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.