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Hypospadias : analysis of a complex genetic disorder /Beleza Meireles, Ana Maria, January 2007 (has links)
Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 5 uppsatser.
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Novas contribuições sobre a correlação genótipo-fenótipo do grupo FGFR3 a partir do estudo de uma coorte de pacientes com fenótipo típico ou sugestivo / New contributions about the genotype-phenotype correlation of the FGFR3 group from the study of a cohort of patients with typical or suggestive phenotypeKanazawa, Thatiane Yoshie, 1988- 24 August 2018 (has links)
Orientadores: Denise Pontes Cavalcanti, Luciana Cardoso Bonadia / Texto em português e inglês / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-24T19:05:42Z (GMT). No. of bitstreams: 1
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Previous issue date: 2014 / Resumo: Entre as osteocondrodisplasias (OCD) destacam-se as displasias esqueléticas do grupo 1 (FGFR3) devido à sua alta frequência. Nesse grupo, além das displasias com fenótipo característico e considerável correlação genótipo-fenótipo, como a acondroplasia (Ach) e a displasia tanatofórica (DT), está a hipocondroplasia (Hch), cujo fenótipo em geral é mais leve, apresenta grande variabilidade clínico-radiológica e heterogeneidade etiológica. O objetivo desse estudo foi sequenciar o gene FGFR3 numa coorte de pacientes com fenótipo típico ou sugestivo. A análise molecular foi feita por sequenciamento direto, começando pelos hot spots e, seguindo com o sequenciamento completo do gene quando os primeiros foram negativos. Foram incluídos 63 pacientes na casuística: 30 Ach, 7 Hch, 10 Hch?, 13 DT-I e 3 DT-II. Dentre os casos de Ach, todos apresentaram a mutação mais comumente associada à Ach (p.G380R), inclusive um paciente com fenótipo atípico e suspeita de mosaicismo somático, não comprovado, devido à assimetria corporal. Dentre os casos de Hch, todos os sete apresentaram a mutação mais comum para este fenótipo (p.N540K) inclusive dois pacientes com uma Hch grave com manifestações clínicas e radiológicas no período neonatal e dez pacientes, diagnosticados como uma Hch duvidosa (Hch?) por apresentarem baixa estatura com alguns sinais radiológicos, não foi encontrada mutação, sendo que em cinco casos, o sequenciamento não foi concluído. Três mutações diferentes, que ocorrem com maior frequência, foram identificadas entre os casos de DT-I, a p.R248C em sete pacientes, entre eles um paciente atípico por apresentar maior sobrevida, p.S249C em três e a p.Y373C em dois. Em todos os casos de DT-II, como esperado, foi encontrada a única mutação até então descrita para este fenótipo (p.K650E). Os resultados deste estudo permitiram a identificação de casos interessantes, ressaltaram a ótima correlação genótipo-fenótipo do grupo FGFR3 e reforçaram a importância da investigação molecular do gene FGFR3 nos casos com fenótipos duvidosos ou atípicos / Abstract: Among osteochondrodysplasias (OCD) stand out the skeletal dysplasias group 1 (FGFR3) due to its high frequency. In this group, besides the conditions with considerable characteristic phenotype and genotype-phenotype correlation, such as achondroplasia (Ach) and thanatophoric dysplasia (TD), there is hypochondroplasia (HCH), whose phenotype is generally milder, with a large clinical and radiological variability and etiological heterogeneity. The aim of this study was to sequence the FGFR3 gene in a cohort of patients with typical or suggestive phenotype. Molecular analysis was performed by direct sequencing, starting with the hot spots, and following with the complete sequencing of the gene when the first were negative. In this sample, 63 patients were included: 30 Ach, 7 Hch, 10 Hch?, 13 DT-I and 3 DT-II. Among the Ach cases, all exhibit the most common mutation associated with Ach (p.G380R), including one patient with an atypical phenotype, with suspicious of somatic mosaicism, not confirmed, due to body asymmetry. Among the Hch cases, all the seven patients showed the most common mutation for this phenotype (p.N540K) including two patients with severe Hch with clinical and radiological manifestations in the neonatal period and ten patients, diagnosed as a doubtful Hch (Hch?), because of their low stature with some radiological signs, no mutation was found, and in five cases, sequencing was not completed. Three different mutations, which occur more frequently, were identified among the DT-I cases, p.R248C in seven patients, including an atypical patient with a long-term survival, p.S249C in three and p.Y373C in two. In all DT-II cases, as expected, the only mutation described so far for this phenotype (p.K650E) was found. The results of this study allowed the identification of interesting cases, emphasized the great genotype-phenotype correlation of FGFR3 group and reinforced the importance of molecular investigation of the FGFR3 gene in cases with doubtful or atypical phenotypes / Mestrado / Ciencias Biomedicas / Mestra em Ciências Médicas
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The role of fibroblast growth factor receptor 3 in post-natal cartilage and bone metabolism /Valverde Franco, Gladys, 1972- January 2008 (has links)
FGFR 3 is one of a family of four high affinity receptors for FGF ligands. Activating mutations in FGFR 3 result in skeletal dysplasias that vary in severity from undetectable to neonatal lethal. Mice with congenital deficiency of FGFR3 develop severe kyphosis and skeletal overgrowth. FGFR3 is also expressed in calvarial pre-osteoblasts, osteoblast and articular chondrocytes, although it biological role in these cells remains undefined. By changing the genetic background of the Fgfr3-/- mice we were able to extend their lifespan and examine its impact on post-natal skeletal growth. To investigate the implication of FGFR 3 in post-natal cartilage and bone metabolism we used a combination of imaging, classic histology, molecular biology and biomechanical testing. The results demonstrated that the synovial joints of young adult Fgfr3-/- mice revealed a progressive deterioration, loss of the joint space width and changes in the subchondral bone. These alterations were accompanied by an increase of cartilage matrix degradation. Increased aggrecan and collagen type II degradation products, generated by MMPs were detected with DIAPEN and COL2-3/4C antibodies. Increased collagen type X, cellular hypertrophy and loss of proteoglycan at the articular surface were also demonstrated. A novel micro-mechanical indentation protocol revealed that the humeral heads of Fgfr3-/- mice were less stiff than those of wild type littermates. On the other hand, young adult Fgfr3-/- mice are osteopenic due to reduced cortical bone thickness and defective trabecular bone mineralization. The reduction in mineralized bone and lack of trabecular connectivity observed by micro-computed tomography were confirmed by histological and histomorphometric analyses, which revealed a significant decrease in calcein labeling of mineralizing surfaces and a significant increase in osteoid in the long bones of 4-month-old Fgfr3-/- mice. Primary cultures of adherent bone marrow-derived cells from Fgfr3-/- mice expressed markers of differentiated osteoblasts but developed fewer mineralized nodules than Fgfr3+/+ cultures of the same age. These data point to a major role for FGFR3 signaling in development and homeostatic maintenance of cartilage and bone post-natally and identify FGFR3 as a potential target for intervention in degenerative disorders of cartilage, osteopenia and those associated with defective bone mineralization.
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The use of a synthetic hedgehog agonist in mouse models of chondrodysplasia /Morrison, David, 1981- January 2008 (has links)
The role of Indian hedgehog (Ihh) signalling in the regulation of endochondral bone formation is well established. Ihh controls the rate of bone growth by negatively regulating differentiation and positively regulating growth plate chondrocyte proliferation. It has been well documented also that mutations resulting in constitutive activation of signalling through FGFR3 in chondrodysplasia, lead to a significant decrease in this important signalling factor accompanied by reduced proliferation of the chondrocytes and a dwarf phenotype. / In an attempt to rescue the chondrodysplasia phenotype hedgehog agonist Hh-Ag 1.4 was injected subcutaneously into mice with achondroplasia (ACH) or with severe achondroplasia with developmental delay and acanthosis negricans (SADDAN) with mixed results. / Administration of a hedgehog agonist in SADDAN mice led to a significant up-regulation of both Ptch and Gli1, as measured by quantitative PCR, indicating that Hh-Ag 1.4 does indeed stimulate hedgehog signalling in vivo. Also, in situ hybridization for Ihh seems to show a down regulation of native Ihh expression in pre-hypertrophic chondrocytes, possibly due to the activation of the negative PTHrP feedback loop. In our study, Hh-Ag 1.4 treatment resulted in an increased growth plate length and reduced size of the hypertrophic zone. The cortical bone flanking the growth plate in mice injected with Hh-Ag 1.4 was 2-3 times thicker than in control mice, which may be attributed to the positive effect of increased Ihh signalling in osteoblastogenesis. Contrary to our expectations, there was also a noticeable reduction in chondrocyte proliferation in mice treated with the agonist. / Overall, the effect on the growth of long bones was not beneficial and the treatment with high doses of Hh-Ag 1.4 did not result in an amelioration of the chondrodysplastic phenotype.
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Enhanced bone formation during distraction osteogenesis in FGFR3 deficient miceHamade, Fares. January 2008 (has links)
Distraction Osteogenesis (DO) is a technique for bone lengthening and filling of bone defects following trauma, infection or resection of tumors. DO consists of an osteotomy of the bone to be lengthened, followed by controlled distraction of the bone segments with an external fixator until the desired lengthening is obtained (distraction phase). This is followed by the consolidation phase, during which the external fixator is kept in place until the newly formed bone in the distracted zone consolidates. This phase is long and may cause numerous problems. Ongoing research aims at finding a method to accelerate the consolidation of the newly formed bone. / Fibroblast Growth Factors (FGF) play a significant role in bone development and repair. FGF 18 has been shown to be the only FGF member to be expressed throughout both the distraction and the consolidation phases of DO. It was also reported that FGF18 is the physiological ligand of FGFR3. Therefore, we hypothesized that FGF18 and FGFR3 may have an important role in DO. / To test this hypothesis, we investigated DO in FGFR3 deficient mice (FGFR3-/-). (FGF18 deficient mice are not viable). A miniaturized DO apparatus was applied to the tibia followed by an osteotomy. Distraction began after a 5-day latency period at a rate of 0.2 mm/12 hours for 12 days. / Samples were collected at 3 time points comparing the mutants (FGFR3-/-) to their wild type litter' sates: end of distraction (17 days post-surgery), mid-consolidation (34 days post-surgery), and end of consolidation (51 days post surgery). The samples were analyzed using X-ray, DEXA, microCT, histology, biomechanical testing and Real-Time PCR. / Our results revealed that FGFR3 deficient mice showed accelerated bone formation compared to the W.T. littermates at mid-consolidation where the parameters measured revealed increased bone mineral density, bone mineral content and trabecular number in the mutant tibial samples. The newly regenerated bone consolidated faster in the FGFR3 knock-out mice and the bone was of better quality as revealed by biomechanical tests in which more force was needed to break the mutant bone because it exhibited higher resistance than the age matched wild-type sample. The marker gene expression patterns revealed an up-regulation of chondrogenic markers that suggest that the knock-out mice follow the endochondral ossification pathway during DO. All results were statistically significant. / These results show that signaling through FGFR3 acts to decrease bone formation during DO. Consequently, blocking FGFR3 may lead to accelerated bone formation in DO. This may have important clinical implications in attempts to improve the functional outcome of DO by decreasing the long duration that the external fixator has to be kept on.
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The use of a synthetic hedgehog agonist in mouse models of chondrodysplasia /Morrison, David, 1981- January 2008 (has links)
No description available.
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Enhanced bone formation during distraction osteogenesis in FGFR3 deficient miceHamade, Fares. January 2008 (has links)
No description available.
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The role of fibroblast growth factor receptor 3 in post-natal cartilage and bone metabolism /Valverde Franco, Gladys, 1972- January 2008 (has links)
No description available.
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Expression of follicle stimulating hormone receptor variants during the sheep estrous cycleSullivan, Rachael R. January 1900 (has links)
Master of Science / Department of Animal Sciences and Industry / Timothy G. Rozell / Several alternatively-spliced mRNA transcripts of the follicle stimulating hormone receptor (FSHR) have been identified in sheep, including FSHR-1 (G protein-coupled form), FSHR-2 (dominant negative form), and FSHR-3 (growth factor type-1 form). Coupling of the FSHR to signaling pathways which activate different downstream effectors leads to speculation that specific splice variants may be transcribed under differing physiological conditions.
This is the first study to correlate expression patterns of FSHR-1, FSHR-2, and FSHR-3 and development of follicles in the mature sheep ovary. In Experiment 1, 8 Suffolk-cross ewes were allowed to come into estrus naturally and were euthanized 24 (n=3), 36 (n=3), and 48 (n=2) hours after the onset of estrus. In Experiment 2, 7 Suffolk-cross ewes received CIDRs for 14 days. At CIDR removal, PMSG (500IU) was administered to treatment ewes (n=3), while controls (n=4) received no PMSG. Ewes were euthanized 24 (n=4; 2 CIDR only, 2 PMSG) or 36 (n=3; 2 CIDR only, 1 PMSG) hours later. All visible follicles were aspirated and pooled according to follicular diameter: small (≤ 2.0 mm), medium (2.1-4.0 mm), large (4.1-6.0 mm), and preovulatory (≥ 6.1 mm). Granulosa cells were separated from follicular fluid by centrifugation. Total RNA was extracted from granulosa cells (GC) and reversed transcribed. The resulting cDNA was subjected to qPCR, using primer sets designed to amplify each variant specifically.
For Experiment 1, regardless of time after onset of estrus, relative expression of FSHR-3 exceeded that of both FSHR-1 and FSHR-2 in medium follicles (p < 0.01), and tended to be higher in small follicles (p=0.09). For Experiment 2, treatment with PMSG did not significantly alter expression patterns of FSHR variants (p=0.18). The FSHR-3 was expressed higher than FSHR-2 in all follicle sizes (p < 0.01) and was numerically more highly expressed than FSHR-1, although this difference was not significant (p > 0.11).
These experiments show that in addition to the well characterized G protein-coupled form of the FSHR, alternatively spliced variants of the FSHR may participate in follicular dynamics during the first follicular wave of the sheep estrous cycle. Furthermore, these results would indicate that an “alternatively” spliced form of the FSHR (FSHR-3) is the predominant form of the FSHR in the sheep.
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Targets of autocrine growth factor signaling in models of tumor progression in vitroIsmail, Amin. January 1900 (has links)
Thesis (Ph.D.). / Written for the Division of Experimental Medicine, Dept. of Medicine. Title from title page of PDF (viewed 2008/07/23). Includes bibliographical references.
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