Cornelia de Lange syndrome is caused by mutations in NIPBL , the human homolog of Drosophila melanogaster Nipped-B
Ian D. Krantz,Jennifer McCallum,Cheryl DeScipio,Maninder Kaur,Lynette A. Gillis,Dinah Yaeger,Lori Jukofsky,Nora Wasserman,Armand Bottani,Colleen A. Morris,Małgorzata J.M. Nowaczyk,Helga V. Toriello,Michael J. Bamshad,John C. Carey,Eric F. Rappaport,Shimako Kawauchi,Arthur D. Lander,Anne L. Calof,Hui Hua Li,Marcella Devoto,Laird G. Jackson +20 more
TLDR
The genomic structure of NIPBL is characterized and it is found that it is widely expressed in fetal and adult tissues and facilitates enhancer-promoter communication and regulates Notch signaling and other developmental pathways in Drosophila melanogaster.Abstract:
Cornelia de Lange syndrome (CdLS; OMIM 122470) is a dominantly inherited multisystem developmental disorder characterized by growth and cognitive retardation; abnormalities of the upper limbs; gastroesophageal dysfunction; cardiac, ophthalmologic and genitourinary anomalies; hirsutism; and characteristic facial features. Genital anomalies, pyloric stenosis, congenital diaphragmatic hernias, cardiac septal defects, hearing loss and autistic and self-injurious tendencies also frequently occur. Prevalence is estimated to be as high as 1 in 10,000 (ref. 4). We carried out genome-wide linkage exclusion analysis in 12 families with CdLS and identified four candidate regions, of which chromosome 5p13.1 gave the highest multipoint lod score of 2.7. This information, together with the previous identification of a child with CdLS with a de novo t(5;13)(p13.1;q12.1) translocation, allowed delineation of a 1.1-Mb critical region on chromosome 5 for the gene mutated in CdLS. We identified mutations in one gene in this region, which we named NIPBL, in four sporadic and two familial cases of CdLS. We characterized the genomic structure of NIPBL and found that it is widely expressed in fetal and adult tissues. The fly homolog of NIPBL, Nipped-B, facilitates enhancer-promoter communication and regulates Notch signaling and other developmental pathways in Drosophila melanogaster.read more
Citations
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Mediator and cohesin connect gene expression and chromatin architecture
Michael H. Kagey,Jamie J. Newman,Steve Bilodeau,Ye Zhan,David A. Orlando,Nynke L. van Berkum,Christopher C. Ebmeier,Jesse Goossens,Peter B. Rahl,Stuart S. Levine,Dylan J. Taatjes,Job Dekker,Richard A. Young +12 more
TL;DR: It is reported that mediator and cohesin physically and functionally connect the enhancers and core promoters of active genes in murine embryonic stem cells.
PatentDOI
Mediator and cohesin connect gene expression and chromatin architecture
TL;DR: In this paper, the authors provide compositions and methods for identifying compounds that modulate Cohesin-Mediator function and apply them to treating a disorder involving altered CO-mediator function.
Journal ArticleDOI
Cohesin mediates transcriptional insulation by CCCTC-binding factor
Kerstin S. Wendt,Keisuke Yoshida,Takehiko Itoh,Masashige Bando,Birgit Koch,Erika Schirghuber,Shuichi Tsutsumi,Genta Nagae,Ko Ishihara,Tsuyoshi Mishiro,Kazuhide Yahata,Fumio Imamoto,Hiroyuki Aburatani,Mitsuyoshi Nakao,Naoko Imamoto,Kazuhiro Maeshima,Katsuhiko Shirahige,Jan-Michael Peters +17 more
TL;DR: It is proposed that cohesin functions as a transcriptional insulator, and it is speculated that subtle deficiencies in this function contribute to ‘cohesinopathies’ such as Cornelia de Lange syndrome.
Journal ArticleDOI
Control of the Embryonic Stem Cell State
TL;DR: This work has provided insights into the transcriptional control of embryonic stem cell state, including the regulatory circuitry underlying pluripotency and uncovered fundamental mechanisms that control mammalian gene expression, connect gene expression to chromosome structure, and contribute to human disease.
Journal ArticleDOI
Cohesin: Its Roles and Mechanisms
Kim Nasmyth,Christian H. Haering +1 more
TL;DR: Evidence suggests that cohesin acts as a novel topological device that traps chromosomal DNA within a large tripartite ring formed by its core subunits.
References
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Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1
Linheng Li,Ian D. Krantz,Yu Deng,Yu Deng,Anna Genin,Amy B. Banta,Colin Collins,Ming Qi,Barbara J. Trask,Wen Lin Kuo,Joanne Cochran,Teresa Costa,Mary Ella M Pierpont,Elizabeth B. Rand,David A. Piccoli,Leroy Hood,Nancy B. Spinner +16 more
TL;DR: Four distinct coding mutations in JAG1 are demonstrated, providing evidence that it is the causal gene for Alagille syndrome, and supporting the hypothesis that haploinsufficiency for this gene is one of the mechanisms causing the Alagile syndrome phenotype.
Journal ArticleDOI
Cohesin's Binding to Chromosomes Depends on a Separate Complex Consisting of Scc2 and Scc4 Proteins
Rafal Ciosk,Masaki Shirayama,Anna Shevchenko,Tomoyuki Tanaka,Attila Tóth,Andrej Shevchenko,Kim Nasmyth +6 more
TL;DR: It is shown that Scc2p forms a complex with a novel protein, Scc4p, which is also necessary for sister cohesion, suggesting that a major role for the SCC2p/SCC4p complex is to facilitate the loading of cohesin complexes onto chromosomes.
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Mutations in the human Delta homologue, DLL3 , cause axial skeletal defects in spondylocostal dysostosis
Michael P. Bulman,Kenro Kusumi,Timothy M. Frayling,Carole McKeown,Christine Garrett,Eric S. Lander,Robb Krumlauf,Andrew T. Hattersley,Sian Ellard,Peter D. Turnpenny +9 more
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