Cohesin and Human Disease

Abstract

Cornelia de Lange syndrome (CdLS) is a dominant multisystem disorder caused by a disruption of cohesin function. The cohesin ring complex is composed of four protein subunits and more than 25 additional proteins involved in its regulation. The discovery that this complex also has a fundamental role in long-range regulation of transcription in Drosophila has shed light on the mechanism likely responsible for its role in development. In addition to the three cohesin proteins involved in CdLS, a second multisystem, recessively inherited, developmental disorder, Roberts-SC phocomelia, is caused by mutations in another regulator of the cohesin complex, ESCO2. Here we review the phenotypes of these disorders, collectively termed cohesinopathies, as well as the mechanism by which cohesin disruption likely causes these diseases. KeywordsCornelia de Lange syndrome; Roberts-SC phocomelia; NIPBL; SMC1A; SMC3; ESCO2 CORNELIA DE LANGE SYNDROMECornelia de Lange syndrome (CdLS) (OMIM #122470 and #300590) was first described in 1849 by Vrolik, who reported a severe example of oligodactyly ( 72 ). In 1916, Brachmann ( 10 ) provided a detailed account of an individual with symmetrical monodactyly, antecubital webbing, dwarfism, cervical ribs, and hirsutism ( 64 ). In the 1930s Cornelia de Lange, a Dutch pediatrician, reported two unrelated girls with strikingly similar features and named the condition after the city in which she worked: degeneration typus amstelodamensis ( 17 , 18 ). Although some literature refers to the disorder as Brachmann-de Lange syndrome (BDLS), the disorder is widely referred to as Cornelia de Lange syndrome in honor of Dr. d e Lange's contributions to the formal characterization of this disorder.CdLS is a dominantly inherited, genetically heterogeneous, multisystem developmental disorder. The phenotype consists of characteristic facial features (including synophrys, long eyelashes, depressed nasal root with an up-tilted tip of the nose and anteverted nares, long philtrum, thin upper lip, small widely spaced teeth, small brachycephalic head, and low-set, DISCLOSURE STATEMENTThe authors are not aware of any biases that might be perceived as affecting the objectivity of this review. HHS Public AccessAuthor manuscript Annu Rev Genomics Hum Genet. Author manuscript; available in PMC 2016 June 06. Published in final edited form as:Annu Rev Genomics Hum Genet. 2008 ; 9: 303-320. doi:10.1146/annurev.genom.9.081307.164211. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript posteriorly angulated ears), hirsutism, various ophthalmologic abnormalities, abnormalities of the upper extremities that range from small hands with single palmar creases and subtle changes in the phalanges and metacarpal bones to severe forms of oligodactyly and truncation of the forearms that primarily involves the ulnar structures, gastroesophageal dysfunction, growth retardation, and neurodevelopmental delay ( 42 , 48 ) ( Figure 1). Other frequently seen findings include ptosis, myopia, intestinal malrotation, c...

Genome-wide Studies of CCCTC-binding Factor (CTCF) and Cohesin Provide Insight into Chromatin Structure and Regulation

“…Cohesin expression is not limited to dividing cells, suggesting additional cellular roles for it. Furthermore, mutations in cohesin underlie diseases such as Cornelia de Lange syndrome (69,70) and developmental defects (71). Because most of these diseaselinked cohesin mutations do not completely abrogate cell division, these disorders may be triggered by malfunction of noncanonical cohesin roles such as altered gene expression rather than loss of chromatid cohesion (66).…”

Timeless functions independently of the Tim-Tipin complex to promote sister chromatid cohesion in normal human fibroblasts

“…The loading of cohesin onto chromatin, the establishment of SCC and the maintenance and dissolution of cohesion are cell cycle-regulated processes. 23 Defective SCC is associated with developmental genetic disorders, including Roberts syndrome, Cordelia de Lange syndrome and Warsaw breakage syndrome, 24,25 and mutations in SCC genes have been detected in cancers. 26 Large-scale genetic screens in yeast have revealed an intricate network of interactions among DNA replication, checkpoint activation and SCC.…”

Sister acts: coordinating DNA replication and cohesion establishment

“…In this review, we discuss how DNA replication and cohesion establishment are coordinated, with specific emphasis on how factors at licensed origins and replication forks modify cohesin's architecture and association with chromatin, and how this in turn affects the dynamics of DNA replication. Highlighting the importance of such regulation, germline mutations that compromise cohesin function are responsible for a constellation of human developmental disorders that have been collectively termed ''cohesinopathies'' (Dorsett 2007;Liu and Krantz 2008). …”