The Experts below are selected from a list of 75879 Experts worldwide ranked by ideXlab platform
Jorieke E H Bergman - One of the best experts on this subject based on the ideXlab platform.
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a novel classification system to predict the pathogenic effects of CHD7 missense variants in charge syndrome
Human Mutation, 2012Co-Authors: Jorieke E H Bergman, Lies H. Hoefsloot, Nicole Janssen, Almer M Van Der Sloot, Hermien E K De Walle, Jeroen Schoots, Nanna D Rendtorff, Lisbeth Tranebjaerg, Conny M A Van RavenswaaijartsAbstract:CHARGE syndrome is characterized by the variable occurrence of multisensory impairment, congenital anomalies, and developmental delay, and is caused by heterozygous mutations in the CHD7 gene. Correct interpretation of CHD7 variants is essential for genetic counseling. This is particularly difficult for missense variants because most variants in the CHD7 gene are private and a functional assay is not yet available. We have therefore developed a novel classification system to predict the pathogenic effects of CHD7 missense variants that can be used in a diagnostic setting. Our classification system combines the results from two computational algorithms (PolyPhen-2 and Align-GVGD) and the prediction of a newly developed structural model of the chromo- and helicase domains of CHD7 with segregation and phenotypic data. The combination of different variables will lead to a more confident prediction of pathogenicity than was previously possible. We have used our system to classify 145 CHD7 missense variants. Our data show that pathogenic missense mutations are mainly present in the middle of the CHD7 gene, whereas benign variants are mainly clustered in the 5' and 3' regions. Finally, we show that CHD7 missense mutations are, in general, associated with a milder phenotype than truncating mutations.
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the results of CHD7 analysis in clinically well characterized patients with kallmann syndrome
The Journal of Clinical Endocrinology and Metabolism, 2012Co-Authors: Jorieke E H Bergman, Marjolijn C J Jongmans, Lies H. Hoefsloot, Willem De Ronde, Bruce H R Wolffenbuttel, Sten L S Drop, Ad R M M Hermus, Gianni Bocca, Conny M A Van RavenswaaijartsAbstract:CONTEXT: Kallmann syndrome (KS) and CHARGE syndrome are rare heritable disorders in which anosmia and hypogonadotropic hypogonadism co-occur. KS is genetically heterogeneous, and there are at least eight genes involved in its pathogenesis, whereas CHARGE syndrome is caused by autosomal dominant mutations in only one gene, the CHD7 gene. Two independent studies showed that CHD7 mutations can also be found in a minority of KS patients. OBJECTIVE: We aimed to investigate whether CHD7 mutations can give rise to isolated KS or whether additional features of CHARGE syndrome always occur. DESIGN: We performed CHD7 analysis in a cohort of 36 clinically well-characterized Dutch patients with KS but without mutations in KAL1 and with known status for the KS genes with incomplete penetrance, FGFR1, PROK2, PROKR2, and FGF8. RESULTS: We identified three heterozygous CHD7 mutations. The CHD7-positive patients were carefully reexamined and were all found to have additional features of CHARGE syndrome. CONCLUSION: The yield of CHD7 analysis in patients with isolated KS seems very low but increases when additional CHARGE features are present. Therefore, we recommend performing CHD7 analysis in KS patients who have at least two additional CHARGE features or semicircular canal anomalies. Identifying a CHD7 mutation has important clinical implications for the surveillance and genetic counseling of patients.
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the results of CHD7 analysis in clinically well characterized patients with kallmann syndrome
The Journal of Clinical Endocrinology and Metabolism, 2012Co-Authors: Jorieke E H Bergman, Marjolijn C J Jongmans, Lies H. Hoefsloot, Willem De Ronde, Bruce H R Wolffenbuttel, Sten L S Drop, Ad R M M Hermus, Gianni Bocca, Conny M A Van RavenswaaijartsAbstract:Context: Kallmann syndrome (KS) and CHARGE syndrome are rare heritable disorders in which anosmia and hypogonadotropic hypogonadism co-occur. KS is genetically heterogeneous, and there are at least eight genes involved in its pathogenesis, whereas CHARGE syndrome is caused by autosomal dominant mutations in only one gene, the CHD7 gene. Two independent studies showed that CHD7 mutations can also be found in a minority of KS patients. Objective: We aimed to investigate whether CHD7 mutations can give rise to isolated KS or whether additional features of CHARGE syndrome always occur. Design: We performed CHD7 analysis in a cohort of 36 clinically well-characterized Dutch patients with KS but without mutations in KAL1 and with known status for the KS genes with incomplete penetrance, FGFR1, PROK2, PROKR2, and FGF8. Results: We identified three heterozygous CHD7 mutations. The CHD7-positive patients were carefully reexamined and were all found to have additional features of CHARGE syndrome. Conclusion: The yi...
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CHD7 mutations and charge syndrome the clinical implications of an expanding phenotype
Journal of Medical Genetics, 2011Co-Authors: Jorieke E H Bergman, Marjolijn C J Jongmans, Lies H. Hoefsloot, N Janssen, Robert M W Hofstra, C M A Van RavenswaaijartsAbstract:Background CHARGE syndrome is a highly variable, multiple congenital anomaly syndrome, of which the complete phenotypic spectrum was only revealed after identification of the causative gene in 2004. CHARGE is an acronym for ocular coloboma, congenital heart defects, choanal atresia, retardation of growth and development, genital hypoplasia, and ear anomalies associated with deafness. This typical combination of clinical features is caused by autosomal dominant mutations in the CHD7 gene. Objective To explore the emerging phenotypic spectrum of CHD7 mutations, with a special focus on the mild end of the spectrum. Methods We evaluated the clinical characteristics in our own cohort of 280 CHD7 positive patients and in previously reported patients with CHD7 mutations and compared these with previously reported patients with CHARGE syndrome but an unknown CHD7 status. We then further explored the mild end of the phenotypic spectrum of CHD7 mutations. Results We discuss that CHARGE syndrome is primarily a clinical diagnosis. In addition, we propose guidelines for CHD7 analysis and indicate when evaluation of the semicircular canals is helpful in the diagnostic process. Finally, we give updated recommendations for clinical surveillance of patients with a CHD7 mutation, based on our exploration of the phenotypic spectrum and on our experience in a multidisciplinary outpatient clinic for CHARGE syndrome. Conclusion CHARGE syndrome is an extremely variable clinical syndrome. CHD7 analysis can be helpful in the diagnostic process, but the phenotype cannot be predicted from the genotype.
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CHD8 interacts with CHD7, a protein which is mutated in CHARGE syndrome
Human molecular genetics, 2010Co-Authors: Tserendulam Batsukh, Jorieke E H Bergman, Lasse Pieper, Anna M. Koszucka, Nina Von Velsen, Sigrid Hoyer-fender, Miriam Elbracht, Lies H. Hoefsloot, Silke PauliAbstract:CHARGE syndrome is an autosomal dominant disorder caused in about two-third of cases by mutations in the CHD7 gene. For other genetic diseases e.g. hereditary spastic paraplegia, it was shown that interacting partners are involved in the underlying cause of the disease. These data encouraged us to search for CHD7 binding partners by a yeast two-hybrid library screen and CHD8 was identified as an interacting partner. The result was confirmed by a direct yeast two-hybrid analysis, co-immunoprecipitation studies and by a bimolecular fluorescence complementation assay. To investigate the function of CHD7 missense mutations in the CHD7-CHD8 interacting area on the binding capacity of both proteins, we included three known missense mutations (p.His2096Arg, p.Val2102Ile and p.Gly2108Arg) and one newly identified missense mutation (p.Trp2091Arg) in the CHD7 gene and performed both direct yeast two-hybrid and co-immunoprecipitation studies. In the direct yeast two-hybrid system, the CHD7-CHD8 interaction was disrupted by the missense mutations p.Trp2091Arg, p.His2096Arg and p.Gly2108Arg, whereas in the co-immunoprecipitation studies disruption of the CHD7-CHD8 interaction by the mutations could not be observed. The results lead to the hypothesis that CHD7 and CHD8 proteins are interacting directly and indirectly via additional linker proteins. Disruption of the direct CHD7-CHD8 interaction might change the conformation of a putative large CHD7-CHD8 complex and could be a disease mechanism in CHARGE syndrome.
Donna M. Martin - One of the best experts on this subject based on the ideXlab platform.
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chromatin remodeler CHD7 is critical for cochlear morphogenesis and neurosensory patterning
Developmental Biology, 2021Co-Authors: Vinodh Balendran, Elizabeth A Hurd, Jennifer M Skidmore, Yehoash Raphael, Elaine K Ritter, Jingxia Gao, Jelka Cimerman, Lisa A Beyer, Donna M. MartinAbstract:Epigenetic regulation of gene transcription by chromatin remodeling proteins has recently emerged as an important contributing factor in inner ear development. Pathogenic variants in CHD7, the gene encoding Chromodomain Helicase DNA binding protein 7, cause CHARGE syndrome, which presents with malformations in the developing ear. CHD7 is broadly expressed in the developing mouse otocyst and mature auditory epithelium, yet the pathogenic effects of CHD7 loss in the cochlea are not well understood. Here we characterized cochlear epithelial phenotypes in mice with deletion of CHD7 throughout the otocyst (using Foxg1Cre/+ and Pax2Cre), in the otic mesenchyme (using TCre), in hair cells (using Atoh1Cre), in developing neuroblasts (using NgnCre), or in spiral ganglion neurons (using ShhCre/+). Pan-otic deletion of CHD7 resulted in shortened cochleae with aberrant projections and axonal looping, disorganized, supernumerary hair cells at the apical turn and a narrowed epithelium with missing hair cells in the middle region. Deletion of CHD7 in the otic mesenchyme had no effect on overall cochlear morphology. Loss of CHD7 in hair cells did not disrupt their formation or organization of the auditory epithelium. Similarly, absence of CHD7 in spiral ganglion neurons had no effect on axonal projections. In contrast, deletion of CHD7 in developing neuroblasts led to smaller spiral ganglia and disorganized cochlear neurites. Together, these observations reveal dosage-, tissue-, and time-sensitive cell autonomous roles for CHD7 in cochlear elongation and cochlear neuron organization, with minimal functions for CHD7 in hair cells. These studies provide novel information about roles for CHD7 in development of auditory neurons.
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atypical phenotypes associated with pathogenic CHD7 variants and a proposal for broadening charge syndrome clinical diagnostic criteria
American Journal of Medical Genetics Part A, 2016Co-Authors: Caitlin L Hale, Adrienne N Niederriter, Glenn E Green, Donna M. MartinAbstract:CHARGE syndrome (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth and/or development, Genital and/or urinary anomalies, and Ear malformations, including deafness and vestibular disorders) is a genetic condition characterized by a specific and recognizable pattern of features. Heterozygous pathogenic variants in the chromodomain helicase DNA-binding protein 7 (CHD7) are the major cause of CHARGE syndrome, and have been identified in 70-90% of individuals fulfilling clinical diagnostic criteria. Since 2004, when CHD7 was discovered as the causative gene for CHARGE syndrome, the phenotypic spectrum associated with pathogenic CHD7 variants has expanded. Predicted pathogenic CHD7 variants have been identified in individuals with isolated features of CHARGE including autism and hypogonadotropic hypogonadism. Here, we present genotype and phenotype data from a cohort of 28 patients who were considered for a diagnosis of CHARGE syndrome, including one patient with atypical presentations and a pathogenic CHD7 variant. We also summarize published literature on pathogenic CHD7 variant positive individuals who have atypical clinical presentations. Lastly, we propose a revision to current clinical diagnostic criteria, including broadening of the major features associated with CHARGE syndrome and addition of pathogenic CHD7 variant status as a major criterion.
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CHD7 functions in the nucleolus as a positive regulator of ribosomal rna biogenesis
Human Molecular Genetics, 2010Co-Authors: Gabriel E Zentner, Michael P Schnetz, Lusy Handoko, Elizabeth A Hurd, Chuanping Wang, Zhenghe Wang, Chialin Wei, Paul J Tesar, Maria Hatzoglou, Donna M. MartinAbstract:De novo mutation of the gene encoding chromodomain helicase DNA-binding protein 7 (CHD7) is the primary cause of CHARGE syndrome, a complex developmental disorder characterized by the co-occurrence of a specific set of birth defects. Recent studies indicate that CHD7 functions as a transcriptional regulator in the nucleoplasm. Here, we report based on immunofluorescence and western blotting of subcellular fractions that CHD7 is also constitutively localized to the nucleolus, the site of rRNA transcription. Standard chromatin immunoprecipitation (ChIP) assays indicate that CHD7 physically associates with rDNA, a result that is also observable upon alignment of whole-genome CHD7 ChIP coupled with massively parallel DNA sequencing data to the rDNA reference sequence. ChIP-chop analyses demonstrate that CHD7 specifically associates with hypomethylated, active rDNA, suggesting a role as a positive regulator of rRNA synthesis. Consistent with this hypothesis, siRNA-mediated depletion of CHD7 results in hypermethylation of the rDNA promoter and a concomitant reduction of 45S pre-rRNA levels. Accordingly, cells overexpressing CHD7 show increased levels of 45S pre-rRNA compared with control cells. Depletion of CHD7 also reduced cell proliferation and protein synthesis. Lastly, compared with wild-type ES cells, the levels of 45S pre-rRNA are reduced in both CHD7(+/-) and CHD7(-/-) mouse ES cells, as well as in CHD7(-/-) whole mouse embryos and multiple tissues dissected from CHD7(+/-) embryos. Together with previously published studies, these results indicate that CHD7 dually functions as a regulator of both nucleoplasmic and nucleolar genes and provide a novel avenue for investigation into the pathogenesis of CHARGE syndrome.
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chromodomain proteins in development lessons from charge syndrome
Clinical Genetics, 2010Co-Authors: Wanda S Layman, Elizabeth A Hurd, Donna M. MartinAbstract:In humans, heterozygous mutations in the ATP-dependent chromatin remodeling gene CHD7 cause CHARGE syndrome, a common cause of deaf-blindness, balance disorders, congenital heart malformations, and olfactory dysfunction with an estimated incidence of approximately 1 in 10,000 newborns. The clinical features of CHARGE in humans and mice are highly variable and incompletely penetrant, and most mutations appear to result in haploinsufficiency of functional CHD7 protein. Mice with heterozygous loss of function mutations in CHD7 are a good model for CHARGE syndrome, and analyses of mouse mutant phenotypes have begun to clarify a role for CHD7 during development and into adulthood. CHD7 heterozygous mutant mice have postnatal delayed growth, inner ear malformations, anosmia/hyposmia, and craniofacial defects, and CHD7 homozygous mutants are embryonic lethal. A central question in developmental biology is how chromodomain proteins like CHD7 regulate important developmental processes, and whether they directly activate or repress downstream gene transcription or act more globally to alter chromatin structure and/or function. CHD7 is expressed in a wide variety of tissues during development, suggesting that it has tissue-specific and developmental stage-specific roles. Here we review recent and ongoing analyses of CHD7 function in mouse models and cell based systems. These studies explore tissue-specific effects of CHD7 deficiency, known CHD7 interacting proteins, and downstream target sites for CHD7 binding. CHD7 is emerging as a critical regulator of important developmental processes in organs affected in human CHARGE syndrome.
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chromodomain proteins in development lessons from charge syndrome
Clinical Genetics, 2010Co-Authors: Wanda S Layman, Elizabeth A Hurd, Donna M. MartinAbstract:In humans, heterozygous mutations in the adenosine triphosphate-dependent chromatin remodeling gene CHD7 cause CHARGE syndrome, a common cause of deaf-blindness, balance disorders, congenital heart malformations, and olfactory dysfunction with an estimated incidence of approximately 1 in 10,000 newborns. The clinical features of CHARGE in humans and mice are highly variable and incompletely penetrant, and most mutations appear to result in haploinsufficiency of functional CHD7 protein. Mice with heterozygous loss of function mutations in CHD7 are a good model for CHARGE syndrome, and analyses of mouse mutant phenotypes have begun to clarify a role for CHD7 during development and into adulthood. CHD7 heterozygous mutant mice have postnatal delayed growth, inner ear malformations, anosmia/hyposmia, and craniofacial defects, and CHD7 homozygous mutants are embryonic lethal. A central question in developmental biology is how chromodomain proteins like CHD7 regulate important developmental processes, and whether they directly activate or repress downstream gene transcription or act more globally to alter chromatin structure and/or function. CHD7 is expressed in a wide variety of tissues during development, suggesting that it has tissue-specific and developmental stage-specific roles. Here, we review recent and ongoing analyses of CHD7 function in mouse models and cell-based systems. These studies explore tissue-specific effects of CHD7 deficiency, known CHD7 interacting proteins, and downstream target sites for CHD7 binding. CHD7 is emerging as a critical regulator of important developmental processes in organs affected by human CHARGE syndrome.
Corentine Marie - One of the best experts on this subject based on the ideXlab platform.
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Oligodendrocyte precursor survival and differentiation requires chromatin remodeling by CHD7 and Chd8
Proceedings of the National Academy of Sciences of the United States of America, 2018Co-Authors: Corentine Marie, Adrien Clavairoly, Magali Frah, Hatem Hmidan, Jun Yan, Chuntao Zhao, Juliette Van Steenwinckel, Romain Daveau, Bernard Zalc, Bassem HassanAbstract:Oligodendrocyte precursor cells (OPCs) constitute the main proliferative cells in the adult brain, and deregulation of OPC proliferation-differentiation balance results in either glioma formation or defective adaptive (re)myelination. OPC differentiation requires significant genetic reprogramming, implicating chromatin remodeling. Mounting evidence indicates that chromatin remodelers play important roles during normal development and their mutations are associated with neurodevelopmental defects, with CHD7 haploinsuficiency being the cause of CHARGE syndrome and CHD8 being one of the strongest autism spectrum disorder (ASD) high-risk-associated genes. Herein, we report on uncharacterized functions of the chromatin remodelers CHD7 and Chd8 in OPCs. Their OPC-chromatin binding profile, combined with transcriptome and chromatin accessibility analyses of CHD7-deleted OPCs, demonstrates that CHD7 protects nonproliferative OPCs from apoptosis by chromatin closing and transcriptional repression of p53 Furthermore, CHD7 controls OPC differentiation through chromatin opening and transcriptional activation of key regulators, including Sox10, Nkx2.2, and Gpr17 However, CHD7 is dispensable for oligodendrocyte stage progression, consistent with Chd8 compensatory function, as suggested by their common chromatin-binding profiles and genetic interaction. Finally, CHD7 and CHD8 bind in OPCs to a majority of ASD risk-associated genes, suggesting an implication of oligodendrocyte lineage cells in ASD neurological defects. Our results thus offer new avenues to understand and modulate the CHD7 and CHD8 functions in normal development and disease.
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Dual Requirement of CHD8 for Chromatin Landscape Establishment and Histone Methyltransferase Recruitment to Promote CNS Myelination and Repair.
Developmental cell, 2018Co-Authors: Chuntao Zhao, Corentine Marie, Magali Frah, Feng Zhang, Chen Dong, Yaqi Deng, Xinran Dong, Yifeng LinAbstract:Disruptive mutations in chromatin remodeler CHD8 cause autism spectrum disorders, exhibiting widespread white matter abnormalities; however, the underlying mechanisms remain elusive. We show that cell-type specific Chd8 deletion in oligodendrocyte progenitors, but not in neurons, results in myelination defects, revealing a cell-intrinsic dependence on CHD8 for oligodendrocyte lineage development, myelination and post-injury remyelination. CHD8 activates expression of BRG1-associated SWI/SNF complexes that in turn activate CHD7, thus initiating a successive chromatin remodeling cascade that orchestrates oligodendrocyte lineage progression. Genomic occupancy analyses reveal that CHD8 establishes an accessible chromatin landscape, and recruits MLL/KMT2 histone methyltransferase complexes distinctively around proximal promoters to promote oligodendrocyte differentiation. Inhibition of histone demethylase activity partially rescues myelination defects of CHD8-deficient mutants. Our data indicate that CHD8 exhibits a dual function through inducing a cascade of chromatin reprogramming and recruiting H3K4 histone methyltransferases to establish oligodendrocyte identity, suggesting potential strategies of therapeutic intervention for CHD8-associated white matter defects.
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the role of CHD7 chd8 chromatin remodelers in oligodendrogenesis and re myelination
2017Co-Authors: Corentine MarieAbstract:Les oligodendrocytes (OLs) sont les cellules myelinisantes du systeme nerveux central, s’enroulant autour des axones et permettant la conduction saltatoire du potentiel d’action. Dans la Sclerose en Plaques, des gaines de myelines sont detruites et l’efficacite de la remyelinisation par les precurseurs d’oligodendrocytes (OPCs) diminue avec la progression de la maladie. Une meilleure comprehension du mecanisme qui controle la generation des OPCs et leur differentiation est donc essentielle pour developper des therapies efficaces de remyelinisation. L’oligodendrogenese, qui comprend les etapes de generation des OPCs, de differenciation et de maturation des OLs, est un processus controle par des facteurs de transcription specifiques incluant Ascl1, Olig2 and Sox10 mais le mecanisme implique est encore peu connu. Sachant que les facteurs du remodelage de la chromatine sont des regulateurs necessaires a la formation de la boucle promoter-enhancer permettant l’initiation de la transcription, nous nous sommes focalise sur CHD7 (Chromodomain-Helicase-DNA-Binding 7), un membre de la famille de proteine CHD. Dans une premiere etude, nous avons montre que CHD7 est hautement enrichi dans le lignage oligodendroglial avec un pic d’expression pendant la differenciation des OLs. Nous avons egalement montre que la deletion conditionnelle de CHD7 diminuait la differentiation des OLs pendant la (re)myelinisation. Dans un seconde etude, nous avons utilise des techniques de genomique sur les OPCs purifies pour etudier la regulation par CHD7 de genes impliques dans la differenciation, la survie et la proliferation des OPCs. Dans ce but, nous avons generer des deletions inductible de CHD7 specifiquement dans les OPCs (CHD7iKO) et nous avons analyse le transcriptome (RNA-seq) d’OPCs purifies a partir de cerveaux de souris P7 compare a des controles. Nous avons trouve que CHD7 activait l’expression des genes implique dans la differenciation des OPCs et la myelinisation et inhibait l’apoptose, sans montre de defaut de proliferation. Pour aller plus loin, nous avons etudie Chd8, un paralogue de CHD7, et nous avons montre qu’il est exprime dans le lignage oligodendrocytaire avec un pic d’expression dans les OL en differenciation, similairement a CHD7. Les donnees de fixation (ChIP-seq) de CHD7 et Chd8 indiquent que ces deux facteurs du remodelage de la chromatine se fixent sur des genes communs relies au processus de differenciation, de survie et de proliferation des OPCs. Integrant ces donnees avec celles de facteurs transcriptionnels cles dans l’oligodendrogenese (Olig2, Ascl1 et Sox10), nous avons construit un modele de la regulation de l’expression de genes controles dans le temps et implique dans chacune des etapes de la differenciation des oligodendrocytes.
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CHD7 cooperates with Sox10 and regulates the onset of CNS myelination and remyelination
Nature Neuroscience, 2016Co-Authors: Corentine Marie, Adrien Clavairoly, Magali Frah, Hatem Hmidan, Chuntao Zhao, Yaqi Deng, Bongwoo Kim, Jincheng Wang, Haibo Wang, Blaise JonesAbstract:Mutations in CHD7, encoding ATP-dependent chromodomain helicase DNA-binding protein 7, in CHARGE syndrome lead to multiple congenital anomalies, including craniofacial malformations, neurological dysfunction and growth delay. Mechanisms underlying the CNS phenotypes remain poorly understood. We found that CHD7 is a direct transcriptional target of oligodendrogenesis-promoting factors Olig2 and Smarca4/Brg1 and is required for proper onset of CNS myelination and remyelination. Genome-occupancy analyses in mice, coupled with transcriptome profiling, revealed that CHD7 interacted with Sox10 and targeted the enhancers of key myelinogenic genes. These analyses identified previously unknown CHD7 targets, including bone formation regulators Osterix (also known as Sp7) and Creb3l2, which are also critical for oligodendrocyte maturation. Thus, CHD7 coordinates with Sox10 to regulate the initiation of myelinogenesis and acts as a molecular nexus of regulatory networks that account for the development of a seemingly diverse array of lineages, including oligodendrocytes and osteoblasts, pointing to previously uncharacterized CHD7 functions in white matter pathogenesis in CHARGE syndrome.
Lies H. Hoefsloot - One of the best experts on this subject based on the ideXlab platform.
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CHD7 mutations are not a major cause of atrioventricular septal and conotruncal heart defects
American Journal of Medical Genetics Part A, 2014Co-Authors: Nicole Corstenjanssen, Lies H. Hoefsloot, Gideon J Du Marchie Sarvaas, Wilhelmina S Kerstjensfrederikse, Ingrid M Van Beynum, Livia Kapusta, Conny M A Van RavenswaaijartsAbstract:Since 2004, CHD7 mutations have been a known cause of CHARGE (Coloboma, Heart defects, Atresia of choane, Retardation of growth and development, Genital hypoplasia, Ear anomalies) syndrome, but the full clinical spectrum of CHD7 mutations is only now gradually emerging. CHD7 mutations have been identified in patients who do not fulfill the clinical criteria for CHARGE syndrome and in patients with overlapping syndromes. Variable congenital heart defects occur in the majority of patients with CHD7 mutations, with an overrepresentation of atrioventricular septal defects and conotruncal heart defects. This prompted us to study CHD7 in 46 patients with these heart defects and one other feature of CHARGE syndrome. We identified two CHD7 variants that were inherited from a healthy parent (c.3778 + 17C > T, c.7294G > A), but no pathogenic CHD7 mutations. We conclude that CHD7 mutations are not a major cause of the atrioventricular septal defects and conotruncal heart defects, not even if one extra phenotypic feature of CHARGE syndrome is present. Therefore, CHD7 analysis should not be performed routinely in this group of patients. However, we do recommend adding CHD7 to massive parallel sequencing gene panels for diagnostic work in patients with syndromic heart defects. (c) 2014 Wiley Periodicals, Inc.
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a novel classification system to predict the pathogenic effects of CHD7 missense variants in charge syndrome
Human Mutation, 2012Co-Authors: Jorieke E H Bergman, Lies H. Hoefsloot, Nicole Janssen, Almer M Van Der Sloot, Hermien E K De Walle, Jeroen Schoots, Nanna D Rendtorff, Lisbeth Tranebjaerg, Conny M A Van RavenswaaijartsAbstract:CHARGE syndrome is characterized by the variable occurrence of multisensory impairment, congenital anomalies, and developmental delay, and is caused by heterozygous mutations in the CHD7 gene. Correct interpretation of CHD7 variants is essential for genetic counseling. This is particularly difficult for missense variants because most variants in the CHD7 gene are private and a functional assay is not yet available. We have therefore developed a novel classification system to predict the pathogenic effects of CHD7 missense variants that can be used in a diagnostic setting. Our classification system combines the results from two computational algorithms (PolyPhen-2 and Align-GVGD) and the prediction of a newly developed structural model of the chromo- and helicase domains of CHD7 with segregation and phenotypic data. The combination of different variables will lead to a more confident prediction of pathogenicity than was previously possible. We have used our system to classify 145 CHD7 missense variants. Our data show that pathogenic missense mutations are mainly present in the middle of the CHD7 gene, whereas benign variants are mainly clustered in the 5' and 3' regions. Finally, we show that CHD7 missense mutations are, in general, associated with a milder phenotype than truncating mutations.
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the results of CHD7 analysis in clinically well characterized patients with kallmann syndrome
The Journal of Clinical Endocrinology and Metabolism, 2012Co-Authors: Jorieke E H Bergman, Marjolijn C J Jongmans, Lies H. Hoefsloot, Willem De Ronde, Bruce H R Wolffenbuttel, Sten L S Drop, Ad R M M Hermus, Gianni Bocca, Conny M A Van RavenswaaijartsAbstract:CONTEXT: Kallmann syndrome (KS) and CHARGE syndrome are rare heritable disorders in which anosmia and hypogonadotropic hypogonadism co-occur. KS is genetically heterogeneous, and there are at least eight genes involved in its pathogenesis, whereas CHARGE syndrome is caused by autosomal dominant mutations in only one gene, the CHD7 gene. Two independent studies showed that CHD7 mutations can also be found in a minority of KS patients. OBJECTIVE: We aimed to investigate whether CHD7 mutations can give rise to isolated KS or whether additional features of CHARGE syndrome always occur. DESIGN: We performed CHD7 analysis in a cohort of 36 clinically well-characterized Dutch patients with KS but without mutations in KAL1 and with known status for the KS genes with incomplete penetrance, FGFR1, PROK2, PROKR2, and FGF8. RESULTS: We identified three heterozygous CHD7 mutations. The CHD7-positive patients were carefully reexamined and were all found to have additional features of CHARGE syndrome. CONCLUSION: The yield of CHD7 analysis in patients with isolated KS seems very low but increases when additional CHARGE features are present. Therefore, we recommend performing CHD7 analysis in KS patients who have at least two additional CHARGE features or semicircular canal anomalies. Identifying a CHD7 mutation has important clinical implications for the surveillance and genetic counseling of patients.
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the results of CHD7 analysis in clinically well characterized patients with kallmann syndrome
The Journal of Clinical Endocrinology and Metabolism, 2012Co-Authors: Jorieke E H Bergman, Marjolijn C J Jongmans, Lies H. Hoefsloot, Willem De Ronde, Bruce H R Wolffenbuttel, Sten L S Drop, Ad R M M Hermus, Gianni Bocca, Conny M A Van RavenswaaijartsAbstract:Context: Kallmann syndrome (KS) and CHARGE syndrome are rare heritable disorders in which anosmia and hypogonadotropic hypogonadism co-occur. KS is genetically heterogeneous, and there are at least eight genes involved in its pathogenesis, whereas CHARGE syndrome is caused by autosomal dominant mutations in only one gene, the CHD7 gene. Two independent studies showed that CHD7 mutations can also be found in a minority of KS patients. Objective: We aimed to investigate whether CHD7 mutations can give rise to isolated KS or whether additional features of CHARGE syndrome always occur. Design: We performed CHD7 analysis in a cohort of 36 clinically well-characterized Dutch patients with KS but without mutations in KAL1 and with known status for the KS genes with incomplete penetrance, FGFR1, PROK2, PROKR2, and FGF8. Results: We identified three heterozygous CHD7 mutations. The CHD7-positive patients were carefully reexamined and were all found to have additional features of CHARGE syndrome. Conclusion: The yi...
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CHD7 mutations and charge syndrome the clinical implications of an expanding phenotype
Journal of Medical Genetics, 2011Co-Authors: Jorieke E H Bergman, Marjolijn C J Jongmans, Lies H. Hoefsloot, N Janssen, Robert M W Hofstra, C M A Van RavenswaaijartsAbstract:Background CHARGE syndrome is a highly variable, multiple congenital anomaly syndrome, of which the complete phenotypic spectrum was only revealed after identification of the causative gene in 2004. CHARGE is an acronym for ocular coloboma, congenital heart defects, choanal atresia, retardation of growth and development, genital hypoplasia, and ear anomalies associated with deafness. This typical combination of clinical features is caused by autosomal dominant mutations in the CHD7 gene. Objective To explore the emerging phenotypic spectrum of CHD7 mutations, with a special focus on the mild end of the spectrum. Methods We evaluated the clinical characteristics in our own cohort of 280 CHD7 positive patients and in previously reported patients with CHD7 mutations and compared these with previously reported patients with CHARGE syndrome but an unknown CHD7 status. We then further explored the mild end of the phenotypic spectrum of CHD7 mutations. Results We discuss that CHARGE syndrome is primarily a clinical diagnosis. In addition, we propose guidelines for CHD7 analysis and indicate when evaluation of the semicircular canals is helpful in the diagnostic process. Finally, we give updated recommendations for clinical surveillance of patients with a CHD7 mutation, based on our exploration of the phenotypic spectrum and on our experience in a multidisciplinary outpatient clinic for CHARGE syndrome. Conclusion CHARGE syndrome is an extremely variable clinical syndrome. CHD7 analysis can be helpful in the diagnostic process, but the phenotype cannot be predicted from the genotype.
Timur Yusufzai - One of the best experts on this subject based on the ideXlab platform.
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The ATP-dependent Chromatin Remodeling Enzymes CHD6, CHD7, and CHD8 Exhibit Distinct Nucleosome Binding and Remodeling Activities
The Journal of biological chemistry, 2017Co-Authors: Benjamin J. Manning, Timur YusufzaiAbstract:Proper chromatin regulation is central to genome function and maintenance. The group III chromodomain–helicase–DNA-binding (CHD) family of ATP-dependent chromatin remodeling enzymes, comprising CHD6, CHD7, CHD8, and CHD9, has well-documented roles in transcription regulation, impacting both organism development and disease etiology. These four enzymes are similar in their constituent domains, but they fill surprisingly non-redundant roles in the cell, with deficiencies in individual enzymes leading to dissimilar disease states such as CHARGE syndrome or autism spectrum disorders. The mechanisms explaining their divergent, non-overlapping functions are unclear. In this study, we performed an in-depth biochemical analysis of purified CHD6, CHD7, and CHD8 and discovered distinct differences in chromatin remodeling specificities and activities among them. We report that CHD6 and CHD7 both bind with high affinity to short linker DNA, whereas CHD8 requires longer DNA for binding. As a result, CHD8 slides nucleosomes into positions with more flanking linker DNA than CHD7. Moreover, we found that, although CHD7 and CHD8 slide nucleosomes, CHD6 disrupts nucleosomes in a distinct non-sliding manner. The different activities of these enzymes likely lead to differences in chromatin structure and, thereby, transcriptional control, at the enhancer and promoter loci where these enzymes bind. Overall, our work provides a mechanistic basis for both the non-redundant roles and the diverse mutant disease states of these enzymes in vivo.
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the chromatin remodeling factor chd5 is a transcriptional repressor of wee1
PLOS ONE, 2014Co-Authors: Jinhua Quan, Guillaume Adelmant, Thomas A Look, Jarrod A Marto, Timur YusufzaiAbstract:Loss of the chromatin remodeling ATPase CHD5 has been linked to the progression of neuroblastoma tumors, yet the underlying mechanisms behind the tumor suppressor role of CHD5 are unknown. In this study, we purified the human CHD5 complex and found that CHD5 is a component of the full NuRD transcriptional repressor complex, which also contains methyl-CpG binding proteins and histone deacetylases. The CHD5/NuRD complex appears mutually exclusive with the related CHD4/NuRD complex as overexpression of CHD5 results in loss of the CHD4 protein in cells. Following a search for genes that are regulated by CHD5 in neuroblastoma cells, we found that CHD5 binds to and represses the G2/M checkpoint gene WEE1. Reintroduction of CHD5 into neuroblastoma cells represses WEE1 expression, demonstrating that CHD5 can function as a repressor in cells. A catalytically inactive mutant version of CHD5 is able to associate with a NuRD cofactor but fails to repress transcription. Our study shows that CHD5 is a NuRD-associated transcriptional repressor and identifies WEE1 as one of the CHD5-regulated genes that may link CHD5 to tumor suppression.
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the tumor suppressor chromodomain helicase dna binding protein 5 chd5 remodels nucleosomes by unwrapping
Journal of Biological Chemistry, 2014Co-Authors: Jinhua Quan, Timur YusufzaiAbstract:Although mutations or deletions of chromodomain helicase DNA-binding protein 5 (CHD5) have been linked to cancer and implicate CHD5 in tumor suppression, the ATP-dependent activity of CHD5 is currently unknown. In this study, we discovered that CHD5 is a chromatin remodeling factor with a unique enzymatic activity. CHD5 can expose nucleosomal DNA at one or two discrete positions in the nucleosome. The exposure of the nucleosomal DNA by CHD5 is dependent on ATP hydrolysis, but continued ATP hydrolysis is not required to maintain the nucleosomes in their remodeled state. The activity of CHD5 is distinct from other related chromatin remodeling ATPases, such as ACF and BRG1, and does not lead to complete disruption or destabilization of the nucleosome. Rather, CHD5 likely initiates remodeling in a manner similar to that of other remodeling factors but does not significantly reposition the nucleosome. While the related factor CHD4 shows strong ATPase activity, it does not unwrap nucleosomes as efficiently as CHD5. Our findings add to the growing evidence that chromatin remodeling ATPases have diverse roles in modulating chromatin structure.