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

Nat Genet. 2014 Nov;46(11):1245-9. doi: 10.1038/ng.3113.

Philippe Chetaille ¹, Christoph Preuss ², Silja Burkhard ³, Jean-Marc Côté ¹, Christine Houde ¹, Julie Castilloux ¹, Jessica Piché ², Natacha Gosset ², Séverine Leclerc ², Florian Wünnemann ², Maryse Thibeault ², Carmen Gagnon ², Antonella Galli ⁴, Elizabeth Tuck ⁴, Gilles R Hickson ⁵, Nour El Amine ⁵, Ines Boufaied ⁵, Emmanuelle Lemyre ⁵, Pascal de Santa Barbara ⁶, Sandrine Faure ⁶, Anders Jonzon ⁷, Michel Cameron ², Harry C Dietz ⁸, Elena Gallo-McFarlane ⁸, D Woodrow Benson ⁹, Claudia Moreau ⁵, Damian Labuda ⁵, FORGE Canada Consortium, Shing H Zhan ¹⁰, Yaoqing Shen ¹⁰, Michèle Jomphe ¹¹, Steven J M Jones ¹⁰, Jeroen Bakkers ³, Gregor Andelfinger ¹²

Affiliations

1 Department of Pediatrics, Centre Mère Enfants Soleil, Centre Hospitalier de l'Université (CHU) de Québec, Quebec City, Quebec, Canada.
2 Cardiovascular Genetics, Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine Research Centre, Université de Montréal, Montreal, Quebec, Canada.
3 Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, Utrecht, the Netherlands.
4 Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
5 Department of Pediatrics, Université de Montréal, Montreal, Quebec, Canada.
6 INSERM U1046, Montpellier, France.
7 Department of Women's and Children's Health, Section for Pediatrics, Astrid Lindgren's Children's Hospital, Uppsala University, Uppsala, Sweden.
8 Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
9 Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
10 Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
11 Projet BALSAC, Université du Québec à Chicoutimi, Chicoutimi, Quebec, Canada.
12 1] Cardiovascular Genetics, Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine Research Centre, Université de Montréal, Montreal, Quebec, Canada. [2] Department of Pediatrics, Université de Montréal, Montreal, Quebec, Canada. [3] Department of Biochemistry, Université de Montréal, Montreal, Quebec, Canada.

PMID: 25282101 DOI: 10.1038/ng.3113

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.

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