Cohesinopathies of a feather flock together

Abstract

Roberts Syndrome (RBS) and Cornelia de Lange Syndrome (CdLS) are severe developmental maladies that present with nearly an identical suite of multi-spectrum birth defects. Not surprisingly, RBS and CdLS arise from mutations within a single pathway--here involving cohesion. Sister chromatid tethering reactions that comprise cohesion are required for high fidelity chromosome segregation, but cohesin tethers also regulate gene transcription, promote DNA repair, and impact DNA replication. Currently, RBS is thought to arise from elevated levels of apoptosis, mitotic failure, and limited progenitor cell proliferation, while CdLS is thought to arise, instead, from transcription dysregulation. Here, we review new information that implicates RBS gene mutations in altered transcription profiles. We propose that cohesin-dependent transcription dysregulation may extend to other developmental maladies; the diagnoses of which are complicated through multi-functional proteins that manifest a sliding scale of diverse and severe phenotypes. We further review evidence that cohesinopathies are more common than currently posited.

Figure 1. Etiologic and peripheral phenotypes of cohesinopathies.

(A) Cohesins maintain sister chromatid tethering required for normal mitosis (chromosomes in gray, microtubules in green) and also (B) stabilize chromatin loops through which developmental transcription programs of gene inductions and repressions are deployed (E = Enhancer in yellow, P = Promoter in brown, I = Insulator in pink, Blue arrow = Transcription). Additional roles for cohesin as boundary elements that demarcate chromatin domains and terminate transcription are not shown. (C) Cohesion mutations exhibit a sliding scale (purple) of phenotypic manifestations that may include chromosome mis-segregation/aneuploidy, chromosome condensation defects, HR/PCS, apoptosis, and genotoxic sensitivities—phenotypes that fail to correlate with genotype. (D) RBS and CdLS cohesion mutations dysregulate transcription profiles, which we speculate produces the developmental defects in all cohesinopathies (RBS, CdLS, and WABS mutated genes shown in lower case). We hypothesize that developmental maladies such as Treacher Collins Syndrome (TCS), Diamond Blackfan Anemia (DBA), and Nijmegan Breakage Syndrome (NBS) are similarly based on transcription dysregulation.