title: 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.
authors.affiliation: Department of Pediatrics, Centre Mère Enfants Soleil, Centre Hospitalier de l'Université (CHU) de Québec, Quebec City, Quebec, Canada.
authors.forename: Philippe
authors.initials: P
authors.lastname: Chetaille
authors.affiliation: Cardiovascular Genetics, Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine Research Centre, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Christoph
authors.initials: C
authors.lastname: Preuss
authors.affiliation: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Silja
authors.initials: S
authors.lastname: Burkhard
authors.affiliation: Department of Pediatrics, Centre Mère Enfants Soleil, Centre Hospitalier de l'Université (CHU) de Québec, Quebec City, Quebec, Canada.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Côté
authors.affiliation: Department of Pediatrics, Centre Mère Enfants Soleil, Centre Hospitalier de l'Université (CHU) de Québec, Quebec City, Quebec, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: Houde
authors.affiliation: Department of Pediatrics, Centre Mère Enfants Soleil, Centre Hospitalier de l'Université (CHU) de Québec, Quebec City, Quebec, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Castilloux
authors.affiliation: Cardiovascular Genetics, Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine Research Centre, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Jessica
authors.initials: J
authors.lastname: Piché
authors.affiliation: Cardiovascular Genetics, Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine Research Centre, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Natacha
authors.initials: N
authors.lastname: Gosset
authors.affiliation: Cardiovascular Genetics, Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine Research Centre, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Séverine
authors.initials: S
authors.lastname: Leclerc
authors.affiliation: Cardiovascular Genetics, Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine Research Centre, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Florian
authors.initials: F
authors.lastname: Wünnemann
authors.affiliation: Cardiovascular Genetics, Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine Research Centre, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Maryse
authors.initials: M
authors.lastname: Thibeault
authors.affiliation: Cardiovascular Genetics, Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine Research Centre, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Carmen
authors.initials: C
authors.lastname: Gagnon
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Antonella
authors.initials: A
authors.lastname: Galli
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Tuck
authors.affiliation: Department of Pediatrics, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Gilles R
authors.initials: GR
authors.lastname: Hickson
authors.affiliation: Department of Pediatrics, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Nour
authors.initials: N
authors.lastname: El Amine
authors.affiliation: Department of Pediatrics, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Ines
authors.initials: I
authors.lastname: Boufaied
authors.affiliation: Department of Pediatrics, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Lemyre
authors.affiliation: INSERM U1046, Montpellier, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: de Santa Barbara
authors.affiliation: INSERM U1046, Montpellier, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Faure
authors.affiliation: Department of Women's and Children's Health, Section for Pediatrics, Astrid Lindgren's Children's Hospital, Uppsala University, Uppsala, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Jonzon
authors.affiliation: Cardiovascular Genetics, Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine Research Centre, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Michel
authors.initials: M
authors.lastname: Cameron
authors.affiliation: Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Harry C
authors.initials: HC
authors.lastname: Dietz
authors.affiliation: Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Gallo-McFarlane
authors.affiliation: Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: D Woodrow
authors.initials: DW
authors.lastname: Benson
authors.affiliation: Department of Pediatrics, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Claudia
authors.initials: C
authors.lastname: Moreau
authors.affiliation: Department of Pediatrics, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Damian
authors.initials: D
authors.lastname: Labuda
authors.affiliation: Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Shing H
authors.initials: SH
authors.lastname: Zhan
authors.affiliation: Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Yaoqing
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Projet BALSAC, Université du Québec à Chicoutimi, Chicoutimi, Quebec, Canada.
authors.forename: Michèle
authors.initials: M
authors.lastname: Jomphe
authors.affiliation: Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Steven J M
authors.initials: SJ
authors.lastname: Jones
authors.affiliation: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Jeroen
authors.identifier: 0000000294180422
authors.initials: J
authors.lastname: Bakkers
authors.affiliation: 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.
authors.forename: Gregor
authors.initials: G
authors.lastname: Andelfinger
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000473:pathology; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics*; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D017615:Enteric Nervous System / Q000473:pathology; D005347:Fibroblasts; D018703:Founder Effect; D041981:Gastrointestinal Tract / Q000503:physiopathology; D055785:Gene Knockdown Techniques; D006801:Humans; D007410:Intestinal Diseases / Q000235:genetics* / Q000503:physiopathology; D007621:Karyotyping; D009119:Muscle Contraction / Q000235:genetics / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D009154:Mutation / Q000235:genetics; D011792:Quebec; D015398:Signal Transduction / Q000235:genetics*; D013577:Syndrome; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015027:Zebrafish; D000097722:Cohesins
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D016212:Transforming Growth Factor beta; D000097722:Cohesins; C496644:SGO1 protein, human