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1.
Somatic mutations in the neurofibromatosis 1 gene in human tumors. 总被引:26,自引:0,他引:26
Y Li G Bollag R Clark J Stevens L Conroy D Fults K Ward E Friedman W Samowitz M Robertson 《Cell》1992,69(2):275-281
The neurofibromatosis 1 (NF1) gene product, neurofibromin, contains a GTPase-activating protein (GAP)-related domain, or NF1 GRD, that is able to down-regulate p21ras by stimulating its intrinsic GTPase. Since p21ras.GTP is a major regulator of growth and differentiation, mutant neurofibromins resulting from somatic mutations in the NF1 gene might interfere with ras signaling pathways and contribute to the development of tumors. We describe an amino acid substitution in the NF1 GRD, altering Lys-1423, that has occurred in three tumor types: colon adenocarcinoma, myelodysplastic syndrome, and anaplastic astrocytoma, and in one family with neurofibromatosis 1. The GAP activity of the mutant NF1 GRD is 200- to 400-fold lower than that of wild type, whereas binding affinity is unaffected. Thus, germline mutations in NF1 that cause neurofibromatosis 1 can also occur in somatic cells and contribute to the development of sporadic tumors, including tumors not associated with neurofibromatosis 1. 相似文献
2.
Penetrance of von Recklinghausen neurofibromatosis: a distinction between predecessors and descendants. 总被引:14,自引:6,他引:8
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This paper reviews the concepts of penetrance and expressivity and examines their application to the specific disorder von Recklinghausen neurofibromatosis. The data suggest that assessments of penetrance among predecessors to probands yield results different from those of assessments of penetrance among descendants to probands. For descendants at risk, penetrance is very close to 100%. For predecessors at risk, extremely variable expressivity may confound estimates of penetrance; as a specific example, a family is described in which two brothers have bona fide von Recklinghausen neurofibromatosis and their mother manifests the neurofibromatosis mutation only as iris Lisch nodules. 相似文献
3.
L O Badalian N A Malygina B A Arkhipov N N Morozov O Iu Borodina 《T?Sitologii?a i genetika》1987,21(4):290-292
It is shown that the average number of sister chromatid exchanges (SCE) per one cell in patients with tuberous sclerosis as well as in those with Recklinghausen's neurofibromatosis do not differ from the control. But the non-parametric methods of analysis have revealed differences in the spontaneous level of SCE is patients with tuberous sclerosis, while no such differences were revealed in patients with Recklinghausen's neurofibromatosis. 相似文献
4.
Genetic linkage studies of chromosome 17 RFLPs in von Recklinghausen neurofibromatosis (NF1) 总被引:6,自引:0,他引:6
M. A. Pericak-Vance L. H. Yamaoka J. M. Vance K. Small G. O. D. Rosenwasser P. C. Gaskell Jr. W. -Y. Hung M. J. Alberts C. S. Haynes M. C. Speer J. R. Gilbert M. Herbstreith A. S. Aylsworth A. D. Roses 《Genomics》1987,1(4):349-352
Recent localization of the gene for von Recklinghausen neurofibromatosis (NF1) to chromosome 17 has led to studies to identify additional tightly linked probes that can be used in defining the primary genetic defect in NF1. We have examined and obtained blood for DNA linkage studies on over 250 individuals from 10 multigeneration neurofibromatosis families. We have analyzed 130 members in 7 families with the available chromosome 17 NF1 linked probes, pE51, D17S71, and D17Z1, as well as two probes generated from our own chromosome 17/19 enriched library (LDR92, LDR152A). Tight linkage was found between NF1 and the centromeric probe D17Z1 (theta = 0.04) and between NF1 and D17S71 (theta = 0.08). A definite recombinant was seen for the D17Z1 marker, which previously had not exhibited crossingover. Chromosome 17 DNA markers pE51, LDR92, and LDR152A gave slightly positive scores, which were not statistically significant. 相似文献
5.
Introduction
Horner's syndrome has a variety of etiologies ranging from benign to serious life-threatening conditions and has been infrequently reported as a presenting symptom of patients with lymphoid neoplasms. Only one case of Burkitt's lymphoma presenting with toothache, paresthesia, and Horner's syndrome has been described and no case reports of diffuse large B-cell lymphoma as the etiology of Horner's syndrome currently exist in the literature. In addition, lymphoid neoplasms have rarely been reported to occur in patients with neurofibromatosis type 1 despite an increased risk of many types of cancer in such cases.Case presentation
A 28-year-old Thai man presented with a progressively enlarged left supraclavicular mass together with a significant weight loss and night sweating for four months. He also noticed hoarseness and ptosis of his left eye associated with double vision for two months. Physical examination revealed large supraclavicular lymphadenopathy and Horner's syndrome (ptosis, miosis, and anhydrosis) on the left side of his face. A large mediastinal mass was clearly detected by chest X-ray and computed tomography and subsequent lymph node biopsy provided a diagnosis of diffuse large B-cell lymphoma. Interestingly, the patient was also definitely diagnosed with neurofibromatosis type 1 from multiple café au lait macules, axillary freckles, three neurofibromas, multiple Lisch nodules, and a history of affected family members. He subsequently received chemotherapy with a good response. Twenty-seven cases of various types of lymphoid neoplasms previously reported to occur in neurofibromatosis type 1 patients were also extracted from the literature. All cases were non-Hodgkin lymphoma and the major subtype was T-cell. Only nine cases were B-cell lymphoma. The majority of cases were young with a median age at lymphoma diagnosis of 9.4 years (range 1.1 to 77 years). Two-thirds of the cases were boys or men. Other concomitant malignancies were brain tumor, colorectal cancer, pheochromocytoma, and acute lymphoblastic leukemia.Conclusions
We describe for the first time a case of diffuse large B-cell lymphoma that occurred in a neurofibromatosis type 1 patient with Horner's syndrome. Horner's syndrome can be an initial manifestation of diffuse large B-cell lymphoma. Patients who present with a classical triad of Horner's syndrome should always be fully investigated for lymphomatous involvement, especially in the thorax. The exact molecular mechanism for diffuse large B-cell lymphoma development in neurofibromatosis type 1 cases remains to be elucidated. 相似文献6.
Cell proteins obtained from cultured normal appearing skin and neurofibromas of neurofibromatosis patients, and normal skin of normal donors were compared by SDS-PAGE and isoelectric focusing analysis. Essentially, identical protein patterns were obtained for the pellet fractions of all the strains. The lysate fraction binding patterns were also similar to each other, but a deficiency of a 42-kilodalton protein with pI 4.3 was observed in the four tumor-derived cell strains examined. These results raise the possibility that tumor-derived fibroblastic cells are of the same cell origin as skin fibroblasts, and that the deficiency of a 42-kilodalton protein could be related to the tumorigenicity in neurofibromatosis. 相似文献
7.
We report a HincII polymorphism in the 5' end of the neurofibromatosis type 1 gene (NF1) as detected with a probe made of exons 1 to 4a (nucleotides 2 to 401 of the cDNA). This HincII site is most probably in an intron. Evidence presented suggests the probe reveals not one but two similar polymorphisms. 相似文献
8.
《Endocrine practice》2007,13(3):269-273
ObjectiveTo describe a rare case of acute myocardial infarction in a patient with neurofibromatosis 1 and pheochromocytoma and to review the literature on the coexistence of these 2 diseases, the causes of myocardial injury in patients with pheochromocytoma, and the utility of genetic testing and pheochromocytoma screening for those patients and their families.MethodsWe present a case report, including the detailed clinical, laboratory, and radiographic data, results of adrenal mass pathology, and results of coronary angiography. We also survey other relevant reports available in the literature.ResultsA 43-year-old woman with a history of longstanding hypertension, neurofibromatosis 1, headaches, sweating, and palpitations presented to the hospital with chest pain and shortness of breath. She was found to have an acute myocardial infarction and pulmonary edema, as well as a right adrenal mass. A pheochromocytoma was suspected, and phenoxybenzamine was added to her treatment regimen. Cardiac catheterization showed nonobstructive coronary disease. The levels of plasma catecholamine metabolites were extremely high. The patient underwent uncomplicated laparoscopic right adrenalectomy 2 weeks after this admission. Surgical pathology confirmed the diagnosis of pheochromocytoma.ConclusionAdrenergic crisis attributable to pheochromocytoma can result in acute myocardial infarction even in the absence of obstructive coronary disease. Inclusion of pheochromocytoma in the differential diagnosis of hypertension in patients with neurofibromatosis is very important and helps avoid mistakes in the management of such patients. (Endocr Pract. 2007;13:269-273) 相似文献
9.
Dieter Kaufmann Ralf Müller Britta Bartelt Michael Wolf Karin Kunzi-Rapp Clemens Oliver Hanemann Raimund Fahsold Christian Hein Walther Vogel Günter Assum 《American journal of human genetics》2001,69(6):1395-1400
Spinal neurofibromatosis (SNF) is considered to be an alternative form of neurofibromatosis, showing multiple spinal tumors and café-au-lait macules. Involvement of the neurofibromatosis type 1 (NF1) locus has been demonstrated, by linkage analysis, for three families with SNF. In one of them, a cosegregating frameshift mutation in exon 46 of the NF1 gene was identified. In the present study, we report four individuals from two families who carry NF1 null mutations that would be expected to cause NF1. Three patients have multiple spinal tumors and no café-au-lait macules, and the fourth has no clinical signs of NF1. In the first family, a missense mutation (Leu2067Pro) in NF1 exon 33 was found, and, in the second, a splice-site mutation (IVS31-5A-->G) enlarging exon 32 by 4 bp at the 5' end was found. The latter mutation has also been observed in an unrelated patient with classical NF1. Both NF1 mutations cause a reduction in neurofibromin of approximately 50%, with no truncated protein present in the cells. This demonstrates that typical NF1 null mutations can result in a phenotype that is distinct from classical NF1, showing only a small spectrum of the NF1 symptoms, such as multiple spinal tumors, but not completely fitting the current clinical criteria for SNF. We speculate that this phenotype is caused by an unknown modifying gene that compensates for some, but not all, of the effects caused by neurofibromin deficiency. 相似文献
10.
Majumder S Grabska J Trikudanathan G Kowalczyk P Stoica-Mustafa E Dasanu CA 《Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]》2012,12(3):211-214
Pheochromocytomas rarely have 'composite' forms in which they demonstrate histologic features of a typical paraganglioma in combination with those of a neural component. Extra-adrenal 'composite' pheochromocytomas are distinctly uncommon. We describe herein a unique case of a 34-year-old female patient with type 1 neurofibromatosis who presented with abdominal pain and paroxysmal hypertension. Imaging revealed a pancreatic mass with biliary and pancreatic ductal dilatation and a hormonal assay led to the diagnosis of functional pheochromocytoma. She underwent surgical resection and histopathology revealed a composite paraganglioma-ganglioneuroma. Clinical, biochemical and radiological aspects of this rare tumor and its association with neurofibromatosis and other hereditary cancer syndromes are discussed. 相似文献
11.
Summary Two male children with familial neurofibromatosis were observed to develop juvenile chronic myelogenous leukemia. These two cases add to previous reports which have described an increased incidence of non-lymphocytic leukemia in patients with neurofibromatosis. In particular, the rare entity juvenile chronic myelogenous leukemia would appear to be the form of non-lymphocytic leukemia that has a definite association with familial neurofibromatosis. 相似文献
12.
On the mutation rate of neurofibromatosis. 总被引:6,自引:0,他引:6
A S Sergeyev 《Humangenetik》1975,28(2):129-138
A genetic study of 124 cases of neurofibromatosis was performed. The contingent of probands was mainly represented by a Russian population, most of the individuals being born in the European part of the RSFSR. Both parents of the probands were examined in only 58 cases, the proportion of sporadic cases in this group being 0.79, as compared to 0.77 for the whole group under study. The existing data evaluated by a direct method are not yet sufficient for a decisive estimation of the penetrance, which, however, cannot be under 80%. Segregation analysis of descendants from particular marriages showed a good correspondance to the hypothesis of Mendelian dominance (32 affected children out of 65). These results analyzed together with those obtained by other authors permit an inference on the full penetrance of neurofibromatosis. The genetic interpretation of sporadic cases as a result of new mutations is presented. The prevalence of neurofibromatosis among the 16-year-old youths was evaluated as 12.8 with 10-(5). This value is suggested to be an estimation of the incidence of the condition in the general population, the mutation rate evaluated by a direct method being equal to 4.4 with 10-(5) divided by 4.9 with 10-minus 5. The increased birth order of probands in sporadic cases (against the theoretical expectation) as well as increased paternal age (as compared with controls) were found to be statistically significant (P equals 0.004 and P equals 0.03, respectively) while the difference in maternal ages was statistically insignificant (P equals 0.008). No statistical relationship between sporadic cases and occupational exposure of parents to deleterious chemical and physical factors was found. 相似文献
13.
Kang BS Cooper DR Jelen F Devedjiev Y Derewenda U Dauter Z Otlewski J Derewenda ZS 《Structure (London, England : 1993)》2003,11(4):459-468
Syntenin, a 33 kDa protein, interacts with several cell membrane receptors and with merlin, the product of the causal gene for neurofibromatosis type II. We report a crystal structure of the functional fragment of human syntenin containing two canonical PDZ domains, as well as binding studies for full-length syntenin, the PDZ tandem, and isolated PDZ domains. We show that the functional properties of syntenin are a result of independent interactions with target peptides, and that each domain is able to bind peptides belonging to two different classes: PDZ1 binds peptides from classes I and III, while PDZ2 interacts with classes I and II. The independent binding of merlin by PDZ1 and syndecan-4 by PDZ2 provides direct evidence for the coupling of syndecan-mediated signaling to actin regulation by merlin. 相似文献
14.
15.
Takako Takano Tomoko Kawashima Yasuko Yamanouchi Ken Kitayama Toru Baba Kenichi Ueno Hideo Hamaguchi 《Human genetics》1992,89(3):281-286
Summary We have performed formal genetic studies on 26 patients (14 males, 12 females) with neurofibromatosis 1 (von Recklinghausen's disease, NF1) in Japan. Family studies of 74 members of 18 kindreds revealed that 50% of the cases were caused by a new mutation; the mutation rate was assumed to be 7.3–10.5 × 10-5. A tendency of paternal age effect, which was not accounted for by the maternal age effect, was observed, but live-birth order had no significant effect. Genetic linkage of neurofibromatosis 1 to the NF1 gene or the genetic marker in the pericentric region of chromosome 17 was established in 3 informative families. 相似文献
16.
Summary We have studied a meningioma and an acoustic neurinoma of a patient with central neurofibromatosis. In the meningioma cells, one chromosome 22 was replaced by an almost metacentric, bisatellited marker chromosome that appeared monocentric after CBG-staining. In situ hybridization with a chromosome 22 centromere specific DNA probe (p22hom48.4) revealed specific signals in the pericentromeric region of the marker chromosome, indicating the presence of at least the short arm and the centromere of chromosome 22. The pericentromeric localization of the hybridization signals suggests the marker consists of an isoformation of the short arm of chromosome 22, resulting in a monosomy for the long arm of chromosome 22. In contrast to these finding in meningioma cells, no chromosomal abnormality could be detected in acoustic neurinoma cells. Our finding provide further evidence that loss of genetic material on the long arm of chromosome 22 is associated with the development of central neurofibromatosis. 相似文献
17.
Functional significance of lysine 1423 of neurofibromin and characterization of a second site suppressor which rescues mutations at this residue and suppresses RAS2Val-19-activated phenotypes. 总被引:3,自引:0,他引:3
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Lysine 1423 of neurofibromin (neurofibromatosis type I gene product [NF1]) plays a crucial role in the function of NF1. Mutations of this lysine were detected in samples from a neurofibromatosis patient as well as from cancer patients. To further understand the significance of this residue, we have mutated it to all possible amino acids. Functional assays using yeast ira complementation have revealed that lysine is the only amino acid that produced functional NF1. Quantitative analyses of different mutant proteins have suggested that their GTPase-activating protein (GAP) activity is drastically reduced as a result of a decrease in their Ras affinity. Such a requirement for a specific residue is not observed in the case of other conserved residues within the GAP-related domain. We also report that another residue, phenylalanine 1434, plays an important role in NF1 function. This was first indicated by the finding that defective NF1s due to an alteration of lysine 1423 to other amino acids can be rescued by a second site intragenic mutation at residue 1434. The mutation partially restored GAP activity in the lysine mutant. When the mutation phenylalanine 1434 to serine was introduced into a wild-type NF1 protein, the resulting protein acquired the ability to suppress activated phenotypes of RAS2Val-19 cells. This suppression, however, does not involve Ras interaction, since the phenylalanine mutant does not stimulate the intrinsic GTPase activity of RAS2Val-19 protein and does not have an increased affinity for Ras proteins. 相似文献
18.
Mia MacCollin Donna Romano Marcia Budarf Christopher Denny James Trofatter Anil Menon Guy Rouleau Bertrand Fontaine Beverly Emanuel James Gusella 《Genomics》1993,15(3)
The widespread use of the sequence-tagged site (STS) as a quick, efficient, and reproducible assay for comparing physical and genetic map information promises to facilitate greatly long-range goals of time mapping of the human genome. We have designed 21 STS assays for loci on human chromosome 22. These assays primarily tag the physical framework markers of the long arm of 22, but additional assays have been designed from known genes and loci in the neurofibromatosis 2 (NF2) region. The availability of these assays will make these loci available to the research community without physical transfer of materials and will serve as start points for further efforts to physically map chromosome 22 with yeast artificial chromosome clones. 相似文献
19.
A highly informative CA/GT repeat polymorphism in intron 38 of the human neurofibromatosis type 1 (NF1) gene 总被引:3,自引:0,他引:3
Conxi Lázaro Antonia Gaona Ganfeng Xu Robert Weiss Xavier Estivill 《Human genetics》1993,92(4):429-430
We describe a polymorphic microsatellite in intron 38 of the neurofibromatosis type 1 (NF1) gene. The microsatellite consists of a CA/GT dinucleotide repeat detecting 8 alleles; it has a heterozygosity of 82 %. 相似文献