alpha gene expression, suggesting that a mechanism of auto-induction exists. Analysis of normal skin biopsies using in situ hybridization and immunohistochemistry demonstrates the in vivo presence of TGF-alpha messenger RNA and protein in the stratified epidermis. 相似文献
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It is widely accepted that the development of carcinoma--the most common form of human cancer--is due to the accumulation of somatic mutations in epithelial cells. The behaviour of carcinomas is also influenced by the tumour microenvironment, which includes extracellular matrix, blood vasculature, inflammatory cells and fibroblasts. Recent studies reveal that fibroblasts have a more profound influence on the development and progression of carcinomas than was previously appreciated. These new findings have important therapeutic implications. 相似文献
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Sub-lethal and lethal radiation damage 总被引:3,自引:0,他引:3
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High frequency of BRAF mutations in nevi 总被引:23,自引:0,他引:23
Pollock PM Harper UL Hansen KS Yudt LM Stark M Robbins CM Moses TY Hostetter G Wagner U Kakareka J Salem G Pohida T Heenan P Duray P Kallioniemi O Hayward NK Trent JM Meltzer PS 《Nature genetics》2003,33(1):19-20
To evaluate the timing of mutations in BRAF (v-raf murine sarcoma viral oncogene homolog B1) during melanocytic neoplasia, we carried out mutation analysis on microdissected melanoma and nevi samples. We observed mutations resulting in the V599E amino-acid substitution in 41 of 60 (68%) melanoma metastases, 4 of 5 (80%) primary melanomas and, unexpectedly, in 63 of 77 (82%) nevi. These data suggest that mutational activation of the RAS/RAF/MAPK pathway in nevi is a critical step in the initiation of melanocytic neoplasia but alone is insufficient for melanoma tumorigenesis. 相似文献
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