The expanding phenotypes of cohesinopathies: one ring to rule them all!

Abstract

Preservation and development of life depend on the adequate segregation of sister chromatids during mitosis and meiosis. This process is ensured by the cohesin multi-subunit complex. Mutations in this complex have been associated with an increasing number of diseases, termed cohesinopathies. The best characterized cohesinopathy is Cornelia de Lange syndrome (CdLS), in which intellectual and growth retardations are the main phenotypic manifestations. Despite some overlap, the clinical manifestations of cohesinopathies vary considerably. Novel roles of the cohesin complex have emerged during the past decades, suggesting that important cell cycle regulators exert important biological effects through noncohesion-related functions and broadening the potential pathomechanisms involved in cohesinopathies. This review focuses on non-cohesion-related functions of the cohesin complex, gene dosage effect, epigenetic regulation and TGF-β in cohesinopathy context, especially in comparison to Chronic Atrial and Intestinal Dysrhythmia (CAID) syndrome, a very distinct cohesinopathy caused by a homozygous Shugoshin-1 (SGO1) mutation (K23E) and characterized by pacemaker failure in both heart (sick sinus syndrome followed by atrial flutter) and gut (chronic intestinal pseudo-obstruction) with no intellectual or growth delay. We discuss the possible impact of SGO1 alterations in human pathologies and the potential impact of the SGO1 K23E mutation in the sinus node and gut development and functions. We suggest that the human phenotypes observed in CdLS, CAID syndrome and other cohesinopathies can inform future studies into the less well-known non-cohesion-related functions of cohesin complex genes.

Evaluating Face2Gene as a Tool to Identify Cornelia de Lange Syndrome by Facial Phenotypes

“…The cohesin complex is not only involved in sister chromatids cohesion, but it also exhibits novel biological functions, such as the regulation of gene transcription [7][8][9], thus extending the range of pathomechanisms relevant for cohesinopathies and potentially explaining the variability in the clinical manifestations of CdLS [10][11][12][13]. Furthermore, other chromatin dysregulation disorders [14], cohesinopathies [15] and/or transcriptomopathies [16] present overlapping phenotypes with CdLS, such as CHOPS syndrome (OMIM #616368), KBG syndrome (OMIM #148050), Rubinstein-Taybi syndrome (RSTS, OMIM #180849, #613684), Wiedemann-Steiner syndrome (WDSTS, OMIM #605130), Coffin-Siris syndrome (CSS, OMIM #135900) and Nicolaides-Baraitser syndrome (NCBRS, OMIM #601358).…”

SMC5/6 is required for replication fork stability and faithful chromosome segregation during neurogenesis

“…Mutations within genes encoding SMC complex components are associated with human developmental defects. Collectively known as cohesinopathies, mutations in cohesin components lead to an array of abnormalities, including growth retardation and cognitive impairment ( Boyle et al, 2015 ; Piché et al, 2019 ). Mutations in condensin components lead to primary microcephaly due to chromosome decatenation failure during mitosis ( Martin et al, 2016 ; Nishide and Hirano, 2014 ).…”

Mutation severity spectrum of rare alleles in the human genome is predictive of disease type

“…The protein-coding products of these genes comprise three of the four subunits of the mitotic cohesion complex responsible for chromosome segregation. Mutations in this complex are known to cause a number of diseases termed cohesinopathies, of which CdLS is the best characterized [71]. One additional chromosome segregation gene from this set, PDS5 cohesin associated factor A (PDS5A), is associated with CdLS in DisGeNET literature [72].…”