The Experts below are selected from a list of 45465 Experts worldwide ranked by ideXlab platform
Eric N Olson - One of the best experts on this subject based on the ideXlab platform.
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requirement of a myocardin related transcription factor for development of mammary myoepithelial cells
Molecular and Cellular Biology, 2006Co-Authors: Shijie Li, James A Richardson, Shurong Chang, Xiaoxia Qi, Eric N OlsonAbstract:The mammary gland consists of a branched ductal system comprised of milk-producing epithelial cells that form ductile tubules surrounded by a myoepithelial cell layer that provides contractility required for milk ejection. Myoepithelial cells bear a striking resemblance to smooth muscle cells, but they are derived from a different embryonic cell lineage, and little is known of the mechanisms that control their differentiation. Members of the myocardin family of transcriptional coactivators cooperate with serum response factor to activate smooth muscle gene expression. We show that female mice homozygous for a Loss-of-Function Mutation of the myocardin-related transcription factor A (MRTF-A) gene are unable to effectively nurse their offspring due to a failure in maintenance of the differentiated state of mammary myoepithelial cells during lactation, resulting in apoptosis of this cell population, a consequent inability to release milk, and premature involution. The phenotype of MRTF-A mutant mice reveals a specific and essential role for MRTF-A in mammary myoepithelial cell differentiation and points to commonalities in the transcriptional mechanisms that control differentiation of smooth muscle and myoepithelial cells.
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requirement of myocardin related transcription factor b for remodeling of branchial arch arteries and smooth muscle differentiation
Proceedings of the National Academy of Sciences of the United States of America, 2005Co-Authors: Jiyeon Oh, James A Richardson, Eric N OlsonAbstract:Myocardin and the myocardin-related transcription factors (MRTFs) A and B act as coactivators for serum response factor, which plays a key role in cardiovascular development. To determine the functions of MRTF-B in vivo, we generated MRTF-B mutant mice by targeted inactivation of the MRTF-B gene. We show that mice homozygous for an MRTF-B Loss-of-Function Mutation die during mid-gestation from a spectrum of cardiovascular defects that includes abnormal patterning of the branchial arch arteries, double-outlet right ventricle, ventricular septal defects, and thin-walled myocardium. These abnormalities are accompanied by a failure in differentiation of smooth muscle cells within the branchial arch arteries, which are derived from the neural crest. The phenotype of MRTF-B mutant mice is distinct from that of mice lacking myocardin, revealing unique roles for these serum response factor coactivators in the development of different subsets of smooth muscle cells in vivo.
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the serum response factor coactivator myocardin is required for vascular smooth muscle development
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Shijie Li, James A Richardson, Zhigao Wang, Dazhi Wang, Eric N OlsonAbstract:Formation of the vascular system requires differentiation and patterning of endothelial and smooth muscle cells (SMCs). Although much attention has focused on development of the vascular endothelial network, the mechanisms that control vascular SMC development are largely unknown. Myocardin is a smooth and cardiac muscle-specific transcriptional coactivator of serum response factor, a ubiquitous transcription factor implicated in smooth muscle gene expression. When expressed ectopically in nonmuscle cells, myocardin can induce smooth muscle differentiation by its association with serum response factor. Here we report that mouse embryos homozygous for a myocardin Loss-of-Function Mutation die by embryonic day 10.5 and show no evidence of vascular SMC differentiation. Myocardin is the only transcription factor known to be necessary and sufficient for vascular SMC differentiation.
Nicolas De Roux - One of the best experts on this subject based on the ideXlab platform.
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A novel Loss-of-Function Mutation in GPR54/KISS1R leads to hypogonadotropic hypogonadism in a highly consanguineous family.
The Journal of clinical endocrinology and metabolism, 2010Co-Authors: Revital Nimri, Nicolas De Roux, Yael Lebenthal, Liora Lazar, Lucie Chevrier, Moshe Phillip, Eva Hernandez-mora, Galia Gat-yablonskiAbstract:The G protein-coupled receptor 54 (GPR54), the kisspeptin receptor, is essential for stimulation of GnRH secretion and induction of puberty. Recently Loss-of-Function Mutations of the GPR54 have been implicated as a cause of isolated idiopathic hypogonadotropic hypogonadism (IHH). The objective of the study was to identify the genetic cause of IHH in a consanguineous pedigree and to characterize the phenotypic features from infancy through early adulthood. In six patients with normosmic IHH belonging to two families of Israeli Muslim-Arab origin highly related to one another, DNA was analyzed for Mutations in the GnRHR and GPR54 genes, with functional analysis of the Mutation found. The five males underwent comprehensive endocrine evaluation and were under longitudinal follow-up; the one female presented in early adulthood. A new homozygous Mutation (c.T815C) in GPR54 leading to a phenylalanine substitution by serine (p.F272S) was detected in all patients. Functional analysis showed an almost complete inhibition of kisspeptin-induced GPR54 signaling and a dramatic decrease of the mutated receptor expression at the cell surface. The males exhibited the same clinical features from infancy to adulthood, characterized by cryptorchidism, a relatively short penis, and no spontaneous pubertal development. The female patient presented at 18 yr with impuberism and primary amenorrhea. Repeated stimulation tests demonstrated complete gonadotropin deficiency throughout follow-up. A novel Loss-of-Function Mutation (p.F272S) in the GPR54 gene is associated with familial normosmic IHH. Underdeveloped external genitalia and impuberism point to the major role of GPR54 in the activation of the gonadotropic axis from intrauterine life to adulthood.
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A novel Loss-of-Function Mutation in GPR54/KISS1R leads to hypogonadotropic hypogonadism in a highly consanguineous family.
The Journal of Clinical Endocrinology and Metabolism, 2010Co-Authors: Revital Nimri, Nicolas De Roux, Yael Lebenthal, Liora Lazar, Lucie Chevrier, Moshe Phillip, Eva Hernandez-mora, Galia Gat-yablonskiAbstract:A novel Loss-of-Function Mutation (p.F272S) in the GPR54 gene is associated with complete familial normosmic hypogonadotropic hypogonadism manifested from infancy to adulthood.
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paediatric phenotype of kallmann syndrome due to Mutations of fibroblast growth factor receptor 1 fgfr1
Molecular and Cellular Endocrinology, 2006Co-Authors: Delphine Zenaty, Juliane Leger, Patricia Bretones, Cecile Lambe, Isabelle Guemas, M David, Nicolas De RouxAbstract:Abstract Kallmann syndrome characterised by hypogonadotropic hypogonadism (HH) and anosmia is genetically heterogeneous with X-linked, autosomal dominant and autosomal recessive forms. The autosomal dominant form due to loss of function Mutation in the fibroblast growth factor receptor 1 (FGFR1) accounts for about 10% of cases. We report here three paediatric cases of Kallmann syndrome with unusual phenotype in two unrelated patients with severe ear anomalies (hypoplasia or agenesis of external ear) associated with classical features, such as cleft palate, dental agenesis, syndactylia, micropenis and cryptorchidism. We found de novo Mutation in these two patients (Cys178Ser and Arg622Gly, respectively), and one inherited Arg622Gln Mutation with intrafamilial variable phenotype. These genotype–phenotype correlations indicate that paediatric phenotypic expression of FGFR1 loss of function Mutations is highly variable, the severity of the oro-facial malformations at birth does not predict gonadotropic function at the puberty and that de novo Mutations of FGFR1 are relatively frequent.
Miriam L Greenberg - One of the best experts on this subject based on the ideXlab platform.
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Deficiency in mitochondrial anionic phospholipid synthesis impairs cell wall biogenesis.
Biochemical Society transactions, 2020Co-Authors: Q. Zhong, Miriam L GreenbergAbstract:Cardiolipin (CL) is the signature lipid of the mitochondrial membrane and plays a key role in mitochondrial physiology and cell viability. The importance of CL is underscored by the finding that the severe genetic disorder Barth syndrome results from defective CL composition and acylation. Disruption of PGS1, which encodes the enzyme that catalyses the committed step of CL synthesis, results in loss of the mitochondrial anionic phospholipids phosphatidylglycerol and CL. The pgs1Delta mutant exhibits severe growth defects at 37 degrees C. To understand the essential functions of mitochondrial anionic lipids at elevated temperatures, we isolated suppressors of pgs1Delta that grew at 37 degrees C. The present review summarizes our analysis of suppression of pgs1Delta growth defects by a mutant that has a Loss-of-Function Mutation in KRE5, a gene involved in cell wall biogenesis.
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deficiency in mitochondrial anionic phospholipid synthesis impairs cell wall biogenesis
Biochemical Society Transactions, 2005Co-Authors: Q. Zhong, Miriam L GreenbergAbstract:Cardiolipin (CL) is the signature lipid of the mitochondrial membrane and plays a key role in mitochondrial physiology and cell viability. The importance of CL is underscored by the finding that the severe genetic disorder Barth syndrome results from defective CL composition and acylation. Disruption of PGS1 ,w hich encodes the enzyme that catalyses the committed step of CL synthesis, results in loss of the mitochondrial anionic phospholipids phosphatidylglycerol and CL. The pgs1∆ mutant exhibits severe growth defects at 37 ◦ C. To understand the essential functions of mitochondrial anionic lipids at elevated temperatures, we isolated suppressors of pgs1∆ that grew at 37 ◦ C. The present review summarizes our analysis of suppression of pgs1∆ growth defects by a mutant that has a Loss-of-Function Mutation in KRE5, a gene involved in cell
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Deficiency in mitochondrial anionic phospholipid synthesis impairs cell wall biogenesis
Biochemical Society Transactions, 2005Co-Authors: Q. Zhong, Miriam L GreenbergAbstract:Cardiolipin (CL) is the signature lipid of the mitochondrial membrane and plays a key role in mitochondrial physiology and cell viability. The importance of CL is underscored by the finding that the severe genetic disorder Barth syndrome results from defective CL composition and acylation. Disruption of PGS1, which encodes the enzyme that catalyses the committed step of CL synthesis, results in loss of the mitochondrial anionic phospholipids phosphatidylglycerol and CL. The pgs1Δ mutant exhibits severe growth defects at 37°C. To understand the essential functions of mitochondrial anionic lipids at elevated temperatures, we isolated suppressors of pgs1Δ that grew at 37°C. The present review summarizes our analysis of suppression of pgs1Δ growth defects by a mutant that has a Loss-of-Function Mutation in KRE5, a gene involved in cell wall biogenesis.
Yiqing Yang - One of the best experts on this subject based on the ideXlab platform.
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a shox2 loss of function Mutation underlying familial atrial fibrillation
International Journal of Medical Sciences, 2018Co-Authors: Ning Li, Ruo-min Di, Ying-jia Xu, Ruo-gu Li, Xiu-mei Li, Zhangsheng Wang, Xinhua Wang, Min Zhang, Qi Qiao, Yiqing YangAbstract:: Atrial fibrillation (AF), as the most common sustained cardiac arrhythmia, is associated with substantially increased morbidity and mortality. Aggregating evidence demonstrates that genetic defects play a crucial role in the pathogenesis of AF, especially in familial AF. Nevertheless, AF is of pronounced genetic heterogeneity, and in an overwhelming majority of cases the genetic determinants underlying AF remain elusive. In the current study, 162 unrelated patients with familial AF and 238 unrelated healthy individuals served as controls were recruited. The coding exons and splicing junction sites of the SHOX2 gene, which encodes a homeobox-containing transcription factor essential for proper development and function of the cardiac conduction system, were sequenced in all study participants. The functional effect of the mutant SHOX2 protein was characterized with a dual-luciferase reporter assay system. As a result, a novel heterozygous SHOX2 Mutation, c.580C>T or p.R194X, was identified in an index patient, which was absent from the 476 control chromosomes. Genetic analysis of the proband's pedigree revealed that the nonsense Mutation co-segregated with AF in the family with complete penetrance. Functional assays demonstrated that the mutant SHOX2 protein had no transcriptional activity compared with its wild-type counterpart. In conclusion, this is the first report on the association of SHOX2 Loss-of-Function Mutation with enhanced susceptibility to familial AF, which provides novel insight into the molecular mechanism underpinning AF, suggesting potential implications for genetic counseling and individualized management of AF patients.
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MEF2C Loss-of-Function Mutation contributes to congenital heart defects.
International Journal of Medical Sciences, 2017Co-Authors: Xiao-hui Qiao, Ritai Huang, Juan Wang, Fei Wang, Xian-ling Zhang, Yiqing YangAbstract:Congenital heart defect (CHD) is the most common form of birth deformity and is responsible for substantial morbidity and mortality in humans. Increasing evidence has convincingly demonstrated that genetic defects play a pivotal role in the pathogenesis of CHD. However, CHD is a genetically heterogeneous disorder and the genetic basis underpinning CHD in the vast majority of cases remains elusive. This study was sought to identify the pathogenic Mutation in the ISL1 gene contributing to CHD. A cohort of 210 unrelated patients with CHD and a total of 256 unrelated healthy individuals used as controls were registered. The coding exons and splicing boundaries of ISL1 were sequenced in all study subjects. The functional effect of an identified ISL1 Mutation was evaluated using a dual-luciferase reporter assay system. A novel heterozygous ISL1 Mutation, c.409G > T or p.E137X, was identified in an index patient with congenital patent ductus arteriosus and ventricular septal defect. Analysis of the proband’s pedigree revealed that the Mutation co-segregated with CHD, which was transmitted in the family in an autosomal dominant pattern with complete penetrance. The nonsense Mutation was absent in 512 control chromosomes. Functional analysis unveiled that the mutant ISL1 protein failed to transactivate the promoter of MEF2C, alone or in synergy with TBX20. This study firstly implicates ISL1 Loss-of-Function Mutation with CHD in humans, which provides novel insight into the molecular mechanism of CHD, implying potential implications for genetic counseling and individually tailored treatment of CHD patients.
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HAND1 Loss-of-Function Mutation Causes Tetralogy of Fallot.
Pediatric Cardiology, 2016Co-Authors: Juan Wang, Ning Li, Xiao-qing Hu, Jian-yun Gu, Jiahong Xu, Yan-jie Li, Xiao-xiao Yang, Yiqing YangAbstract:As the most prevalent form of birth defect in humans worldwide, congenital heart disease (CHD) is responsible for substantial morbidity and is still the leading cause of birth defect-related demises. Increasing evidence demonstrates that genetic defects play an important role in the pathogenesis of CHD, and Mutations in multiple genes, especially in those coding for cardiac core transcription factors, have been causally linked to various CHDs. Nevertheless, CHD is a genetically heterogeneous disease and the genetic determinants underpinning CHD in an overwhelming majority of patients remain elusive. In the current study, genomic DNA was extracted from venous blood samples of 165 unrelated patients with CHD, and the coding exons and splicing junction sites of the HAND1 gene, which encodes a basic helix-loop-helix transcription factor essential for cardiovascular development, were sequenced. As a result, a novel heterozygous Mutation, p.R118C, was identified in a patient with tetralogy of Fallot (TOF). The missense Mutation, which was absent in 600 referential chromosomes, altered the amino acid that was completely conserved evolutionarily. Biological assays with a dual-luciferase reporter assay system revealed that the R118C-mutant HAND1 protein had significantly reduced transcriptional activity when compared with its wild-type counterpart. Furthermore, the Mutation significantly decreased the synergistic activation of a downstream target gene between HAND1 and GATA4, another cardiac core transcription factor associated with TOF. To our knowledge, this is the first report on the association of a HAND1 Loss-of-Function Mutation with enhanced susceptibility to TOF in humans. The findings provide novel insight into the molecular etiology underlying TOF, suggesting potential implications for the improved prophylactic and therapeutic strategies for TOF.
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PITX2 Loss-of-Function Mutation contributes to tetralogy of Fallot.
Gene, 2015Co-Authors: Jun Wang, Ying-jia Xu, Ruo-gu Li, Ritai Huang, Fang Yuan, Xin-kai Qu, Yiqing YangAbstract:Congenital heart disease (CHD) is the most prevalent developmental abnormality in humans and is the most common non-infectious cause of infant morbidity and mortality. Increasing evidence demonstrates that genetic defects are involved in the pathogenesis of CHD. However, CHD is genetically heterogeneous, and the genetic determinants underpinning CHD in most patients remain unknown. In this study, the whole coding region of the PITX2 gene (isoform c) was sequenced in 185 unrelated patients with CHD. The available relatives of a Mutation carrier and 300 unrelated healthy individuals used as controls were also genotyped for PITX2. The functional characteristics of the Mutation were delineated by using a dual-luciferase reporter assay system. As a result, a novel heterozygous PITX2 Mutation, p.Q102L, was identified in a patient with tetralogy of Fallot (TOF). Genetic analysis of the index patient's pedigree showed that the Mutation co-segregated with TOF. The Mutation was absent in 600 reference chromosomes. Biochemical analysis revealed that the Q102L-mutant PITX2 is associated with significantly reduced transcriptional activity compared with its wild-type counterpart. Furthermore, the Mutation markedly decreased the synergistic activation between PITX2 and NKX2-5. This study firstly associates PITX2 Loss-of-Function Mutation with increased susceptibility to TOF, providing novel insight into the molecular mechanism of CHD.
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a novel pitx2c loss of function Mutation associated with familial atrial fibrillation
European Journal of Medical Genetics, 2014Co-Authors: Jun Wang, Daifu Zhang, Yiqing YangAbstract:Abstract Atrial fibrillation (AF) represents the most prevalent form of sustained cardiac arrhythmia and contributes substantially to cardiovascular morbidity and mortality. Aggregating evidence demonstrates that genetic risk factors play an important role in the pathogenesis of AF. However, AF is a genetically heterogeneous disease and the genetic defects responsible for AF in an overwhelming majority of patients remain unclear. In the present study, the whole coding region and splice junction sites of the PITX2c gene, which encodes a paired-like homeobox transcription factor essential for normal cardiovascular development, were sequenced in 160 unrelated patients with lone AF, and a novel heterozygous Mutation, c.349C > T equivalent to p.P117S, was identified in a patient with positive family history of AF. The missense Mutation, which co-segregated with AF in the family with complete penetrance and was absent in 700 unrelated ethnically matched healthy individuals, altered the amino acid completely conserved evolutionarily across species and was predicted to be pathogenic by MutationTaster and PolyPhen-2. Biological assays revealed that the mutant PITX2c protein was associated with significantly decreased transcriptional activity when compared with its wild-type counterpart. The findings implicate PITX2c Loss-of-Function Mutation in familial AF for the first time, providing novel insight into the molecular pathology of AF.
Daniella Magen - One of the best experts on this subject based on the ideXlab platform.
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Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with a Loss-of-Function Mutation in CDK5
Human Genetics, 2015Co-Authors: Daniella Magen, Ayala Ofir, Liron Berger, Dorit Goldsher, Ayelet Eran, Nassser Katib, Yousif Nijem, Euvgeni Vlodavsky, Doron M. Behar, Yakov FelligAbstract:Lissencephaly comprises a heterogeneous group of developmental brain disorders of varying severity, involving abnormal cortical gyration. We studied a highly consanguineous Israeli Moslem family with a lethal form of autosomal recessive lissencephaly with cerebellar hypoplasia (LCH). Using microarray-based homozygosity mapping in the reported family, combined with whole exome sequencing in one affected infant, we identified a homozygous splice site Mutation g.IVS8+1G>A in cyclin-dependent kinase 5 ( CDK5 ), causing complete skipping of exon 8, and leading to a frame shift and premature stop codon (p.V162S fs X19). The Mutation co-segregated with the disease phenotype in all 29 study participants (4 patients and 25 healthy relatives), and was not identified in 200 ethnically matched control chromosomes. The p.V162S fs X19 Mutation causes lack of endogenous CDK5 expression in affected dermal fibroblasts and brain tissue at the mRNA and protein levels, consistent with nonsense-mediated mRNA decay. Functional analysis of the p.V162S fs X19 Mutation, using a yeast complementation assay, showed Loss-of-Function of the mutant CDK5 gene product, thereby implicating its role in the pathogenesis of autosomal recessive LCH in the studied family.
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erratum to autosomal recessive lissencephaly with cerebellar hypoplasia is associated with a loss of function Mutation in cdk5
Human Genetics, 2015Co-Authors: Daniella Magen, Ayala Ofir, Liron Berger, Dorit Goldsher, Ayelet Eran, Nassser Katib, Yousif NijemAbstract:Lissencephaly comprises a heterogeneous group of developmental brain disorders of varying severity, involving abnormal cortical gyration. We studied a highly consanguineous Israeli Moslem family with a lethal form of autosomal recessive lissencephaly with cerebellar hypoplasia (LCH). Using microarray-based homozygosity mapping in the reported family, combined with whole exome sequencing in one affected infant, we identified a homozygous splice site Mutation g.IVS8+1G>A in cyclin-dependent kinase 5 (CDK5), causing complete skipping of exon 8, and leading to a frame shift and premature stop codon (p.V162SfsX19). The Mutation co-segregated with the disease phenotype in all 29 study participants (4 patients and 25 healthy relatives), and was not identified in 200 ethnically matched control chromosomes. The p.V162SfsX19 Mutation causes lack of endogenous CDK5 expression in affected dermal fibroblasts and brain tissue at the mRNA and protein levels, consistent with nonsense-mediated mRNA decay. Functional analysis of the p.V162SfsX19 Mutation, using a yeast complementation assay, showed Loss-of-Function of the mutant CDK5 gene product, thereby implicating its role in the pathogenesis of autosomal recessive LCH in the studied family.
