Mutations in SGOL1 cause a novel cohesinopathy affecting heart and gut rhythm

Abstract

The pacemaking activity of specialized tissues in the heart and gut results in lifelong rhythmic contractions. Here we describe a new syndrome characterized by Chronic Atrial and Intestinal Dysrhythmia, termed CAID syndrome, in 16 French Canadians and 1 Swede. We show that a single shared homozygous founder mutation in SGOL1, a component of the cohesin complex, causes CAID syndrome. Cultured dermal fibroblasts from affected individuals showed accelerated cell cycle progression, a higher rate of senescence and enhanced activation of TGF-β signaling. Karyotypes showed the typical railroad appearance of a centromeric cohesion defect. Tissues derived from affected individuals displayed pathological changes in both the enteric nervous system and smooth muscle. Morpholino-induced knockdown of sgol1 in zebrafish recapitulated the abnormalities seen in humans with CAID syndrome. Our findings identify CAID syndrome as a novel generalized dysrhythmia, suggesting a new role for SGOL1 and the cohesin complex in mediating the integrity of human cardiac and gut rhythm.

Spontaneous development of Alzheimer's disease‐associated brain pathology in a Shugoshin‐1 mouse cohesinopathy model

“…In humans, the homolog SgoL1 is frequently mutated or abnormally expressed in cancers, affecting the mitotic process (Iwaizumi et al., 2009; Kahyo et al., 2011; Matsuura et al., 2013; Wang et al., 2015). Congenital mutations in human SgoL1 lead to chronic atrial and intestinal dysrhythmia syndrome, affecting the heart and gut rhythm (Chetaille et al., 2014). However, whether the mutations affect AD is unknown.…”

“…Chetaille et al. (2014) originally reported only 17 patients. The disease‐associated SgoL1 missense mutation was found in <1% in public database.…”

Whole-genome sequencing in French Canadians from Quebec

“…This rapid expansion and migration gave rise to regional populations with genetic features that can be explained by founder effects (Bherer et al 2011;Gauvin et al 2014;Moreau et al 2011a;Roy-Gagnon et al 2011). Geneticists have taken advantage of this genetic homogeneity in the French-Canadian founder population of Quebec to map genes involved in rare and common human diseases (Chami et al 2014;Chetaille et al 2014;Laprise 2014;Scriver 2001). To date, however, no WGS project has explored the pattern of rare genetic variation in French Canadians from Quebec, as well as its contribution to disease aetiology.…”

Cornelia de Lange Syndrome: A Variable Disorder of Cohesin Pathology

“…Notably, other disorders have been identified to be caused by mutations in proteins that regulate the complex [8][9][10][11], but the CdLS spectrum is by far the most prevalent disorder recognized to date [58 •• ].…”

“…In addition to improving our understanding of CdLS over recent years, mutations in additional cohesin regulatory proteins [8][9][10][11] have been described to cause clinical presentations markedly different from CdLS. Since the term ''cohesinopathy'' does not accurately clarify this distinction, and may lead to confusion in the context of CdLS, the term ''Cornelia de Lange syndrome spectrum disorder'' has recently been proposed [12, 13 •• ].…”