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Nat Genet. 2014 Nov;46(11):1245-9. doi: 10.1038/ng.3113. Epub 2014 Oct 5.

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

Author information

  • 1Department of Pediatrics, Centre Mère Enfants Soleil, Centre Hospitalier de l'Université (CHU) de Québec, Quebec City, Quebec, Canada.
  • 2Cardiovascular Genetics, Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine Research Centre, Université de Montréal, Montreal, Quebec, Canada.
  • 3Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, Utrecht, the Netherlands.
  • 4Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
  • 5Department of Pediatrics, Université de Montréal, Montreal, Quebec, Canada.
  • 6INSERM U1046, Montpellier, France.
  • 7Department of Women's and Children's Health, Section for Pediatrics, Astrid Lindgren's Children's Hospital, Uppsala University, Uppsala, Sweden.
  • 8Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
  • 9Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
  • 10Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
  • 11Projet BALSAC, Université du Québec à Chicoutimi, Chicoutimi, Quebec, Canada.
  • 121] 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.

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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PMID:
25282101
[PubMed - indexed for MEDLINE]
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