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Matthew A Deardorff - One of the best experts on this subject based on the ideXlab platform.
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cornelia de lange syndrome
Jcpsp-journal of The College of Physicians and Surgeons Pakistan, 2016Co-Authors: Matthew A Deardorff, Sarah E Noon, Ian D KrantzAbstract:Clinical characteristics Classic Cornelia de Lange syndrome (CdLS) is characterized by distinctive facial features, growth retardation (prenatal onset; Diagnosis/testing Diagnosis is based on clinical findings and/or the identification of a heterozygous pathogenic variant in NIPBL, RAD21, or SMC3 or a hemizygous pathogenic variant in HDAC8 or SMC1A. Management Treatment of manifestations: Aggressive management of gastroesophageal reflux with assessment of potential gastrointestinal malrotation in all affected individuals; consideration of fundoplication if reflux is severe. Supplementary formulas and/or gastrostomy tube placement to meet nutritional needs as necessary. Physical, occupational, and speech therapy to optimize psychomotor development and communication skills. Standard treatment for hearing loss, cardiac defects, seizures, vesicoureteral reflux, and cryptorchidism. Prevention of secondary complications: Preoperative evaluation for thrombocytopenia and cardiac disease with careful monitoring of the airway during anesthesia; malignant hyperthermia precautions. Surveillance: Annual GI evaluation, monitoring of growth and psychomotor development; routine eye and hearing evaluations, and monitoring of heart and kidney abnormalities. Genetic counseling NIPBL-related CdLS, RAD21-related CdLS, and SMC3-related CdLS are inherited in an autosomal dominant manner; HDAC8-related CdLS and SMC1A-related CdLS are inherited in an X-linked manner. The majority of affected individuals have a de novo heterozygous pathogenic variant in NIPBL; fewer than 1% of individuals with NIPBL-related CdLS have an affected parent. When the parents are clinically unaffected, the risk to the sibs of a proband with NIPBL-related CdLS is estimated to be 1.5% because of the possibility of germline mosaicism. The risk to sibs of a proband with HDAC8-related CdLS or SMC1A-related CdLS depends on the status of the proband's mother. Prenatal testing for pregnancies at increased risk is possible for families in which the pathogenic variant has been identified.
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congenital heart disease in cornelia de lange syndrome phenotype and genotype analysis
American Journal of Medical Genetics Part A, 2012Co-Authors: Kathryn C Chatfield, Jennifer R Li, Antonie D Kline, Matthew A Deardorff, Maninder Kaur, Dinah Clark, Samantha A Schrier, Laird S Jackson, Elizabeth Goldmuntz, Ian D KrantzAbstract:Congenital heart disease (CHD) has been reported to occur in 14–70% of individuals with Cornelia de Lange syndrome (CdLS, OMIM 122470) and accounts for significant morbidity and mortality when present. Charts from a cohort of 479 patients with CdLS were reviewed for cardiac evaluations, gene testing and information to determine phenotypic severity. Two hundred fifty-nine individuals had either documented structural defects or minor cardiac findings. The presence of CHD was then quantified as a function of mutation status and severity of CdLS: mild, moderate, or severe. Different types of CHD were also evaluated by mutation status to assess for any genotype –phenotype correlation. NIPBL, SMC1A, and SMC3 mutation-positive patients were equally likely to have CHD, although the number of SMC1A and SMC3 mutation-positive patients were small in comparison. Structural CHDs were more likely to be present in individuals with moderate and severe CdLS than in the mild phenotype. This study evaluates the trends of CHD seen in the CdLS population and correlates these findings with genotype.
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hdac8 mutations in cornelia de lange syndrome affect the cohesin acetylation cycle
Nature, 2012Co-Authors: Erwan Watrin, Matthew A Deardorff, Masashige Bando, Ryuichiro Nakato, Takehiko Itoh, Masashi Minamino, Katsuya Saitoh, Makiko Komata, Yuki KatouAbstract:The deacetylase enzyme HDAC8 is identified as a crucial regulator of cohesin in humans, and loss-of-function mutations in the HDAC8 gene are found in patients with Cornelia de Lange syndrome. The cohesin complex is important for sister-chromatid cohesion and chromosome segregation, as well as for other chromosomal processes such as gene expression and DNA repair. Cornelia de Lange syndrome (CdLS) is a human developmental disorder associated with significant cognitive deficits and structural birth defects. It is caused by mutations in genes that encode subunits of the cohesin complex or the cohesin regulator NIPL. Here, a deacetylase enzyme, HDAC8, is shown to be a critical regulator of cohesin in human cells, and loss-of-function HDAC8 mutations are found in six patients with CdLS from different families. Cornelia de Lange syndrome (CdLS) is a dominantly inherited congenital malformation disorder, caused by mutations in the cohesin-loading protein NIPBL1,2 for nearly 60% of individuals with classical CdLS3,4,5, and by mutations in the core cohesin components SMC1A (∼5%) and SMC3 (<1%) for a smaller fraction of probands6,7. In humans, the multisubunit complex cohesin is made up of SMC1, SMC3, RAD21 and a STAG protein. These form a ring structure that is proposed to encircle sister chromatids to mediate sister chromatid cohesion8 and also has key roles in gene regulation9. SMC3 is acetylated during S-phase to establish cohesiveness of chromatin-loaded cohesin10,11,12,13, and in yeast, the class I histone deacetylase Hos1 deacetylates SMC3 during anaphase14,15,16. Here we identify HDAC8 as the vertebrate SMC3 deacetylase, as well as loss-of-function HDAC8 mutations in six CdLS probands. Loss of HDAC8 activity results in increased SMC3 acetylation and inefficient dissolution of the ‘used’ cohesin complex released from chromatin in both prophase and anaphase. SMC3 with retained acetylation is loaded onto chromatin, and chromatin immunoprecipitation sequencing analysis demonstrates decreased occupancy of cohesin localization sites that results in a consistent pattern of altered transcription seen in CdLS cell lines with either NIPBL or HDAC8 mutations.
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hdac8 mutations in cornelia de lange syndrome affect the cohesin acetylation cycle
Nature, 2012Co-Authors: Matthew A Deardorff, Ryuichiro Nakato, Takehiko Itoh, Masashi Minamino, Katsuya Saitoh, Makiko Komata, Masashige Ando, Erwa Watri, Yuki KatouAbstract:Cornelia de Lange syndrome (CdLS) is a dominantly inherited congenital malformation disorder, caused by mutations in the cohesin-loading protein NIPBL for nearly 60% of individuals with classical CdLS, and by mutations in the core cohesin components SMC1A (~5%) and SMC3 (<1%) for a smaller fraction of probands. In humans, the multisubunit complex cohesin is made up of SMC1, SMC3, RAD21 and a STAG protein. These form a ring structure that is proposed to encircle sister chromatids to mediate sister chromatid cohesion and also has key roles in gene regulation. SMC3 is acetylated during S-phase to establish cohesiveness of chromatin-loaded cohesin, and in yeast, the class I histone deacetylase Hos1 deacetylates SMC3 during anaphase. Here we identify HDAC8 as the vertebrate SMC3 deacetylase, as well as loss-of-function HDAC8 mutations in six CdLS probands. Loss of HDAC8 activity results in increased SMC3 acetylation and inefficient dissolution of the ‘used’ cohesin complex released from chromatin in both prophase and anaphase. SMC3 with retained acetylation is loaded onto chromatin, and chromatin immunoprecipitation sequencing analysis demonstrates decreased occupancy of cohesin localization sites that results in a consistent pattern of altered transcription seen in CdLS cell lines with either NIPBL or HDAC8 mutations.
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mutations and variants in the cohesion factor genes nipbl SMC1A and smc3 in a cohort of 30 unrelated patients with cornelia de lange syndrome
American Journal of Medical Genetics Part A, 2010Co-Authors: Maria Concepcion Gilrodriguez, Matthew A Deardorff, Beatriz Puisac, Milagros Ciero, Eduardo Lopezvinas, Maria Pilar Ribate, Maria Arnedo, Jesus Legarreta, Juan C De KaramAbstract:Cornelia de Lange syndrome (CdLS) manifests facial dysmorphic features, growth and cognitive impairment, and limb malformations. Mutations in three genes (NIPBL, SMC1A, and SMC3) of the cohesin complex and its regulators have been found in affected patients. Here, we present clinical and molecular characterization of 30 unrelated patients with CdLS. Eleven patients had mutations in NIPBL (37%) and three patients had mutations in SMC1A (10%), giving an overall rate of mutations of 47%. Several patients shared the same mutation in NIPBL (p.R827GfsX2) but had variable phenotypes, indicating the influence of modifiers in CdLS. Patients with NIPBL mutations had a more severe phenotype than those with mutations in SMC1A or those without identified mutations. However, a high incidence of palate defects was noted in patients with SMC1A mutations. In addition, we observed a similar phenotype in both male and female patients with SMC1A mutations. Finally, we report the first patient with an SMC1A mutation and the Sandifer complex. © 2010 Wiley-Liss, Inc.
Ian D Krantz - One of the best experts on this subject based on the ideXlab platform.
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recognition of the cornelia de lange syndrome phenotype with facial dysmorphology novel analysis
Clinical Genetics, 2016Co-Authors: Lina Baselvanagaite, Ian D Krantz, Lior Wolf, Melanie Orin, Lidia Larizza, Cristina Gervasini, Matthew A DeardoffAbstract:Facial analysis systems are becoming available to healthcare providers to aid in the recognition of dysmorphic phenotypes associated with a multitude of genetic syndromes. These technologies automatically detect facial points and extract various measurements from images to recognize dysmorphic features and evaluate similarities to known facial patterns (gestalts). To evaluate such systems' usefulness for supporting the clinical practice of healthcare professionals, the recognition accuracy of the Cornelia de Lange syndrome (CdLS) phenotype was examined with FDNA's automated facial dysmorphology novel analysis (FDNA) technology. In the first experiment, 2D facial images of CdLS patients with either an NIPBL or SMC1A gene mutation as well as non-CdLS patients which were assessed by dysmorphologists in a previous study were evaluated by the FDNA technology; the average detection rate of experts was 77% while the system's detection rate was 87%. In the second study, when a new set of NIPBL, SMC1A and non-CdLS patient photos was evaluated, the detection rate increased to 94%. The results from both studies indicated that the system's detection rate was comparable to that of dysmorphology experts. Therefore, utilizing such technologies may be a useful tool in a clinical setting.
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cornelia de lange syndrome
Jcpsp-journal of The College of Physicians and Surgeons Pakistan, 2016Co-Authors: Matthew A Deardorff, Sarah E Noon, Ian D KrantzAbstract:Clinical characteristics Classic Cornelia de Lange syndrome (CdLS) is characterized by distinctive facial features, growth retardation (prenatal onset; Diagnosis/testing Diagnosis is based on clinical findings and/or the identification of a heterozygous pathogenic variant in NIPBL, RAD21, or SMC3 or a hemizygous pathogenic variant in HDAC8 or SMC1A. Management Treatment of manifestations: Aggressive management of gastroesophageal reflux with assessment of potential gastrointestinal malrotation in all affected individuals; consideration of fundoplication if reflux is severe. Supplementary formulas and/or gastrostomy tube placement to meet nutritional needs as necessary. Physical, occupational, and speech therapy to optimize psychomotor development and communication skills. Standard treatment for hearing loss, cardiac defects, seizures, vesicoureteral reflux, and cryptorchidism. Prevention of secondary complications: Preoperative evaluation for thrombocytopenia and cardiac disease with careful monitoring of the airway during anesthesia; malignant hyperthermia precautions. Surveillance: Annual GI evaluation, monitoring of growth and psychomotor development; routine eye and hearing evaluations, and monitoring of heart and kidney abnormalities. Genetic counseling NIPBL-related CdLS, RAD21-related CdLS, and SMC3-related CdLS are inherited in an autosomal dominant manner; HDAC8-related CdLS and SMC1A-related CdLS are inherited in an X-linked manner. The majority of affected individuals have a de novo heterozygous pathogenic variant in NIPBL; fewer than 1% of individuals with NIPBL-related CdLS have an affected parent. When the parents are clinically unaffected, the risk to the sibs of a proband with NIPBL-related CdLS is estimated to be 1.5% because of the possibility of germline mosaicism. The risk to sibs of a proband with HDAC8-related CdLS or SMC1A-related CdLS depends on the status of the proband's mother. Prenatal testing for pregnancies at increased risk is possible for families in which the pathogenic variant has been identified.
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mutant cohesin affects rna polymerase ii regulation in cornelia de lange syndrome
Scientific Reports, 2015Co-Authors: Linda Mannini, Ian D Krantz, Francesco Cucco, C Amato, I M Rizzo, Steve Bilodeau, Antonio MusioAbstract:In addition to its role in sister chromatid cohesion, genome stability and integrity, the cohesin complex is involved in gene transcription. Mutations in core cohesin subunits SMC1A, SMC3 and RAD21, or their regulators NIPBL and HDAC8, cause Cornelia de Lange syndrome (CdLS). Recent evidence reveals that gene expression dysregulation could be the underlying mechanism for CdLS. These findings raise intriguing questions regarding the potential role of cohesin-mediated transcriptional control and pathogenesis. Here, we identified numerous dysregulated genes occupied by cohesin by combining the transcriptome of CdLS cell lines carrying mutations in SMC1A gene and ChIP-Seq data. Genome-wide analyses show that genes changing in expression are enriched for cohesin-binding. In addition, our results indicate that mutant cohesin impairs both RNA polymerase II (Pol II) transcription initiation at promoters and elongation in the gene body. These findings highlight the pivotal role of cohesin in transcriptional regulation and provide an explanation for the typical gene dysregulation observed in CdLS patients.
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mutation spectrum and genotype phenotype correlation in cornelia de lange syndrome
Human Mutation, 2013Co-Authors: Linda Mannini, Ian D Krantz, Francesco Cucco, Valentina Quarantotti, Antonio MusioAbstract:Cornelia de Lange syndrome (CdLS) is a clinically and genetically heterogeneous developmental disorder. Clinical features include growth retardation, intellectual disability, limb defects, typical facial dysmorphism, and other systemic involvement. The increased understanding of the genetic basis of CdLS has led to diagnostic improvement and expansion of the phenotype. Mutations in five genes (NIPBL, SMC1A, SMC3, RAD21, and HDAC8), all regulators or structural components of cohesin, have been identified. Approximately 60% of CdLS cases are due to NIPBL mutations, 5% caused by mutations in SMC1A, RAD21, and HDAC8 and one proband was found to carry a mutation in SMC3. To date, 311 CdLS-causing mutations are known including missense, nonsense, small deletions and insertions, splice site mutations, and genomic rearrangements. Phenotypic variability is seen both intra- and intergenically. This article reviews the spectrum of CdLS mutations with a particular emphasis on their correlation to the clinical phenotype.
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congenital heart disease in cornelia de lange syndrome phenotype and genotype analysis
American Journal of Medical Genetics Part A, 2012Co-Authors: Kathryn C Chatfield, Jennifer R Li, Antonie D Kline, Matthew A Deardorff, Maninder Kaur, Dinah Clark, Samantha A Schrier, Laird S Jackson, Elizabeth Goldmuntz, Ian D KrantzAbstract:Congenital heart disease (CHD) has been reported to occur in 14–70% of individuals with Cornelia de Lange syndrome (CdLS, OMIM 122470) and accounts for significant morbidity and mortality when present. Charts from a cohort of 479 patients with CdLS were reviewed for cardiac evaluations, gene testing and information to determine phenotypic severity. Two hundred fifty-nine individuals had either documented structural defects or minor cardiac findings. The presence of CHD was then quantified as a function of mutation status and severity of CdLS: mild, moderate, or severe. Different types of CHD were also evaluated by mutation status to assess for any genotype –phenotype correlation. NIPBL, SMC1A, and SMC3 mutation-positive patients were equally likely to have CHD, although the number of SMC1A and SMC3 mutation-positive patients were small in comparison. Structural CHDs were more likely to be present in individuals with moderate and severe CdLS than in the mild phenotype. This study evaluates the trends of CHD seen in the CdLS population and correlates these findings with genotype.
Antonio Musio - One of the best experts on this subject based on the ideXlab platform.
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the multiple facets of the SMC1A gene
Gene, 2020Co-Authors: Antonio MusioAbstract:Abstract Structural Maintenance of Chromosomes (SMCs) are part of a large family of ring complexes that participates in a number of DNA transactions. Among SMCs, SMC1A gene is unique. It encodes a subunit of the cohesin-core complex that tethers sister chromatids together to ensure correct chromosome segregation in both mitosis and meiosis. As a member of the cohesin ring, SMC1A takes part in gene transcription regulation and genome organization; and it participates in the DNA Damage Repair (DDR) pathway, being phosphorylated by Ataxia Telangiectasia Mutated (ATM) and Ataxia Telangiectasia and Rad3 Related (ATR) threonine/serine kinases. It is also a component of the Recombination protein complex (RC-1) involved in DNA repair by recombination. SMC1A pathogenic variants have been described in Cornelia de Lange syndrome (CdLS), a human rare disease, and recently SMC1A variants have been associated with epilepsy or resembling Rett syndrome phenotype. Finally, SMC1A variants have been identified in several human cancers. In this review, our current knowledge of the SMC1A gene has been summarized.
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mutant cohesin affects rna polymerase ii regulation in cornelia de lange syndrome
Scientific Reports, 2015Co-Authors: Linda Mannini, Ian D Krantz, Francesco Cucco, C Amato, I M Rizzo, Steve Bilodeau, Antonio MusioAbstract:In addition to its role in sister chromatid cohesion, genome stability and integrity, the cohesin complex is involved in gene transcription. Mutations in core cohesin subunits SMC1A, SMC3 and RAD21, or their regulators NIPBL and HDAC8, cause Cornelia de Lange syndrome (CdLS). Recent evidence reveals that gene expression dysregulation could be the underlying mechanism for CdLS. These findings raise intriguing questions regarding the potential role of cohesin-mediated transcriptional control and pathogenesis. Here, we identified numerous dysregulated genes occupied by cohesin by combining the transcriptome of CdLS cell lines carrying mutations in SMC1A gene and ChIP-Seq data. Genome-wide analyses show that genes changing in expression are enriched for cohesin-binding. In addition, our results indicate that mutant cohesin impairs both RNA polymerase II (Pol II) transcription initiation at promoters and elongation in the gene body. These findings highlight the pivotal role of cohesin in transcriptional regulation and provide an explanation for the typical gene dysregulation observed in CdLS patients.
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mutation spectrum and genotype phenotype correlation in cornelia de lange syndrome
Human Mutation, 2013Co-Authors: Linda Mannini, Ian D Krantz, Francesco Cucco, Valentina Quarantotti, Antonio MusioAbstract:Cornelia de Lange syndrome (CdLS) is a clinically and genetically heterogeneous developmental disorder. Clinical features include growth retardation, intellectual disability, limb defects, typical facial dysmorphism, and other systemic involvement. The increased understanding of the genetic basis of CdLS has led to diagnostic improvement and expansion of the phenotype. Mutations in five genes (NIPBL, SMC1A, SMC3, RAD21, and HDAC8), all regulators or structural components of cohesin, have been identified. Approximately 60% of CdLS cases are due to NIPBL mutations, 5% caused by mutations in SMC1A, RAD21, and HDAC8 and one proband was found to carry a mutation in SMC3. To date, 311 CdLS-causing mutations are known including missense, nonsense, small deletions and insertions, splice site mutations, and genomic rearrangements. Phenotypic variability is seen both intra- and intergenically. This article reviews the spectrum of CdLS mutations with a particular emphasis on their correlation to the clinical phenotype.
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SMC1A codon 496 mutations affect the cellular response to genotoxic treatments
American Journal of Medical Genetics Part A, 2012Co-Authors: Linda Mannini, Stefania Menga, Alessandra Tonelli, Silvia Zanotti, Maria Teresa Bassi, Cinzia Magnani, Antonio MusioAbstract:Cornelia de Lange syndrome is a pleiotropic developmental syndrome characterized by growth and cognitive impairment, facial dysmorphic features, limb anomalies, and other malformations. Mutations in core cohesin genes SMC1A and SMC3, and the cohesin regulatory gene, NIPBL, have been identified in Cornelia de Lange syndrome probands. Patients with NIPBL mutations have more severe phenotypes when compared to those with mutations in SMC1A or SMC3. To date, 26 distinct SMC1A mutations have been identified in patients with Cornelia de Lange syndrome. Here, we describe a 3-year-old girl with psychomotor and cognitive impairment, mild facial dysmorphic features but no limb anomaly, heterozygous for a c.1487G>A mutation in SMC1A which predicts p.Arg496His. We show that this mutation leads to an impairment of the cellular response to genotoxic treatments. © 2011 Wiley Periodicals, Inc.
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spectrum and consequences of SMC1A mutations the unexpected involvement of a core component of cohesin in human disease
Human Mutation, 2010Co-Authors: Linda Mannini, Ian D Krantz, Jinglan Liu, Antonio MusioAbstract:SMC1A encodes a structural component of the cohesin complex, which is necessary for sister chromatid cohesion. In addition to its canonical role, cohesin has been shown to be involved in gene expression regulation and maintenance of genome stability. Recently, it has been demonstrated that mutations in the SMC1A gene are responsible for Cornelia de Lange syndrome (CdLS). CdLS is a genetically heterogeneous multisystem developmental disorder with variable expressivity, typically characterized by consistent facial dysmorphia, upper extremity malformations, hirsutism, cardiac defects, growth and cognitive retardation, gastrointestinal abnormalities, and other systemic involvement. SMC1A mutations have also been identified in colorectal cancers. So far a total of 26 different mutations of the SMC1A gene have been reported. All mutations reported to date are either missense or small in-frame deletions that maintain the open reading frame and presumably result in a protein with residual function. The mutations involve all domains of the protein but appear to cluster in key functional loci. At the functional level, elucidation of the effects that specific SMC1A mutations have on cohesin activity will be necessary to understand the etiopathology of CdLS and its possible involvement in tumorigenesis. In this review, we summarize the current knowledge of SMC1A mutations. Hum Mutat 30:1–6, 2009. © 2009 Wiley-Liss, Inc.
Linda Mannini - One of the best experts on this subject based on the ideXlab platform.
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mutant cohesin affects rna polymerase ii regulation in cornelia de lange syndrome
Scientific Reports, 2015Co-Authors: Linda Mannini, Ian D Krantz, Francesco Cucco, C Amato, I M Rizzo, Steve Bilodeau, Antonio MusioAbstract:In addition to its role in sister chromatid cohesion, genome stability and integrity, the cohesin complex is involved in gene transcription. Mutations in core cohesin subunits SMC1A, SMC3 and RAD21, or their regulators NIPBL and HDAC8, cause Cornelia de Lange syndrome (CdLS). Recent evidence reveals that gene expression dysregulation could be the underlying mechanism for CdLS. These findings raise intriguing questions regarding the potential role of cohesin-mediated transcriptional control and pathogenesis. Here, we identified numerous dysregulated genes occupied by cohesin by combining the transcriptome of CdLS cell lines carrying mutations in SMC1A gene and ChIP-Seq data. Genome-wide analyses show that genes changing in expression are enriched for cohesin-binding. In addition, our results indicate that mutant cohesin impairs both RNA polymerase II (Pol II) transcription initiation at promoters and elongation in the gene body. These findings highlight the pivotal role of cohesin in transcriptional regulation and provide an explanation for the typical gene dysregulation observed in CdLS patients.
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mutation spectrum and genotype phenotype correlation in cornelia de lange syndrome
Human Mutation, 2013Co-Authors: Linda Mannini, Ian D Krantz, Francesco Cucco, Valentina Quarantotti, Antonio MusioAbstract:Cornelia de Lange syndrome (CdLS) is a clinically and genetically heterogeneous developmental disorder. Clinical features include growth retardation, intellectual disability, limb defects, typical facial dysmorphism, and other systemic involvement. The increased understanding of the genetic basis of CdLS has led to diagnostic improvement and expansion of the phenotype. Mutations in five genes (NIPBL, SMC1A, SMC3, RAD21, and HDAC8), all regulators or structural components of cohesin, have been identified. Approximately 60% of CdLS cases are due to NIPBL mutations, 5% caused by mutations in SMC1A, RAD21, and HDAC8 and one proband was found to carry a mutation in SMC3. To date, 311 CdLS-causing mutations are known including missense, nonsense, small deletions and insertions, splice site mutations, and genomic rearrangements. Phenotypic variability is seen both intra- and intergenically. This article reviews the spectrum of CdLS mutations with a particular emphasis on their correlation to the clinical phenotype.
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SMC1A codon 496 mutations affect the cellular response to genotoxic treatments
American Journal of Medical Genetics Part A, 2012Co-Authors: Linda Mannini, Stefania Menga, Alessandra Tonelli, Silvia Zanotti, Maria Teresa Bassi, Cinzia Magnani, Antonio MusioAbstract:Cornelia de Lange syndrome is a pleiotropic developmental syndrome characterized by growth and cognitive impairment, facial dysmorphic features, limb anomalies, and other malformations. Mutations in core cohesin genes SMC1A and SMC3, and the cohesin regulatory gene, NIPBL, have been identified in Cornelia de Lange syndrome probands. Patients with NIPBL mutations have more severe phenotypes when compared to those with mutations in SMC1A or SMC3. To date, 26 distinct SMC1A mutations have been identified in patients with Cornelia de Lange syndrome. Here, we describe a 3-year-old girl with psychomotor and cognitive impairment, mild facial dysmorphic features but no limb anomaly, heterozygous for a c.1487G>A mutation in SMC1A which predicts p.Arg496His. We show that this mutation leads to an impairment of the cellular response to genotoxic treatments. © 2011 Wiley Periodicals, Inc.
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spectrum and consequences of SMC1A mutations the unexpected involvement of a core component of cohesin in human disease
Human Mutation, 2010Co-Authors: Linda Mannini, Ian D Krantz, Jinglan Liu, Antonio MusioAbstract:SMC1A encodes a structural component of the cohesin complex, which is necessary for sister chromatid cohesion. In addition to its canonical role, cohesin has been shown to be involved in gene expression regulation and maintenance of genome stability. Recently, it has been demonstrated that mutations in the SMC1A gene are responsible for Cornelia de Lange syndrome (CdLS). CdLS is a genetically heterogeneous multisystem developmental disorder with variable expressivity, typically characterized by consistent facial dysmorphia, upper extremity malformations, hirsutism, cardiac defects, growth and cognitive retardation, gastrointestinal abnormalities, and other systemic involvement. SMC1A mutations have also been identified in colorectal cancers. So far a total of 26 different mutations of the SMC1A gene have been reported. All mutations reported to date are either missense or small in-frame deletions that maintain the open reading frame and presumably result in a protein with residual function. The mutations involve all domains of the protein but appear to cluster in key functional loci. At the functional level, elucidation of the effects that specific SMC1A mutations have on cohesin activity will be necessary to understand the etiopathology of CdLS and its possible involvement in tumorigenesis. In this review, we summarize the current knowledge of SMC1A mutations. Hum Mutat 30:1–6, 2009. © 2009 Wiley-Liss, Inc.
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spectrum and consequences of SMC1A mutations the unexpected involvement of a core component of cohesin in human disease
Human Mutation, 2010Co-Authors: Linda Mannini, Ian D Krantz, Jinglan Liu, Antonio MusioAbstract:SMC1A encodes a structural component of the cohesin complex, which is necessary for sister chromatid cohesion. In addition to its canonical role, cohesin has been shown to be involved in gene expression regulation and maintenance of genome stability. Recently, it has been demonstrated that mutations in the SMC1A gene are responsible for Cornelia de Lange syndrome (CdLS). CdLS is a genetically heterogeneous multisystem developmental disorder with variable expressivity, typically characterized by consistent facial dysmorphia, upper extremity malformations, hirsutism, cardiac defects, growth and cognitive retardation, gastrointestinal abnormalities, and other systemic involvement. SMC1A mutations have also been identified in colorectal cancers. So far a total of 26 different mutations of the SMC1A gene have been reported. All mutations reported to date are either missense or small in-frame deletions that maintain the open reading frame and presumably result in a protein with residual function. The mutations involve all domains of the protein but appear to cluster in key functional loci. At the functional level, elucidation of the effects that specific SMC1A mutations have on cohesin activity will be necessary to understand the etiopathology of CdLS and its possible involvement in tumorigenesis. In this review, we summarize the current knowledge of SMC1A mutations.
Paolo Aretini - One of the best experts on this subject based on the ideXlab platform.
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Overexpression of the cohesin-core subunit SMC1A contributes to colorectal cancer development
Journal of Experimental & Clinical Cancer Research, 2019Co-Authors: Patrizia Sarogni, Adele Servadio, Simonetta Astigiano, Barbara D’alessio, Veronica Gatti, Dubravka Cukrov, Silvia Baldari, Maria Michela Pallotta, Orazio Palumbo, Paolo AretiniAbstract:Cancer cells are characterized by chromosomal instability (CIN) and it is thought that errors in pathways involved in faithful chromosome segregation play a pivotal role in the genesis of CIN. Cohesin forms a large protein ring that binds DNA strands by encircling them. In addition to this central role in chromosome segregation, cohesin is also needed for DNA repair, gene transcription regulation and chromatin architecture. Though mutations in both cohesin and cohesin-regulator genes have been identified in many human cancers, the contribution of cohesin to cancer development is still under debate. Normal mucosa, early adenoma, and carcinoma samples deriving from 16 subjects affected by colorectal cancer (CRC) were analyzed by OncoScan for scoring both chromosome gains and losses (CNVs) and loss of heterozygosity (LOH). Then the expression of SMC1A was analyzed by immunochemistry in 66 subjects affected by CRC. The effects of SMC1A overexpression and mutated SMC1A were analyzed in vivo using immunocompromised mouse models. Finally, we measured global gene expression profiles in induced-tumors by RNA-seq. Here we showed that SMC1A cohesin core gene was present as extra-copies, mutated, and overexpressed in human colorectal carcinomas. We then demonstrated that cohesin overexpression led to the development of aggressive cancers in immunocompromised mice through gene expression dysregulation. Collectively, these results support a role of defective cohesin in the development of human colorectal cancer.
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Overexpression of the cohesin-core subunit SMC1A contributes to colorectal cancer development
BMC, 2019Co-Authors: Patrizia Sarogni, Adele Servadio, Simonetta Astigiano, Barbara D’alessio, Veronica Gatti, Dubravka Cukrov, Silvia Baldari, Maria Michela Pallotta, Orazio Palumbo, Paolo AretiniAbstract:Abstract Background Cancer cells are characterized by chromosomal instability (CIN) and it is thought that errors in pathways involved in faithful chromosome segregation play a pivotal role in the genesis of CIN. Cohesin forms a large protein ring that binds DNA strands by encircling them. In addition to this central role in chromosome segregation, cohesin is also needed for DNA repair, gene transcription regulation and chromatin architecture. Though mutations in both cohesin and cohesin-regulator genes have been identified in many human cancers, the contribution of cohesin to cancer development is still under debate. Methods Normal mucosa, early adenoma, and carcinoma samples deriving from 16 subjects affected by colorectal cancer (CRC) were analyzed by OncoScan for scoring both chromosome gains and losses (CNVs) and loss of heterozygosity (LOH). Then the expression of SMC1A was analyzed by immunochemistry in 66 subjects affected by CRC. The effects of SMC1A overexpression and mutated SMC1A were analyzed in vivo using immunocompromised mouse models. Finally, we measured global gene expression profiles in induced-tumors by RNA-seq. Results Here we showed that SMC1A cohesin core gene was present as extra-copies, mutated, and overexpressed in human colorectal carcinomas. We then demonstrated that cohesin overexpression led to the development of aggressive cancers in immunocompromised mice through gene expression dysregulation. Conclusion Collectively, these results support a role of defective cohesin in the development of human colorectal cancer
