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21.
Histamine reduces boron neutron capture therapy‐induced mucositis in an oral precancer model 下载免费PDF全文
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The GAP-related domain of tuberin, the product of the TSC2 gene, is a target for missense mutations in tuberous sclerosis 总被引:5,自引:0,他引:5
Maheshwar MM; Cheadle JP; Jones AC; Myring J; Fryer AE; Harris PC; Sampson JR 《Human molecular genetics》1997,6(11):1991-1996
Tuberous sclerosis is an autosomal dominant trait in which the
dysregulation of cellular proliferation and differentiation results in the
development of hamartomatous growths in many organs. The TSC2 gene is one
of two genes determining tuberous sclerosis. Inactivating germline
mutations of TSC2 in patients with tuberous sclerosis and somatic loss of
heterozygosity at the TSC2 locus in the associated hamartomas indicate that
TSC2 functions as a tumour suppressor gene and that loss of function is
critical to expression of the tuberous sclerosis phenotype. The TSC2
product, tuberin, has a region of homology with the GTPase activating
protein rap1GAP and stimulates the GTPase activity of rap1a and rab5a in
vitro. Here we show that the region of homology between tuberin and human
rap1GAP and the murine GAP mSpa1 is more extensive than previously reported
and spans approximately 160 amino acid residues encoded within exons 34-38
of the TSC2 gene. Single strand conformation polymorphism analysis of these
exons in 173 unrelated patients with tuberous sclerosis and direct
sequencing of variant conformers together with study of additional family
members enabled characterisation of disease associated mutations in 14
cases. Missense mutations, which occurred in exons 36, 37 and 38 were
identified in eight cases, four of whom shared the same recurrent change
P1675L. Each of the five different missense mutations identified was shown
to occur de novo in at least one sporadic case of tuberous sclerosis. The
high proportion of missense mutations detected in the region of the TSC2
gene encoding the GAP-related domain supports its key role in the
regulation of cellular growth.
相似文献
26.
Elastin point mutations cause an obstructive vascular disease, supravalvular aortic stenosis 总被引:7,自引:2,他引:7
Li DY; Toland AE; Boak BB; Atkinson DL; Ensing GJ; Morris CA; Keating MT 《Human molecular genetics》1997,6(7):1021-1028
Supravalvular aortic stenosis (SVAS) is an inherited obstructive vascular
disease that affects the aorta, carotid, coronary and pulmonary arteries.
Previous molecular genetic data have led to the hypothesis that SVAS
results from mutations in the elastin gene, ELN. In these studies, the
disease phenotype was linked to gross DNA rearrangements (35 and 85 kb
deletions and a translocation) in three SVAS families. However, gross
rearrangements of ELN have not been identified in most cases of autosomal
dominant SVAS. To define the spectrum of ELN mutations responsible for this
disorder, we refined the genomic structure of human ELN and used this
information in mutational analyses. ELN point mutations co-segregate with
the disease in four familial cases and are associated with SVAS in three
sporadic cases. Two of the mutations are nonsense, one is a single base
pair deletion and four are splice site mutations. In one sporadic case, the
mutation arose de novo. These data demonstrate that point mutations of ELN
cause autosomal dominant SVAS.
相似文献
27.
AM Innes KM Boycott EG Puffenberger D Redl IM MacDonald AE Chudley C Beaulieu R Perrier T Gillan A Wade JS Parboosingh 《Clinical genetics》2010,78(5):424-431
Innes AM, Boycott KM, Puffenberger EG, Redl D, MacDonald IM, Chudley AE, Beaulieu C, Perrier R, Gillan T, Wade A, Parboosingh JS. A founder mutation in BBS2 is responsible for Bardet‐Biedl syndrome in the Hutterite population: utility of SNP arrays in genetically heterogeneous disorders. Bardet‐Biedl syndrome (BBS) is a multisystem genetically heterogeneous disorder, the clinical features of which are largely the consequence of ciliary dysfunction. BBS is typically inherited in an autosomal recessive fashion, and mutations in at least 14 genes have been identified. Here, we report the identification of a founder mutation in the BBS2 gene as the cause for the increased incidence of this developmental disorder in the Hutterite population. To ascertain the Hutterite BBS locus, we performed a genome‐wide single nucleotide polymorphism (SNP) analysis on a single patient and his three unaffected siblings from a Hutterite family. The analysis identified two large SNP blocks that were homozygous in the patient but not in his unaffected siblings, one of these regions contained the BBS2 gene. Sequence analysis and subsequent RNA studies identified and confirmed a novel splice site mutation, c.472‐2A>G, in BBS2. This mutation was also found in homozygous form in three subsequently studied Hutterite BBS patients from two different leuts, confirming that this is a founder mutation in the Hutterite population. Further studies are required to determine the frequency of this mutation and its role, if any, in the expression of other ciliopathies in this population. 相似文献
28.
Chatzipanteli K Garcia R Marcillo AE Loor KE Kraydieh S Dietrich WD 《Journal of neurotrauma》2002,19(5):639-651
Nitric oxide (NO) has been shown to play an important role in the pathophysiology of traumatic brain injury (TBI) and cerebral ischemia. However, its contribution to the pathogenesis of traumatic spinal cord injury (SCI) remains to be clarified. This study determined the time course of constitutive and inducible nitric oxide synthases (cNOS and iNOS, respectively) after SCI. Rats underwent moderate SCI at T10 using the NYU impactor device and were allowed to survive for 3, 6, or 24 h and 3 days after SCI (n = 5 in each group). For the determination of enzymatic activities, spinal cords were dissected into five segments, including levels rostral and caudal (remote) to the injury site. Other rats were perfusion fixed for the immunohistochemical localization of iNOS protein levels. cNOS activity was significantly decreased at 3 and 6 h within the traumatized T10 segment and at 3, 6, and 24 h at the rostral (T9) level (p < 0.05). Rostral (T8) and caudal (T11, T12) to the injury site cNOS activity was also decreased at 3 h after injury (p < 0.05). However, cNOS activity returned to control levels within 6 h at T8, T11 and T12 and at one day at T10 and T9 segments. iNOS enzymatic activity was elevated at all time points tested (p < 0.05), with the most robust increase observed at 24 h. Immunostaining for iNOS at 24 h revealed that a significant cellular source of iNOS protein appeared to be invading polymorphonuclear leukocytes (PMNLs). To assess the functional consequences of iNOS inhibition, aminoguanidine treatment was initiated 5 min after SCI and rats tested using the BBB open field locomotor score. Treated rats demonstrated significantly improved hindlimb function up to 7 weeks after SCI. Histopathological analysis of contusion volume showed that aminoguanidine treatment decreased lesion volume by 37% (p < 0.05). In conclusion, these results indicate that (1) cNOS and iNOS activities are regionally and temporally affected after moderate SCI, (2) the early accumulation of PMNLs are a potentially significant source of NO-induced cytotoxic products, and (3) acute aminoguanidine treatment significantly improves functional and histopathological outcome after SCI. 相似文献
29.
Gizelda T B Casella Alexander Marcillo Mary Bartlett Bunge Patrick M Wood 《Experimental neurology》2002,173(1):63-76
Blood vessels identified by laminin staining were studied in uninjured spinal cord and at 2, 4, 7, and 14 days following a moderate contusion (weight drop) injury. At 2 days after injury most blood vessels had been destroyed in the lesion epicenter; neurons and astrocytes were also absent, and few ED1+ cells were seen infiltrating the lesion center. By 4 days, laminin associated with vessel staining was increased and ED1+ cells appeared to be more numerous in the lesion. By 7 days after injury, the new vessels formed a continuous cordon oriented longitudinally through the lesion center. ED1+ cells were abundant at this time point and were found in the same area as the newly formed vessels. Astrocyte migration from the margins of the lesion into the new cordon was apparent. By 14 days, a decrease in the number of vessels in the lesion center was observed; in contrast, astrocytes were more prominent in those areas. In addition to providing a blood supply to the lesion site, protecting the demise of the newly formed vascular bridge might provide an early scaffold to hasten axonal regeneration across the injury site. 相似文献
30.
Phorbol ester-sensitive EL4 murine thymoma cells respond to phorbol 12-
myristate 13-acetate with activation of ERK mitogen-activated protein
kinases, synthesis of interleukin-2, and death, whereas phorbol ester-
resistant variants of this cell line do not exhibit these responses.
Additional aspects of the resistant phenotype were examined, using a
newly-established resistant cell line. Phorbol ester induced morphological
changes, ERK activation, calcium-dependent activation of the c-Jun
N-terminal kinase (JNK), interleukin-2 synthesis, and growth inhibition in
sensitive but not resistant cells. A series of protein kinase C activators
caused membrane translocation of protein kinase C's (PKCs) alpha, eta, and
theta in both cell lines. While PKC eta was expressed at higher levels in
sensitive than in resistant cells, overexpression of PKC eta did not
restore phorbol ester-induced ERK activation to resistant cells. In
sensitive cells, PKC activators had similar effects on cell viability and
ERK activation, but differed in their abilities to induce JNK activation
and interleukin-2 synthesis. PD 098059, an inhibitor of the mitogen
activated protein (MAP)/ERK kinase kinase MEK, partially inhibited ERK
activation and completely blocked phorbol ester-induced cell death in
sensitive cells. Thus MEK and/or ERK activation, but not JNK activation or
interleukin-2 synthesis, appears to be required for phorbol ester-induced
toxicity. Alterations in phorbol ester response pathways, rather than
altered expression of PKC isoforms, appear to confer phorbol ester
resistance to EL4 cells.
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