The Experts below are selected from a list of 1422 Experts worldwide ranked by ideXlab platform
Kwan-hyuck Baek - One of the best experts on this subject based on the ideXlab platform.
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A single extra copy of Down syndrome critical region 1–4 results in impaired hepatic glucose homeostasis
Elsevier, 2019Co-Authors: Dong Soo Seo, Gia Cac Chau, Kwan-hyuck BaekAbstract:Objectives: During fasting, hepatic gluconeogenesis is induced to maintain energy homeostasis. Moreover, abnormal dysregulation of hepatic glucose production is commonly observed in type 2 diabetes. However, the signaling components controlling hepatic glucose production to maintain normal glucose levels are not fully understood. Here, we examined the physiological role of Down syndrome critical region 1–4 (DSCR1-4), an endogenous calcineurin signaling inhibitor in the liver that mediates metabolic adaptation to fasting. Methods: We assessed the effect of cyclosporine A, an inhibitor of calcineurin signaling on gluconeogenic gene expression in primary hepatocytes. DSCR1-4 expression was examined in diet- and genetically-induced mouse models of obesity. We also investigated the metabolic phenotype of a single extra copy of DSCR1-4 in transgenic mice and how DSCR1-4 regulates glucose homeostasis in the liver. Results: Treatment with cyclosporin A increased hepatic glucose production and gluconeogenic gene expression. The expression of DSCR1-4 was induced by refeeding and overexpressed in obese mouse livers. Moreover, transgenic mice with a single extra copy of DSCR1-4 exhibited pyruvate intolerance and impaired glucose homeostasis. Mechanistically, DSCR1-4 overexpression increased phosphorylation of the cAMP response element-binding protein, which led to elevated expression levels of gluconeogenic genes and, thus, enhanced hepatic glucose production during fasting. Conclusion: A single extra copy of DSCR1-4 results in dysregulated hepatic glucose homeostasis and pyruvate intolerance. Our findings suggest that nutrient-sensitive DSCR1-4 is a novel target for controlling hepatic gluconeogenesis in diabetes. Keywords: Hepatic glucose homeostasis, DSCR1-4, Diabetes, Calcineuri
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A single extra copy of Down syndrome critical region 1-4 results in impaired hepatic glucose homeostasis.
Molecular metabolism, 2018Co-Authors: Dong Soo Seo, Gia Cac Chau, Kwan-hyuck BaekAbstract:Abstract Objectives During fasting, hepatic gluconeogenesis is induced to maintain energy homeostasis. Moreover, abnormal dysregulation of hepatic glucose production is commonly observed in type 2 diabetes. However, the signaling components controlling hepatic glucose production to maintain normal glucose levels are not fully understood. Here, we examined the physiological role of Down syndrome critical region 1–4 (DSCR1-4), an endogenous calcineurin signaling inhibitor in the liver that mediates metabolic adaptation to fasting. Methods We assessed the effect of cyclosporine A, an inhibitor of calcineurin signaling on gluconeogenic gene expression in primary hepatocytes. DSCR1-4 expression was examined in diet- and genetically-induced mouse models of obesity. We also investigated the metabolic phenotype of a single extra copy of DSCR1-4 in transgenic mice and how DSCR1-4 regulates glucose homeostasis in the liver. Results Treatment with cyclosporin A increased hepatic glucose production and gluconeogenic gene expression. The expression of DSCR1-4 was induced by refeeding and overexpressed in obese mouse livers. Moreover, transgenic mice with a single extra copy of DSCR1-4 exhibited pyruvate intolerance and impaired glucose homeostasis. Mechanistically, DSCR1-4 overexpression increased phosphorylation of the cAMP response element-binding protein, which led to elevated expression levels of gluconeogenic genes and, thus, enhanced hepatic glucose production during fasting. Conclusion A single extra copy of DSCR1-4 results in dysregulated hepatic glucose homeostasis and pyruvate intolerance. Our findings suggest that nutrient-sensitive DSCR1-4 is a novel target for controlling hepatic gluconeogenesis in diabetes.
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A single extra copy of DSCR1 improves survival of mice developing spontaneous lung tumors through suppression of tumor angiogenesis.
Cancer letters, 2013Co-Authors: Jimin Shin, Jang Choon Lee, Kwan-hyuck BaekAbstract:The incidence of most solid tumors is remarkably reduced in individuals with Down syndrome. Using mouse models of Down syndrome, we have previously shown that this decrease in tumor incidence is due, in part, to suppression of tumor angiogenesis as a consequence of attenuated calcineurin signaling in endothelial cells. Our prior studies utilized xenografted tumors in a transgenic mouse model with three copies of the Down syndrome critical region-1 (DSCR1) gene, a chromosome 21-encoded endogenous calcineurin inhibitor. These data indicate that upregulated DSCR1 contributes to broad cancer protection by suppressing tumor angiogenesis through inhibiting the calcineurin pathway in the vascular endothelium. However, it still remains to be confirmed whether a single extra copy of DSCR1 is also sufficient to suppress tumor angiogenesis in slow growing spontaneous tumors that more accurately recapitulate molecular features of human malignancies. In this study, utilizing LSL-Kras(G12D) mice, an inducible and autochthonous model of human lung adenocarcinoma, on a DSCR1 transgenic mouse background, we show that a single extra transgenic copy of DSCR1 provides a survival advantage in these mice developing spontaneous lung tumors driven by oncogenic Kras(G12D) without affecting either initiation or progression of spontaneous lung tumors. Furthermore, we show that DSCR1 trisomy significantly reduces microvessel density in lung tumors and thus limits the growth of lung tumors through decreased proliferation and increased apoptosis of lung tumor cells. These data provide evidence that a single extra copy of DSCR1 is sufficient to suppress tumor angiogenesis during spontaneous lung tumorigenesis and further support our hypothesis that suppression of tumor angiogenesis by an additional copy of DSCR1 contributes to the reduced cancer incidence in individuals with Down syndrome and the calcineurin pathway in the tumor vasculature is a potential target for cancer treatment.
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Trisomy of the DSCR1 gene suppresses early progression of pancreatic intraepithelial neoplasia driven by oncogenic Kras
Biochemical and biophysical research communications, 2013Co-Authors: Jang Choon Lee, Jimin Shin, Kwan-hyuck BaekAbstract:Individuals with Down syndrome exhibit remarkably reduced incidence of most solid tumors including pancreatic cancer. Multiple mechanisms arising from the genetic complexity underlying Down syndrome has been suggested to contribute to such a broad cancer protection. In this study, utilizing a genetically engineered mouse model of pancreatic cancer, we demonstrate that trisomy of the Down syndrome critical region-1 (DSCR1), an endogenous calcineurin inhibitor localized on chromosome 21, suppresses the progression of pancreatic intraepithelial neoplasia-1A (PanIN-1A) to PanIN-1B lesions without affecting the initiation of PanIN lesions mediated by oncogenic Kras(G12D). In addition, we show that DSCR1 trisomy attenuates nuclear localization of nuclear factor of activated T-cells (NFAT) accompanied by upregulation of the p15(Ink4b) tumor suppressor and reduction of cell proliferation in early PanIN lesions. Our data suggest that attenuation of calcineurin-NFAT signaling in neoplastic pancreatic ductal epithelium by a single extra copy of DSCR1 is sufficient to inhibit the progression of early PanIN lesions driven by oncogenic Kras, and thus may be a potential mechanism underlying reduced incidence of pancreatic cancer in Down syndrome individuals.
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down s syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1
Nature, 2009Co-Authors: Kwan-hyuck Baek, Sam S. Yoon, Alexander Zaslavsky, Ryan C Lynch, Carmella Britt, Yoshiaki Okada, Richard J Siarey, William M Lensch, Inhyun Park, Takashi MinamiAbstract:Individuals with Down's syndrome are known to have a lower rate of certain solid cancers. New work from Baek et al. shows that a mouse model with an extra copy of the chromosome 21 gene DSCR1 (encoding Down syndrome critical region protein 1) exhibits decreased tumour growth due to reduced angiogenesis. They provide evidence that together with another chromosome 21 gene, Dyrk1a, a modest increase in DSCR1 expression limits angiogenesis by decreasing the activity of the calcineurin pathway. These data provide a mechanism for the reduced cancer incidence in Down's syndrome and identify the calcineurin signalling pathway, and its regulators DSCR1 and DYRK1A, as potential therapeutic targets in cancers arising in all individuals. Individuals with Down's syndrome are known to have a lower rate of certain solid cancers. Now, a mouse model with one extra copy of DSCR1, a gene located on chromosome 21, is shown to display decreased tumour growth; this is thought to be via suppression of angiogenesis mediated by decreasing the activity of the calcineurin pathway. The incidence of many cancer types is significantly reduced in individuals with Down’s syndrome1,2,3,4, and it is thought that this broad cancer protection is conferred by the increased expression of one or more of the 231 supernumerary genes on the extra copy of chromosome 21. One such gene is Down’s syndrome candidate region-1 (DSCR1, also known as RCAN1), which encodes a protein that suppresses vascular endothelial growth factor (VEGF)-mediated angiogenic signalling by the calcineurin pathway5,6,7,8,9,10. Here we show that DSCR1 is increased in Down’s syndrome tissues and in a mouse model of Down’s syndrome. Furthermore, we show that the modest increase in expression afforded by a single extra transgenic copy of DSCR1 is sufficient to confer significant suppression of tumour growth in mice, and that such resistance is a consequence of a deficit in tumour angiogenesis arising from suppression of the calcineurin pathway. We also provide evidence that attenuation of calcineurin activity by DSCR1, together with another chromosome 21 gene Dyrk1a, may be sufficient to markedly diminish angiogenesis. These data provide a mechanism for the reduced cancer incidence in Down’s syndrome and identify the calcineurin signalling pathway, and its regulators DSCR1 and DYRK1A, as potential therapeutic targets in cancers arising in all individuals.
Karen T. Chang - One of the best experts on this subject based on the ideXlab platform.
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DSCR1-mediated TET1 splicing regulates miR-124 expression to control adult hippocampal neurogenesis.
The EMBO journal, 2019Co-Authors: Chiyeol Choi, Taehoon Kim, Karen T. Chang, Kyung-tai MinAbstract:Whether epigenetic factors such as DNA methylation and microRNAs interact to control adult hippocampal neurogenesis is not fully understood. Here, we show that Down syndrome critical region 1 (DSCR1) protein plays a key role in adult hippocampal neurogenesis by modulating two epigenetic factors: TET1 and miR-124. We find that DSCR1 mutant mice have impaired adult hippocampal neurogenesis. DSCR1 binds to TET1 introns to regulate splicing of TET1, thereby modulating TET1 level. Furthermore, TET1 controls the demethylation of the miRNA-124 promoter to modulate miR-124 expression. Correcting the level of TET1 in DSCR1 knockout mice is sufficient to prevent defective adult neurogenesis. Importantly, restoring DSCR1 level in a Down syndrome mouse model effectively rescued adult neurogenesis and learning and memory deficits. Our study reveals that DSCR1 plays a critical upstream role in epigenetic regulation of adult neurogenesis and provides insights into potential therapeutic strategy for treating cognitive defects in Down syndrome.
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DSCR1 is required for both axonal growth cone extension and steering
The Journal of cell biology, 2016Co-Authors: Wei Wang, Karen T. Chang, Asit Rai, Eun Mi Hur, Zeev Smilansky, Kyung-tai MinAbstract:Local information processing in the growth cone is essential for correct wiring of the nervous system. As an axon navigates through the developing nervous system, the growth cone responds to extrinsic guidance cues by coordinating axon outgrowth with growth cone steering. It has become increasingly clear that axon extension requires proper actin polymerization dynamics, whereas growth cone steering involves local protein synthesis. However, molecular components integrating these two processes have not been identified. Here, we show that Down syndrome critical region 1 protein (DSCR1) controls axon outgrowth by modulating growth cone actin dynamics through regulation of cofilin activity (phospho/dephospho-cofilin). Additionally, DSCR1 mediates brain-derived neurotrophic factor-induced local protein synthesis and growth cone turning. Our study identifies DSCR1 as a key protein that couples axon growth and pathfinding by dually regulating actin dynamics and local protein synthesis.
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Bidirectional Regulation of Amyloid Precursor Protein-Induced Memory Defects by Nebula/DSCR1: A Protein Upregulated in Alzheimer's Disease and Down Syndrome
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2015Co-Authors: Jillian L. Shaw, Shixing Zhang, Karen T. ChangAbstract:Aging individuals with Down syndrome (DS) have an increased risk of developing Alzheimer's disease (AD), a neurodegenerative disorder characterized by impaired memory. Memory problems in both DS and AD individuals usually develop slowly and progressively get worse with age, but the cause of this age-dependent memory impairment is not well understood. This study examines the functional interactions between Down syndrome critical region 1 (DSCR1) and amyloid-precursor protein (APP), proteins upregulated in both DS and AD, in regulating memory. Using Drosophila as a model, we find that overexpression of nebula (fly homolog of DSCR1) initially protects against APP-induced memory defects by correcting calcineurin and cAMP signaling pathways but accelerates the rate of memory loss and exacerbates mitochondrial dysfunction in older animals. We report that transient upregulation of Nebula/DSCR1 or acute pharmacological inhibition of calcineurin in aged flies protected against APP-induced memory loss. Our data suggest that calcineurin dyshomeostasis underlies age-dependent memory impairments and further imply that chronic Nebula/DSCR1 upregulation may contribute to age-dependent memory impairments in AD in DS. SIGNIFICANCE STATEMENT Most Down syndrome (DS) individuals eventually develop Alzheimer's disease (AD)-like dementia, but mechanisms underlying this age-dependent memory impairment remain poorly understood. This study examines Nebula/Down syndrome critical region 1 (DSCR1) and amyloid-precursor protein (APP), proteins upregulated in both DS and AD, in regulating memory. We uncover a previously unidentified role for Nebula/DSCR1 in modulating APP-induced memory defects during aging. We show that upregulation of Nebula/DSCR1, an inhibitor of calcineurin, rescues APP-induced memory defects in young flies but enhances memory loss of older flies. Excitingly, transient Nebula/DSCR1 overexpression or calcineurin inhibition in aged flies ameliorates APP-mediated memory problems. These results suggest that chronic Nebula/DSCR1 upregulation may contribute to age-dependent memory loss in DS and AD and points to correcting calcineurin signaling as a means to improve memory during aging.
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bidirectional regulation of amyloid precursor protein induced memory defects by nebula DSCR1 a protein upregulated in alzheimer s disease and down syndrome
The Journal of Neuroscience, 2015Co-Authors: Jillian L. Shaw, Karen T. Chang, Shixing ZhangAbstract:Aging individuals with Down syndrome (DS) have an increased risk of developing Alzheimer's disease (AD), a neurodegenerative disorder characterized by impaired memory. Memory problems in both DS and AD individuals usually develop slowly and progressively get worse with age, but the cause of this age-dependent memory impairment is not well understood. This study examines the functional interactions between Down syndrome critical region 1 (DSCR1) and amyloid-precursor protein (APP), proteins upregulated in both DS and AD, in regulating memory. Using Drosophila as a model, we find that overexpression of nebula (fly homolog of DSCR1) initially protects against APP-induced memory defects by correcting calcineurin and cAMP signaling pathways but accelerates the rate of memory loss and exacerbates mitochondrial dysfunction in older animals. We report that transient upregulation of Nebula/DSCR1 or acute pharmacological inhibition of calcineurin in aged flies protected against APP-induced memory loss. Our data suggest that calcineurin dyshomeostasis underlies age-dependent memory impairments and further imply that chronic Nebula/DSCR1 upregulation may contribute to age-dependent memory impairments in AD in DS. SIGNIFICANCE STATEMENT Most Down syndrome (DS) individuals eventually develop Alzheimer's disease (AD)-like dementia, but mechanisms underlying this age-dependent memory impairment remain poorly understood. This study examines Nebula/Down syndrome critical region 1 (DSCR1) and amyloid-precursor protein (APP), proteins upregulated in both DS and AD, in regulating memory. We uncover a previously unidentified role for Nebula/DSCR1 in modulating APP-induced memory defects during aging. We show that upregulation of Nebula/DSCR1, an inhibitor of calcineurin, rescues APP-induced memory defects in young flies but enhances memory loss of older flies. Excitingly, transient Nebula/DSCR1 overexpression or calcineurin inhibition in aged flies ameliorates APP-mediated memory problems. These results suggest that chronic Nebula/DSCR1 upregulation may contribute to age-dependent memory loss in DS and AD and points to correcting calcineurin signaling as a means to improve memory during aging.
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Nebula/DSCR1 Upregulation Delays Neurodegeneration and Protects against APP-Induced Axonal Transport Defects by Restoring Calcineurin and GSK-3β Signaling
PLoS genetics, 2013Co-Authors: Jillian L. Shaw, Karen T. ChangAbstract:Post-mortem brains from Down syndrome (DS) and Alzheimer's disease (AD) patients show an upregulation of the Down syndrome critical region 1 protein (DSCR1), but its contribution to AD is not known. To gain insights into the role of DSCR1 in AD, we explored the functional interaction between DSCR1 and the amyloid precursor protein (APP), which is known to cause AD when duplicated or upregulated in DS. We find that the Drosophila homolog of DSCR1, Nebula, delays neurodegeneration and ameliorates axonal transport defects caused by APP overexpression. Live-imaging reveals that Nebula facilitates the transport of synaptic proteins and mitochondria affected by APP upregulation. Furthermore, we show that Nebula upregulation protects against axonal transport defects by restoring calcineurin and GSK-3β signaling altered by APP overexpression, thereby preserving cargo-motor interactions. As impaired transport of essential organelles caused by APP perturbation is thought to be an underlying cause of synaptic failure and neurodegeneration in AD, our findings imply that correcting calcineurin and GSK-3β signaling can prevent APP-induced pathologies. Our data further suggest that upregulation of Nebula/DSCR1 is neuroprotective in the presence of APP upregulation and provides evidence for calcineurin inhibition as a novel target for therapeutic intervention in preventing axonal transport impairments associated with AD.
Katherine E. Yutzey - One of the best experts on this subject based on the ideXlab platform.
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restoration of DSCR1 to disomy in the trisomy 16 mouse model of down syndrome does not correct cardiac or craniofacial development anomalies
Developmental Dynamics, 2005Co-Authors: Alexander W. Lange, Beverly A Rothermel, Katherine E. YutzeyAbstract:The Down syndrome critical region 1 (DSCR1) gene is located in syntenic regions of human chromosome 21 and mouse chromosome 16 and encodes a regulatory protein in the calcineurin/NFAT pathway. DSCR1 expression in the embryonic brain, craniofacial structures, and heart is consistent with a role in contributing to Down syndrome developmental anomalies. In the trisomy 16 (Ts16) murine model of Down syndrome, expression of DSCR1 isoforms is elevated and NFAT transcriptional activity is decreased in the developing heart and brain. The individual contribution of DSCR1 to Down syndrome-related anomalies was examined by specific restoration of DSCR1 to disomic levels in Ts16 embryos. However, genetic restoration of DSCR1 did not rescue major morphological abnormalities in cardiac or craniofacial development. These data demonstrate that trisomy of DSCR1 alone does not significantly contribute to developmental defects in Ts16 mice and underscore the complexity of developmental anomalies associated with Down syndrome.
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DSCR1 gene expression is dependent on NFATc1 during cardiac valve formation and colocalizes with anomalous organ development in trisomy 16 mice
Developmental Biology, 2004Co-Authors: Alexander W. Lange, Jeffery D. Molkentin, Katherine E. YutzeyAbstract:Abstract The Down syndrome critical region 1 (DSCR1) gene is present in the region of human chromosome 21 and the syntenic region of mouse chromosome 16, trisomy of which is associated with congenital heart defects observed in Down syndrome. DSCR1 encodes a regulatory protein in the calcineurin/NFAT signal transduction pathway. During valvuloseptal development in the heart, DSCR1 is expressed in the endocardium of the developing atrioventricular and semilunar valves, the muscular interventricular septum, and the ventricular myocardium. Human DSCR1 contains an NFAT-rich calcineurin-responsive element adjacent to exon 4. Transgenic mice generated with a homologous regulatory region of the mouse DSCR1 gene linked to lacZ (DSCR1(e4)/lacZ) show gene activation in the endocardium of the developing valves and aorticopulmonary septum of the heart, recapitulating a specific subdomain of endogenous DSCR1 cardiac expression. DSCR1(e4)/lacZ expression in the developing valve endocardium colocalizes with NFATc1 and, endocardial DSCR1(e4)/lacZ, is notably reduced or absent in NFATc1−/− embryos. Furthermore, expression of the endogenous DSCR1(e4) isoform is decreased in the outflow tract of NFATc1−/− hearts, and the DSCR1(e4) intragenic element is trans-activated by NFATc1 in cell culture. In trisomy 16 (Ts16) mice, expression of endogenous DSCR1 and DSCR1(e4)/lacZ colocalizes with anomalous valvuloseptal development, and transgenic Ts16 hearts have increased β-galactosidase activity. DSCR1 and DSCR1(e4)/lacZ also are expressed in other organ systems affected by trisomy 16 in mice or trisomy 21 in humans including the brain, eye, ear, face, and limbs. Together, these results show that DSCR1(e4) expression in the developing valve endocardium is dependent on NFATc1 and support a role for DSCR1 in normal cardiac valvuloseptal formation as well as the abnormal development of several organ systems affected in individuals with Down syndrome.
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DSCR1 gene expression is dependent on nfatc1 during cardiac valve formation and colocalizes with anomalous organ development in trisomy 16 mice
Developmental Biology, 2004Co-Authors: Alexander W. Lange, Jeffery D. Molkentin, Katherine E. YutzeyAbstract:The Down syndrome critical region 1 (DSCR1) gene is present in the region of human chromosome 21 and the syntenic region of mouse chromosome 16, trisomy of which is associated with congenital heart defects observed in Down syndrome. DSCR1 encodes a regulatory protein in the calcineurin/NFAT signal transduction pathway. During valvuloseptal development in the heart, DSCR1 is expressed in the endocardium of the developing atrioventricular and semilunar valves, the muscular interventricular septum, and the ventricular myocardium. Human DSCR1 contains an NFAT-rich calcineurin-responsive element adjacent to exon 4. Transgenic mice generated with a homologous regulatory region of the mouse DSCR1 gene linked to lacZ (DSCR1(e4)/lacZ) show gene activation in the endocardium of the developing valves and aorticopulmonary septum of the heart, recapitulating a specific subdomain of endogenous DSCR1 cardiac expression. DSCR1(e4)/lacZ expression in the developing valve endocardium colocalizes with NFATc1 and, endocardial DSCR1(e4)/lacZ, is notably reduced or absent in NFATc1(-/-) embryos. Furthermore, expression of the endogenous DSCR1(e4) isoform is decreased in the outflow tract of NFATc1(-/-) hearts, and the DSCR1(e4) intragenic element is trans-activated by NFATc1 in cell culture. In trisomy 16 (Ts16) mice, expression of endogenous DSCR1 and DSCR1(e4)/lacZ colocalizes with anomalous valvuloseptal development, and transgenic Ts16 hearts have increased beta-galactosidase activity. DSCR1 and DSCR1(e4)/lacZ also are expressed in other organ systems affected by trisomy 16 in mice or trisomy 21 in humans including the brain, eye, ear, face, and limbs. Together, these results show that DSCR1(e4) expression in the developing valve endocardium is dependent on NFATc1 and support a role for DSCR1 in normal cardiac valvuloseptal formation as well as the abnormal development of several organ systems affected in individuals with Down syndrome.
Michael Baudis - One of the best experts on this subject based on the ideXlab platform.
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identification of a 21q22 duplication in a silver russell syndrome patient further narrows down the down syndrome critical region
American Journal of Medical Genetics Part A, 2010Co-Authors: Thomas Eggermann, Nadine Schonherr, Sabrina Spengler, Susanne Jager, Bernd Denecke, Gerhard Binder, Michael BaudisAbstract:Several duplications of chromosome 21q helped to narrow down the Down syndrome (DS) critical region (DSCR) to chromosomal band 21q22 with an approximate length of 5.4 Mb. Recently, it has been suggested that the facial gestalt of DS has been linked to the distal part of the DSCR whereas the proximal region harboring DSCR1/RCAN and DSCAM should be associated with the cardiac abnormalities. Here, we report on a patient with Silver-Russell syndrome (SRS) and a paternally inherited 0.46 Mb duplication in 21q22 affecting the KCNE1 and DSCR1/RCAN genes. The identification of an involvement of KCNE1 was interesting because it encodes the beta-subunit of the KvLQT1 channel as the slow component of the cardiac delayed rectifier K(+) current. Since duplication of the KCNQ1 gene encoding the alpha-subunit of the same channel was reported recently in another SRS patient, we screened both genes for mutations in a cohort of SRS patients without detecting pathologic variants. We presume that the duplication of the two functionally linked genes in different patients with the same disorder is a coincidental finding. However, the lack of DS typical clinical features in our case allows us to further narrow down the DSCR in 21q22. We conclude that DSCR1/RCAN is not sufficient for generating phenotypic features associated with DS but our observation does not contradict a possible role for DSCR1/RCAN in mediating DYRK1A-based effects. (c) 2010 Wiley-Liss, Inc.
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Identification of a 21q22 duplication in a Silver-Russell syndrome patient further narrows down the Down syndrome critical region.
American journal of medical genetics. Part A, 2010Co-Authors: Thomas Eggermann, Nadine Schonherr, Sabrina Spengler, Susanne Jager, Bernd Denecke, Gerhard Binder, Michael BaudisAbstract:Several duplications of chromosome 21q helped to narrow down the Down syndrome (DS) critical region (DSCR) to chromosomal band 21q22 with an approximate length of 5.4 Mb. Recently, it has been suggested that the facial gestalt of DS has been linked to the distal part of the DSCR whereas the proximal region harboring DSCR1/RCAN and DSCAM should be associated with the cardiac abnormalities. Here, we report on a patient with Silver-Russell syndrome (SRS) and a paternally inherited 0.46 Mb duplication in 21q22 affecting the KCNE1 and DSCR1/RCAN genes. The identification of an involvement of KCNE1 was interesting because it encodes the beta-subunit of the KvLQT1 channel as the slow component of the cardiac delayed rectifier K(+) current. Since duplication of the KCNQ1 gene encoding the alpha-subunit of the same channel was reported recently in another SRS patient, we screened both genes for mutations in a cohort of SRS patients without detecting pathologic variants. We presume that the duplication of the two functionally linked genes in different patients with the same disorder is a coincidental finding. However, the lack of DS typical clinical features in our case allows us to further narrow down the DSCR in 21q22. We conclude that DSCR1/RCAN is not sufficient for generating phenotypic features associated with DS but our observation does not contradict a possible role for DSCR1/RCAN in mediating DYRK1A-based effects.
Alexander W. Lange - One of the best experts on this subject based on the ideXlab platform.
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restoration of DSCR1 to disomy in the trisomy 16 mouse model of down syndrome does not correct cardiac or craniofacial development anomalies
Developmental Dynamics, 2005Co-Authors: Alexander W. Lange, Beverly A Rothermel, Katherine E. YutzeyAbstract:The Down syndrome critical region 1 (DSCR1) gene is located in syntenic regions of human chromosome 21 and mouse chromosome 16 and encodes a regulatory protein in the calcineurin/NFAT pathway. DSCR1 expression in the embryonic brain, craniofacial structures, and heart is consistent with a role in contributing to Down syndrome developmental anomalies. In the trisomy 16 (Ts16) murine model of Down syndrome, expression of DSCR1 isoforms is elevated and NFAT transcriptional activity is decreased in the developing heart and brain. The individual contribution of DSCR1 to Down syndrome-related anomalies was examined by specific restoration of DSCR1 to disomic levels in Ts16 embryos. However, genetic restoration of DSCR1 did not rescue major morphological abnormalities in cardiac or craniofacial development. These data demonstrate that trisomy of DSCR1 alone does not significantly contribute to developmental defects in Ts16 mice and underscore the complexity of developmental anomalies associated with Down syndrome.
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DSCR1 gene expression is dependent on NFATc1 during cardiac valve formation and colocalizes with anomalous organ development in trisomy 16 mice
Developmental Biology, 2004Co-Authors: Alexander W. Lange, Jeffery D. Molkentin, Katherine E. YutzeyAbstract:Abstract The Down syndrome critical region 1 (DSCR1) gene is present in the region of human chromosome 21 and the syntenic region of mouse chromosome 16, trisomy of which is associated with congenital heart defects observed in Down syndrome. DSCR1 encodes a regulatory protein in the calcineurin/NFAT signal transduction pathway. During valvuloseptal development in the heart, DSCR1 is expressed in the endocardium of the developing atrioventricular and semilunar valves, the muscular interventricular septum, and the ventricular myocardium. Human DSCR1 contains an NFAT-rich calcineurin-responsive element adjacent to exon 4. Transgenic mice generated with a homologous regulatory region of the mouse DSCR1 gene linked to lacZ (DSCR1(e4)/lacZ) show gene activation in the endocardium of the developing valves and aorticopulmonary septum of the heart, recapitulating a specific subdomain of endogenous DSCR1 cardiac expression. DSCR1(e4)/lacZ expression in the developing valve endocardium colocalizes with NFATc1 and, endocardial DSCR1(e4)/lacZ, is notably reduced or absent in NFATc1−/− embryos. Furthermore, expression of the endogenous DSCR1(e4) isoform is decreased in the outflow tract of NFATc1−/− hearts, and the DSCR1(e4) intragenic element is trans-activated by NFATc1 in cell culture. In trisomy 16 (Ts16) mice, expression of endogenous DSCR1 and DSCR1(e4)/lacZ colocalizes with anomalous valvuloseptal development, and transgenic Ts16 hearts have increased β-galactosidase activity. DSCR1 and DSCR1(e4)/lacZ also are expressed in other organ systems affected by trisomy 16 in mice or trisomy 21 in humans including the brain, eye, ear, face, and limbs. Together, these results show that DSCR1(e4) expression in the developing valve endocardium is dependent on NFATc1 and support a role for DSCR1 in normal cardiac valvuloseptal formation as well as the abnormal development of several organ systems affected in individuals with Down syndrome.
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DSCR1 gene expression is dependent on nfatc1 during cardiac valve formation and colocalizes with anomalous organ development in trisomy 16 mice
Developmental Biology, 2004Co-Authors: Alexander W. Lange, Jeffery D. Molkentin, Katherine E. YutzeyAbstract:The Down syndrome critical region 1 (DSCR1) gene is present in the region of human chromosome 21 and the syntenic region of mouse chromosome 16, trisomy of which is associated with congenital heart defects observed in Down syndrome. DSCR1 encodes a regulatory protein in the calcineurin/NFAT signal transduction pathway. During valvuloseptal development in the heart, DSCR1 is expressed in the endocardium of the developing atrioventricular and semilunar valves, the muscular interventricular septum, and the ventricular myocardium. Human DSCR1 contains an NFAT-rich calcineurin-responsive element adjacent to exon 4. Transgenic mice generated with a homologous regulatory region of the mouse DSCR1 gene linked to lacZ (DSCR1(e4)/lacZ) show gene activation in the endocardium of the developing valves and aorticopulmonary septum of the heart, recapitulating a specific subdomain of endogenous DSCR1 cardiac expression. DSCR1(e4)/lacZ expression in the developing valve endocardium colocalizes with NFATc1 and, endocardial DSCR1(e4)/lacZ, is notably reduced or absent in NFATc1(-/-) embryos. Furthermore, expression of the endogenous DSCR1(e4) isoform is decreased in the outflow tract of NFATc1(-/-) hearts, and the DSCR1(e4) intragenic element is trans-activated by NFATc1 in cell culture. In trisomy 16 (Ts16) mice, expression of endogenous DSCR1 and DSCR1(e4)/lacZ colocalizes with anomalous valvuloseptal development, and transgenic Ts16 hearts have increased beta-galactosidase activity. DSCR1 and DSCR1(e4)/lacZ also are expressed in other organ systems affected by trisomy 16 in mice or trisomy 21 in humans including the brain, eye, ear, face, and limbs. Together, these results show that DSCR1(e4) expression in the developing valve endocardium is dependent on NFATc1 and support a role for DSCR1 in normal cardiac valvuloseptal formation as well as the abnormal development of several organ systems affected in individuals with Down syndrome.
