[Abstract unavailable

Genome-wide studies using cells from patients with Cornelia de Lange Syndrome reveal a role for cohesin in regulating gene expression in human cells.

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...

Rett syndrome (RTT) is an X-linked dominant disabling neurodevelopmental disorder caused by loss of function mutations in the MECP2 gene, located at Xq28, which encodes a multifunctional protein. MECP2 expression is regulated in a developmental stage and cell-type-specific manner. The need for tightly controlled MeCP2 levels in brain is strongly suggested by neurologically abnormal phenotypes of mouse models with mild overexpression and by mental retardation in human males with MECP2 duplication. We set out to identify long-range cis-regulatory sequences that differentially regulate MECP2 transcription and, when mutated, may contribute to the pathogenesis of RTT, autism or X-linked mental retardation. By inter-species sequence comparisons, we detected 27 highly conserved non-coding DNA sequences within a 210 kb region covering MECP2. We functionally confirmed four enhancer and two silencer elements by performing luciferase reporter assays in four different human cell lines. The transcription factor binding capability of the identified regulatory elements was tested by gel shift assays. To locate the human MECP2 core promoter, we dissected the promoter region by reporter assays with deletion constructs. We then used chromosome conformation capture methods to document long-range interactions of three enhancers and two silencers with the MECP2 promoter. Acting over distances of up to 130 kb, these elements may influence chromatin configurations and regulate MECP2 transcription. Our study has defined the "MECP2 functional expression module" and identified enhancer and silencer elements that are likely to be responsible for the tissue-specific, developmental stage-specific or splice-variant-specific control of MeCP2 protein expression.