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Review
. 2019 Nov;18(21):2828-2848.
doi: 10.1080/15384101.2019.1658476. Epub 2019 Sep 13.

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

Jessica Piché  1 , Patrick Piet Van Vliet  1   2   3 , Michel Pucéat  2   3   4 , Gregor Andelfinger  1
Affiliations
Review

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

Jessica Piché et al. Cell Cycle. 2019 Nov.

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 non-cohesion-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. Abbreviations: AD: Alzheimer Disease; AFF4: AF4/FMR2 Family Member 4; ANKRD11: Ankyrin Repeat Domain 11; APC: Anaphase Promoter Complex; ASD: Atrial Septal Defect; ATRX: ATRX Chromatin Remodeler; ATRX: Alpha Thalassemia X-linked intellectual disability syndrome; BIRC5: Baculoviral IAP Repeat Containing 5; BMP: Bone Morphogenetic Protein; BRD4: Bromodomain Containing 4; BUB1: BUB1 Mitotic Checkpoint Serine/Threonine Kinase; CAID: Chronic Atrial and Intestinal Dysrhythmia; CDK1: Cyclin Dependent Kinase 1; CdLS: Cornelia de Lange Syndrome; CHD: Congenital Heart Disease; CHOPS: Cognitive impairment, coarse facies, Heart defects, Obesity, Pulmonary involvement, Short stature, and skeletal dysplasia; CIPO: Chronic Intestinal Pseudo-Obstruction; c-kit: KIT Proto-Oncogene Receptor Tyrosine Kinase; CoATs: Cohesin Acetyltransferases; CTCF: CCCTC-Binding Factor; DDX11: DEAD/H-Box Helicase 11; ERG: Transcriptional Regulator ERG; ESCO2: Establishment of Sister Chromatid Cohesion N-Acetyltransferase 2; GJC1: Gap Junction Protein Gamma 1; H2A: Histone H2A; H3K4: Histone H3 Lysine 4; H3K9: Histone H3 Lysine 9; HCN4: Hyperpolarization Activated Cyclic Nucleotide Gated Potassium and Sodium Channel 4;p HDAC8: Histone deacetylases 8; HP1: Heterochromatin Protein 1; ICC: Interstitial Cells of Cajal; ICC-MP: Myenteric Plexus Interstitial cells of Cajal; ICC-DMP: Deep Muscular Plexus Interstitial cells of Cajal; If: Pacemaker Funny Current; IP3: Inositol trisphosphate; JNK: C-Jun N-Terminal Kinase; LDS: Loeys-Dietz Syndrome; LOAD: Late-Onset Alzheimer Disease; MAPK: Mitogen-Activated Protein Kinase; MAU: MAU Sister Chromatid Cohesion Factor; MFS: Marfan Syndrome; NIPBL: NIPBL, Cohesin Loading Factor; OCT4: Octamer-Binding Protein 4; P38: P38 MAP Kinase; PDA: Patent Ductus Arteriosus; PDS5: PDS5 Cohesin Associated Factor; P-H3: Phospho Histone H3; PLK1: Polo Like Kinase 1; POPDC1: Popeye Domain Containing 1; POPDC2: Popeye Domain Containing 2; PP2A: Protein Phosphatase 2; RAD21: RAD21 Cohesin Complex Component; RBS: Roberts Syndrome; REC8: REC8 Meiotic Recombination Protein; RNAP2: RNA polymerase II; SAN: Sinoatrial node; SCN5A: Sodium Voltage-Gated Channel Alpha Subunit 5; SEC: Super Elongation Complex; SGO1: Shogoshin-1; SMAD: SMAD Family Member; SMC1A: Structural Maintenance of Chromosomes 1A; SMC3: Structural Maintenance of Chromosomes 3; SNV: Single Nucleotide Variant; SOX2: SRY-Box 2; SOX17: SRY-Box 17; SSS: Sick Sinus Syndrome; STAG2: Cohesin Subunit SA-2; TADs: Topology Associated Domains; TBX: T-box transcription factors; TGF-β: Transforming Growth Factor β; TGFBR: Transforming Growth Factor β receptor; TOF: Tetralogy of Fallot; TREK1: TREK-1 K(+) Channel Subunit; VSD: Ventricular Septal Defect; WABS: Warsaw Breakage Syndrome; WAPL: WAPL Cohesin Release Factor.

Keywords: CAID syndrome; Cohesinopathies; SGO1; TGF-β signaling; cohesin complex; epigenetics.

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Figures

Figure 1.
Figure 1.
Components (SMC1, SMC3, RAD21, and STAG1/2) and partners of the cohesin complex. Colors indicate proteins whose mutated forms are involved in cohesinopathies. Blue: CdLS (NIPBL, HDAC8, SMC1A, SMC3, RAD21, BRD4, ANKRD11), Orange: RBS (ESCO2), Pink: WBS (DDX11), Red: ATRX (ATRX), Yellow: CHOPS (AFF4), Green: STAG2-related X-linked Intellectual Deficiency (STAG2) and Purple: CAID syndrome (SGO1) .
Figure 2.
Figure 2.
Functions of the cohesin complex in cohesion and in non-cohesion-related mechanisms.
Figure 3.
Figure 3.
(a) Schematic representation of SGO1 isoforms. (b) Schematic structure of SGO1 (isoform A2) and binding sites. Numbers refer to SGO1 exons. In sillico 3D reconstruction and electronic cloud of (c) the native SGO1 protein (d) the K23E mutated SGO1 protein. I-TASSER server was used for protein structure and function prediction. The K23E mutation alters the 3D configuration and the electronic cloud in the N-terminal region.
Figure 4.
Figure 4.
Comparison of the canonical and noncanonical findings of SGO1 K23E mutation with SGO1 haploinsufficiency in mice and other cohesinopathies to highlight the differences between each condition. Blue: Cohesinopathies. Green: CAID syndrome (SGO1 K23E mutation). Purple: Sgo1± mice. Direct findings are indicated by arrows.
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Grants and funding

This work was supported by the Fonds de Recherche en Santé du Québec (FRSQ), the Canadian Institutes of Health Research (CIHR), the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (ZonMW), the Fonds for Wetenschappelijk Onderzoek (FWO), and the Agence Nationale de Recherche (ANR) for the E-RARE CoHEART network.