Cohesinopathies of a feather flock together.

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

Developmental and cytological phenotypes of cohesinopathies and potentially related maladies.

<p>Partial list of developmental and cytological effects in response to cohesion pathway mutations.</p>*<p>Craniofacial dysmorphia include micrognathia, ear abnormalities, wide-set eyes, beaked or prominent nose, arched eyebrows, or low-set ears.</p>+<p>Limb reductions are often symmetric and involve all four limbs in RBS but predominant in upper extremities in CdLS. Limb reduction appears limited to the radius in NBS and FA.</p>**<p>Organ abnormalities may include renal, urinary, gonadal, gastroesophageal, and others.</p>++<p>Detection of cryptic HR/PCS may require cell exposure to mitomycin. ND (Not Diagnostic): most studies document that HR/PCS is not elevated in CdLS cells <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Revenkova1" target="_blank">[17]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Castronovo1" target="_blank">[18]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Vrouwe1" target="_blank">[20]</a>, but see <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Kaur1" target="_blank">[48]</a>. While HR/PCS is thus not efficacious as a diagnostic tool, numerous chromosomal aberrations are evident in CdLS cells upon exposure to genotoxic agents <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Vrouwe1" target="_blank">[20]</a>, revealing that CdLS cells may be predispositioned to PCS/HR. Bolded text represents examples of historical cytological diagnostic markers (HR/PCS for RBS, Clastogen sensitivity for FA). Phenotypes shown for potentially cohesinopathic-related developmental maladies (Ribosomopathies TCS and DBA, Nijmegen Breakage Disease, Fanconi Anemia—last four columns) that we speculate are similarly predicated on transcriptional dysregulation <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Vega1" target="_blank">[1]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Schule1" target="_blank">[2]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Musio1" target="_blank">[5]</a>–<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Krantz1" target="_blank">[8]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Morita1" target="_blank">[14]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Liu1" target="_blank">[26]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Gimigliano1" target="_blank">[33]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Leem1" target="_blank">[41]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Kaur1" target="_blank">[48]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-vanderLelij1" target="_blank">[55]</a>–<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-CapoChichi1" target="_blank">[57]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-vanderLelij3" target="_blank">[61]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Kee1" target="_blank">[63]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Auerbach1" target="_blank">[78]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Genetics1" target="_blank">[79]</a>.</p