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Sally J Davies - One of the best experts on this subject based on the ideXlab platform.
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novel mutations of the Growth Hormone 1 gh1 gene disclosed by modulation of the clinical selection criteria for individuals with short stature
Human Mutation, 2003Co-Authors: David Stuart Millar, M D Lewis, Martin Horan, Victoria Elizabeth Newsway, T Easter, John Gregory, Linda Fryklund, Martin Norin, Elizabeth Crowne, Sally J DaviesAbstract:Subtle mutations in the Growth Hormone 1 (GH1) gene have been regarded as a comparatively rare cause of short stature. Such lesions were sought in a group of 41 individuals selected for short stature, reduced height velocity, and bone age delay; a group of 11 individuals with short stature and idiopathic Growth Hormone deficiency (IGHD); and a group of 154 controls. Heterozygous mutations were identified in all three groups but disproportionately in the individuals with short stature, both with (odds ratio 25.2; 95% CI, 5.1–132.2) and without (odds ratio 3.6; 95% CI, 1.0–12.9) IGHD. Twenty-four novel GH1 gene lesions were found. Thirteen novel missense mutations were characterized by assaying the signal transduction activity of in vitro expressed variants; six (T27I, K41R, N47D, S71F, S108R, and T175A) exhibited a reduced ability to activate the JAK/STAT pathway. Molecular modeling suggested that both K41R and T175A might compromise GH receptor binding. Seven GH variants (R16C, K41R, S71F, E74K, Q91L, S108C, and a functional polymorphism, V110I) manifested reduced secretion in rat pituitary cells after allowance had been made for the level of expression attributable to the associated GH1 proximal promoter haplotype. A further leader peptide variant (L-11P) was not secreted. Eleven novel mutations in the GH1 gene promoter were assessed by reporter gene assay but only two, including a GH2 gene-templated gene conversion, were found to be associated with a significantly reduced level of expression. Finally, a novel intron 2 acceptor splice-site mutation, detected in a family with autosomal dominant type II IGHD, was shown to lead to the skipping of exon 3 from the GH1 transcript. A total of 15 novel GH1 gene mutations were thus considered to be of probable phenotypic significance. Such lesions are more prevalent than previously recognized and although most may be insufficient on their own to account for the observed clinical phenotype, they are nevertheless likely to play a contributory role in the etiology of short stature.
David Stuart Millar - One of the best experts on this subject based on the ideXlab platform.
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novel mutations of the Growth Hormone 1 gh1 gene disclosed by modulation of the clinical selection criteria for individuals with short stature
Human Mutation, 2003Co-Authors: David Stuart Millar, M D Lewis, Martin Horan, Victoria Elizabeth Newsway, T Easter, John Gregory, Linda Fryklund, Martin Norin, Elizabeth Crowne, Sally J DaviesAbstract:Subtle mutations in the Growth Hormone 1 (GH1) gene have been regarded as a comparatively rare cause of short stature. Such lesions were sought in a group of 41 individuals selected for short stature, reduced height velocity, and bone age delay; a group of 11 individuals with short stature and idiopathic Growth Hormone deficiency (IGHD); and a group of 154 controls. Heterozygous mutations were identified in all three groups but disproportionately in the individuals with short stature, both with (odds ratio 25.2; 95% CI, 5.1–132.2) and without (odds ratio 3.6; 95% CI, 1.0–12.9) IGHD. Twenty-four novel GH1 gene lesions were found. Thirteen novel missense mutations were characterized by assaying the signal transduction activity of in vitro expressed variants; six (T27I, K41R, N47D, S71F, S108R, and T175A) exhibited a reduced ability to activate the JAK/STAT pathway. Molecular modeling suggested that both K41R and T175A might compromise GH receptor binding. Seven GH variants (R16C, K41R, S71F, E74K, Q91L, S108C, and a functional polymorphism, V110I) manifested reduced secretion in rat pituitary cells after allowance had been made for the level of expression attributable to the associated GH1 proximal promoter haplotype. A further leader peptide variant (L-11P) was not secreted. Eleven novel mutations in the GH1 gene promoter were assessed by reporter gene assay but only two, including a GH2 gene-templated gene conversion, were found to be associated with a significantly reduced level of expression. Finally, a novel intron 2 acceptor splice-site mutation, detected in a family with autosomal dominant type II IGHD, was shown to lead to the skipping of exon 3 from the GH1 transcript. A total of 15 novel GH1 gene mutations were thus considered to be of probable phenotypic significance. Such lesions are more prevalent than previously recognized and although most may be insufficient on their own to account for the observed clinical phenotype, they are nevertheless likely to play a contributory role in the etiology of short stature.
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human Growth Hormone 1 gh1 gene expression complex haplotype dependent influence of polymorphic variation in the proximal promoter and locus control region
Human Mutation, 2003Co-Authors: Martin Horan, David Stuart Millar, Linda Fryklund, Jurgen Hedderich, Geraint F Lewis, Vicky Newsway, Annie M Procter, Michael Krawczak, David Neil CooperAbstract:The proximal promoter region of the human pituitary expressed Growth Hormone (GH1) gene is highly polymorphic, containing at least 15 single nucleotide polymorphisms (SNPs). This variation is manifest in 40 different haplotypes, the high diversity being explicable in terms of gene conversion, recurrent mutation, and selection. Functional analysis showed that 12 haplotypes were associated with a significantly reduced level of reporter gene expression whereas 10 haplotypes were associated with a significantly increased level. The former tend to be more prevalent in the general population than the latter (p<0.01), possibly as a consequence of selection. Although individual SNPs contributed to promoter strength in a highly interactive and non-additive fashion, haplotype partitioning was successful in identifying six SNPs as major determinants of GH1 gene expression. The prediction and functional testing of hitherto unobserved super-maximal and sub-minimal promoter haplotypes was then used to test the efficacy of the haplotype partitioning approach. Electrophoretic mobility shift assays demonstrated that five SNP sites exhibit allele-specific protein binding. An association was noted between adult height and the mean in vitro expression value corresponding to an individual's GH1 promoter haplotype combination (p=0.028) although only 3.3% of the variance of adult height was found to be explicable by reference to this parameter. Three additional SNPs, identified within sites I and II of the upstream locus control region (LCR), were ascribed to three distinct LCR haplotypes. A series of LCR-GH1 proximal promoter constructs were used to demonstrate that 1) the LCR enhanced proximal promoter activity by up to 2.8-fold depending upon proximal promoter haplotype, and that 2) the activity of a given proximal promoter haplotype was also differentially enhanced by different LCR haplotypes. The genetic basis of inter-individual differences in GH1 gene expression thus appears to be extremely complex.
Gómez Zorita Saioa - One of the best experts on this subject based on the ideXlab platform.
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Obesitateak minbizia izateko arriskua handitzen du… Zer mekanismo daude tartean?
'UPV EHU Press', 2020Co-Authors: Gómez Zorita Saioa, Trepiana Arin Jenifer, Eseberri Itziar, Portillo Baquedano, María PuyAbstract:Cancer is one of the most important public health problems of the last years, due to the fact that tumour incidence has increased dramatically over the last decade. Among other factors, the dietary pattern notably influences the development of cancer, as well as obesity and its comorbidities do. They increase the risk of developing several types of cancer: thyroid, esophagus, liver, gallbladder, colon, kidney and multiple myeloma cancer in men and women, breast and endometrium cancer in women and prostate cancer in men. However, the mechanism by which obesity can induce cancer has not been widely investigated. The known mechanisms that contribute to the association between cancer and obesity are related to hormonal changes, such as insulin and insulin-like Growth Hormone-1 (IGF-1), or sex steroids. Not only Hormones can affect cancer development, but also adipokines (leptin and adiponectin) and inflammation. In the same way, patients with obesity and cancer have a higher risk of suffering metastasis, consequently having a lower survival rate. As pre-clinical research has shown, obesity can induce metastasis in melanoma and lung cancer models. Since it has been reported a relationship between obesity and a high mortality rate in oncological patients, it is essential to use drugs to treat obesity and metabolic syndrome in cancer patients, such as metformin, thiazolidinediones and statins. Finally, it is noteworthy to mention that further research is needed to better understand the mechanisms involved in this process, and even to find biomarkers that may be useful for an early cancer diagnosis.; Minbizia egungo osasun-arazo publiko garrantzitsuenetarikoa da; izan ere, tumoreen intzidentzia izugarri handitu da azken hamarkadetan. Beste faktore askoren artean, elikadura-patroiak nabarmen eragiten du minbiziaren garapenean; hala nola, obesitateak eta haren komorbilitateek. Hainbat minbizi mota garatzeko arriskua areagotzen dute, besteak beste gizon eta emakumezkoetan tiroide, hestegorri, gibel, behazun-besikula, kolon, giltzurrun eta mieloma anitzeko minbiziak, bular eta endometrioko minbiziak emakumezkoen kasuan eta prostatakoa gizonezkoenean. Azken urteetan nahiko ikertu da obesitatea-minbizia harremanean, baina oraindik ez dira ondorio garbiak lortu erlazio hori ezartzen duten mekanismo-multzoei dagokienez. Minbiziaren eta obesitatearen arteko asoziazioari laguntzen dioten mekanismoak aldaketa hormonalekin erlazionaturikoak izaten dira, besteak beste intsulina, intsulinaren antzekoa den 1 hazkuntza hormona (IGF-1) edo sexu esteroideak. Hormonak ez ezik, adipokinek (leptina eta adiponektina) eta hanturak ere parte hartzen dute minbiziaren garapenean.Era berean, obesitatea eta minbizia pairatzen duten pazienteek metastasi-arrisku handiagoa dute, eta ondorioz, biziraupen-ratio baxuagoa. Ikerketa pre-klinikoetan ikusi ahal izan denez, obesitateak metastasia bultzatzen du melanoma eta birika-minbizi ereduetan. Obesitateak paziente onkologikoen hilkortasun-tasa altuarekin duen lotura ikusita, ezinbestekotzat jotzen da minbizia duten pazienteetan, elikadura-patroi osasuntsuarekin eta jarduera fisikoarekin batera, obesitatea eta sindrome metabolikoa tratatzeko farmakoen erabilera; besteak beste, metformina, tiazolidinedionak eta estatinak erabili ohi dira. Amaitzeko, aipatzekoa da ikerlan gehiagoren beharra dagoela parte hartzen duten mekanismoak ondo ulertu ahal izateko, eta are gehiago, etorkizunean minbiziaren diagnostiko goiztiarrerako baliagarriak izan litezkeen bio-markatzaileak aurkitzeko
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Obesitateak minbizia izateko arriskua handitzen du... Zer mekanismo daude tartean?
Euskal Herriko Unibertsitatea, 2020Co-Authors: Gómez Zorita Saioa, Trepiana Arin Jenifer, Eseberri Itziar, Portillo, María PuyAbstract:Cancer is one of the most important public health problems of the last years, due to the fact that tumour incidence has increased dramatically over the last decade. Among other factors, the dietary pattern notably influences the development of cancer, as well as obesity and its comorbidities do. They increase the risk of developing several types of cancer: thyroid, esophagus, liver, gallbladder, colon, kidney and multiple myeloma cancer in men and women, breast and endometrium cancer in women and prostate cancer in men. However, the mechanism by which obesity can induce cancer has not been widely investigated. The known mechanisms that contribute to the association between cancer and obesity are related to hormonal changes, such as insulin and insulin-like Growth Hormone-1 (IGF-1), or sex steroids. Not only Hormones can affect cancer development, but also adipokines (leptin and adiponectin) and inflammation. In the same way, patients with obesity and cancer have a higher risk of suffering metastasis, consequently having a lower survival rate. As pre-clinical research has shown, obesity can induce metastasis in melanoma and lung cancer models. Since it has been reported a relationship between obesity and a high mortality rate in oncological patients, it is essential to use drugs to treat obesity and metabolic syndrome in cancer patients, such as metformin, thiazolidinediones and statins. Finally, it is noteworthy to mention that further research is needed to better understand the mechanisms involved in this process, and even to find biomarkers that may be useful for an early cancer diagnosis.Minbizia egungo osasun-arazo publiko garrantzitsuenetarikoa da; izan ere, tumoreen intzidentzia izugarri handitu da azken hamarkadetan. Beste faktore askoren artean, elikadura-patroiak nabarmen eragiten du minbiziaren garapenean; hala nola, obesitateak eta haren komorbilitateek. Hainbat minbizi mota garatzeko arriskua areagotzen dute, besteak beste gizon eta emakumezkoetan tiroide, hestegorri, gibel, behazun-besikula, kolon, giltzurrun eta mieloma anitzeko minbiziak, bular eta endometrioko minbiziak emakumezkoen kasuan eta prostatakoa gizonezkoenean. Azken urteetan nahiko ikertu da obesitatea-minbizia harremanean, baina oraindik ez dira ondorio garbiak lortu erlazio hori ezartzen duten mekanismo-multzoei dagokienez. Minbiziaren eta obesitatearen arteko asoziazioari laguntzen dioten mekanismoak aldaketa hormonalekin erlazionaturikoak izaten dira, besteak beste intsulina, intsulinaren antzekoa den 1 hazkuntza hormona (IGF-1) edo sexu-esteroideak. Hormonak ez ezik, adipokinek (leptina eta adiponektina) eta hanturak ere parte hartzen dute minbiziaren garapenean. Era berean, obesitatea eta minbizia pairatzen duten pazienteek metastasi-arrisku handiagoa dute, eta ondorioz, biziraupen-ratio baxuagoa. Ikerketa pre-klinikoetan ikusi ahal izan denez, obesitateak metastasia bultzatzen du melanoma eta birika-minbizi ereduetan. Obesitateak paziente onkologikoen hilkortasun-tasa altuarekin duen lotura ikusita, ezinbestekotzat jotzen da minbizia duten pazienteetan, elikadura-patroi osasuntsuarekin eta jarduera fisikoarekin batera, obesitatea eta sindrome metabolikoa tratatzeko farmakoen erabilera; besteak beste, metformina, tiazolidinedionak eta estatinak erabili ohi dira. Amaitzeko, aipatzekoa da ikerlan gehiagoren beharra dagoela parte hartzen duten mekanismoak ondo ulertu ahal izateko, eta are gehiago, etorkizunean minbiziaren diagnostiko goiztiarrerako baliagarriak izan litezkeen bio-markatzaileak aurkitzeko
Martin Horan - One of the best experts on this subject based on the ideXlab platform.
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novel mutations of the Growth Hormone 1 gh1 gene disclosed by modulation of the clinical selection criteria for individuals with short stature
Human Mutation, 2003Co-Authors: David Stuart Millar, M D Lewis, Martin Horan, Victoria Elizabeth Newsway, T Easter, John Gregory, Linda Fryklund, Martin Norin, Elizabeth Crowne, Sally J DaviesAbstract:Subtle mutations in the Growth Hormone 1 (GH1) gene have been regarded as a comparatively rare cause of short stature. Such lesions were sought in a group of 41 individuals selected for short stature, reduced height velocity, and bone age delay; a group of 11 individuals with short stature and idiopathic Growth Hormone deficiency (IGHD); and a group of 154 controls. Heterozygous mutations were identified in all three groups but disproportionately in the individuals with short stature, both with (odds ratio 25.2; 95% CI, 5.1–132.2) and without (odds ratio 3.6; 95% CI, 1.0–12.9) IGHD. Twenty-four novel GH1 gene lesions were found. Thirteen novel missense mutations were characterized by assaying the signal transduction activity of in vitro expressed variants; six (T27I, K41R, N47D, S71F, S108R, and T175A) exhibited a reduced ability to activate the JAK/STAT pathway. Molecular modeling suggested that both K41R and T175A might compromise GH receptor binding. Seven GH variants (R16C, K41R, S71F, E74K, Q91L, S108C, and a functional polymorphism, V110I) manifested reduced secretion in rat pituitary cells after allowance had been made for the level of expression attributable to the associated GH1 proximal promoter haplotype. A further leader peptide variant (L-11P) was not secreted. Eleven novel mutations in the GH1 gene promoter were assessed by reporter gene assay but only two, including a GH2 gene-templated gene conversion, were found to be associated with a significantly reduced level of expression. Finally, a novel intron 2 acceptor splice-site mutation, detected in a family with autosomal dominant type II IGHD, was shown to lead to the skipping of exon 3 from the GH1 transcript. A total of 15 novel GH1 gene mutations were thus considered to be of probable phenotypic significance. Such lesions are more prevalent than previously recognized and although most may be insufficient on their own to account for the observed clinical phenotype, they are nevertheless likely to play a contributory role in the etiology of short stature.
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human Growth Hormone 1 gh1 gene expression complex haplotype dependent influence of polymorphic variation in the proximal promoter and locus control region
Human Mutation, 2003Co-Authors: Martin Horan, David Stuart Millar, Linda Fryklund, Jurgen Hedderich, Geraint F Lewis, Vicky Newsway, Annie M Procter, Michael Krawczak, David Neil CooperAbstract:The proximal promoter region of the human pituitary expressed Growth Hormone (GH1) gene is highly polymorphic, containing at least 15 single nucleotide polymorphisms (SNPs). This variation is manifest in 40 different haplotypes, the high diversity being explicable in terms of gene conversion, recurrent mutation, and selection. Functional analysis showed that 12 haplotypes were associated with a significantly reduced level of reporter gene expression whereas 10 haplotypes were associated with a significantly increased level. The former tend to be more prevalent in the general population than the latter (p<0.01), possibly as a consequence of selection. Although individual SNPs contributed to promoter strength in a highly interactive and non-additive fashion, haplotype partitioning was successful in identifying six SNPs as major determinants of GH1 gene expression. The prediction and functional testing of hitherto unobserved super-maximal and sub-minimal promoter haplotypes was then used to test the efficacy of the haplotype partitioning approach. Electrophoretic mobility shift assays demonstrated that five SNP sites exhibit allele-specific protein binding. An association was noted between adult height and the mean in vitro expression value corresponding to an individual's GH1 promoter haplotype combination (p=0.028) although only 3.3% of the variance of adult height was found to be explicable by reference to this parameter. Three additional SNPs, identified within sites I and II of the upstream locus control region (LCR), were ascribed to three distinct LCR haplotypes. A series of LCR-GH1 proximal promoter constructs were used to demonstrate that 1) the LCR enhanced proximal promoter activity by up to 2.8-fold depending upon proximal promoter haplotype, and that 2) the activity of a given proximal promoter haplotype was also differentially enhanced by different LCR haplotypes. The genetic basis of inter-individual differences in GH1 gene expression thus appears to be extremely complex.
Linda Fryklund - One of the best experts on this subject based on the ideXlab platform.
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novel mutations of the Growth Hormone 1 gh1 gene disclosed by modulation of the clinical selection criteria for individuals with short stature
Human Mutation, 2003Co-Authors: David Stuart Millar, M D Lewis, Martin Horan, Victoria Elizabeth Newsway, T Easter, John Gregory, Linda Fryklund, Martin Norin, Elizabeth Crowne, Sally J DaviesAbstract:Subtle mutations in the Growth Hormone 1 (GH1) gene have been regarded as a comparatively rare cause of short stature. Such lesions were sought in a group of 41 individuals selected for short stature, reduced height velocity, and bone age delay; a group of 11 individuals with short stature and idiopathic Growth Hormone deficiency (IGHD); and a group of 154 controls. Heterozygous mutations were identified in all three groups but disproportionately in the individuals with short stature, both with (odds ratio 25.2; 95% CI, 5.1–132.2) and without (odds ratio 3.6; 95% CI, 1.0–12.9) IGHD. Twenty-four novel GH1 gene lesions were found. Thirteen novel missense mutations were characterized by assaying the signal transduction activity of in vitro expressed variants; six (T27I, K41R, N47D, S71F, S108R, and T175A) exhibited a reduced ability to activate the JAK/STAT pathway. Molecular modeling suggested that both K41R and T175A might compromise GH receptor binding. Seven GH variants (R16C, K41R, S71F, E74K, Q91L, S108C, and a functional polymorphism, V110I) manifested reduced secretion in rat pituitary cells after allowance had been made for the level of expression attributable to the associated GH1 proximal promoter haplotype. A further leader peptide variant (L-11P) was not secreted. Eleven novel mutations in the GH1 gene promoter were assessed by reporter gene assay but only two, including a GH2 gene-templated gene conversion, were found to be associated with a significantly reduced level of expression. Finally, a novel intron 2 acceptor splice-site mutation, detected in a family with autosomal dominant type II IGHD, was shown to lead to the skipping of exon 3 from the GH1 transcript. A total of 15 novel GH1 gene mutations were thus considered to be of probable phenotypic significance. Such lesions are more prevalent than previously recognized and although most may be insufficient on their own to account for the observed clinical phenotype, they are nevertheless likely to play a contributory role in the etiology of short stature.
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human Growth Hormone 1 gh1 gene expression complex haplotype dependent influence of polymorphic variation in the proximal promoter and locus control region
Human Mutation, 2003Co-Authors: Martin Horan, David Stuart Millar, Linda Fryklund, Jurgen Hedderich, Geraint F Lewis, Vicky Newsway, Annie M Procter, Michael Krawczak, David Neil CooperAbstract:The proximal promoter region of the human pituitary expressed Growth Hormone (GH1) gene is highly polymorphic, containing at least 15 single nucleotide polymorphisms (SNPs). This variation is manifest in 40 different haplotypes, the high diversity being explicable in terms of gene conversion, recurrent mutation, and selection. Functional analysis showed that 12 haplotypes were associated with a significantly reduced level of reporter gene expression whereas 10 haplotypes were associated with a significantly increased level. The former tend to be more prevalent in the general population than the latter (p<0.01), possibly as a consequence of selection. Although individual SNPs contributed to promoter strength in a highly interactive and non-additive fashion, haplotype partitioning was successful in identifying six SNPs as major determinants of GH1 gene expression. The prediction and functional testing of hitherto unobserved super-maximal and sub-minimal promoter haplotypes was then used to test the efficacy of the haplotype partitioning approach. Electrophoretic mobility shift assays demonstrated that five SNP sites exhibit allele-specific protein binding. An association was noted between adult height and the mean in vitro expression value corresponding to an individual's GH1 promoter haplotype combination (p=0.028) although only 3.3% of the variance of adult height was found to be explicable by reference to this parameter. Three additional SNPs, identified within sites I and II of the upstream locus control region (LCR), were ascribed to three distinct LCR haplotypes. A series of LCR-GH1 proximal promoter constructs were used to demonstrate that 1) the LCR enhanced proximal promoter activity by up to 2.8-fold depending upon proximal promoter haplotype, and that 2) the activity of a given proximal promoter haplotype was also differentially enhanced by different LCR haplotypes. The genetic basis of inter-individual differences in GH1 gene expression thus appears to be extremely complex.
