Diverse Developmental Disorders from The One Ring: Distinct Molecular Pathways Underlie the Cohesinopathies

Abstract

The multi-subunit protein complex, cohesin, is responsible for sister chromatid cohesion during cell division. The interaction of cohesin with DNA is controlled by a number of additional regulatory proteins. Mutations in cohesin, or its regulators, cause a spectrum of human developmental syndromes known as the “cohesinopathies.” Cohesinopathy disorders include Cornelia de Lange Syndrome and Roberts Syndrome. The discovery of novel roles for chromatid cohesion proteins in regulating gene expression led to the idea that cohesinopathies are caused by dysregulation of multiple genes downstream of mutations in cohesion proteins. Consistent with this idea, Drosophila, mouse, and zebrafish cohesinopathy models all show altered expression of developmental genes. However, there appears to be incomplete overlap among dysregulated genes downstream of mutations in different components of the cohesion apparatus. This is surprising because mutations in all cohesion proteins would be predicted to affect cohesin’s roles in cell division and gene expression in similar ways. Here we review the differences and similarities between genetic pathways downstream of components of the cohesion apparatus, and discuss how such differences might arise, and contribute to the spectrum of cohesinopathy disorders. We propose that mutations in different elements of the cohesion apparatus have distinct developmental outcomes that can be explained by sometimes subtly different molecular effects.

Cornelia de Lange individuals with new and recurrent SMC1A mutations enhance delineation of mutation repertoire and phenotypic spectrum

“…Recurrent mutations could delineate clusters for genotype-phenotype correlations that may either predict disease outcome and evolution, or disclose the actions of modifiers. Individuals carrying novel mutations could enhance the understanding of the mechanisms by which altered SMC1A proteins dysregulate multiple downstream genes [Revenkova et al, 2009;Gimigliano et al, 2012;Horsfield et al, 2012].…”

Control of Vertebrate Development by MYC

“…Finally, the collection of related developmental disorders known as cohesinopathies that include Cornelia de Lange syndrome and Roberts syndrome are linked to misregulation of MYC (Horsfield et al 2012). Cohesinopathies are caused by mutations in components of the cohesin complex, including the cohesin subunits NIPPED-B, SMC1 and SMC3, RAD21, and the cohesin acetyltransferase ESCO2 (Horsfield et al 2012).…”

“…Cohesinopathies are caused by mutations in components of the cohesin complex, including the cohesin subunits NIPPED-B, SMC1 and SMC3, RAD21, and the cohesin acetyltransferase ESCO2 (Horsfield et al 2012). Cohesinopathies show considerable overlapping pathology with VACTERAL association and Feingold syndromes, suggesting potential involvement of MYCN.…”

“…For example, these disorders typically feature short stature, dysmorphic facial features including micrognathia, limb defects, hearing loss, gastrointestinal defects including atresia, cardiac defects, genitourinary defects, and mental retardation (van Bokhoven et al 2005;ShawSmith 2006;Horsfield et al 2012). Interestingly, the cohesin complex, which is best known for its functions in sister chromatid exchange (Horsfield et al 2012), shares with MYC the property of preferentially binding to genes being actively transcribed (Misulovin et al 2008). Furthermore, cohesin has been linked to stimulation of transcription elongation through release of paused RNA polymerase II complexes (Fay et al 2011).…”

Structural maintenance of chromosome complexes and bone development: the beginning of a wonderful relationship?

“…Furthermore, studies have associated cohesin and condensin with several human developmental disorders and cancer. [9][10][11] Cohesin Cohesin is a four-subunit SMC complex that mediates sister chromatid cohesion, the process in which the newly replicated DNA strands, assembled into distinct chromatin fibers, are held together from the time of their formation until their separation during mitosis and meiosis ( Figure 1). Cohesion maintains the fidelity of chromosome segregation by ensuring the bipolar attachment of the sister chromatids centromeres to the spindle.…”