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

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

doi:10.1038/ng.3113

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

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

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

87 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1245-9
Number of pages	5
Journal	Nature Genetics
Volume	46
Issue number	11
DOIs	https://doi.org/10.1038/ng.3113
Publication status	Published - Nov 2014

Keywords

Abnormalities, Multiple
Animals
Arrhythmias, Cardiac
Cell Cycle
Cell Cycle Proteins
Chromosomal Proteins, Non-Histone
Enteric Nervous System
Fibroblasts
Founder Effect
Gastrointestinal Tract
Gene Knockdown Techniques
Humans
Intestinal Diseases
Karyotyping
Muscle Contraction
Muscle, Smooth, Vascular
Mutation
Quebec
Signal Transduction
Syndrome
Transforming Growth Factor beta
Zebrafish

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Chetaille, P., Preuss, C., Burkhard, S., Côté, J.-M., Houde, C., Castilloux, J., Piché, J., Gosset, N., Leclerc, S., Wünnemann, F., Thibeault, M., Gagnon, C., Galli, A., Tuck, E., Hickson, G. R., El Amine, N., Boufaied, I., Lemyre, E., de Santa Barbara, P. (2014). Mutations in SGOL1 cause a novel cohesinopathy affecting heart and gut rhythm. Nature Genetics, 46(11), 1245-9. https://doi.org/10.1038/ng.3113

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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.",

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Chetaille, P, Preuss, C, Burkhard, S, Côté, J-M, Houde, C, Castilloux, J, Piché, J, Gosset, N, Leclerc, S, Wünnemann, F, Thibeault, M, Gagnon, C, Galli, A, Tuck, E, Hickson, GR, El Amine, N, Boufaied, I, Lemyre, E, de Santa Barbara, P, Faure, S, Jonzon, A, Cameron, M, Dietz, HC, Gallo-McFarlane, E, Benson, DW, Moreau, C, Labuda, D, Zhan, SH, Shen, Y, Jomphe, M, Jones, SJM, Bakkers, J, Andelfinger, G 2014, 'Mutations in SGOL1 cause a novel cohesinopathy affecting heart and gut rhythm', Nature Genetics, vol. 46, no. 11, pp. 1245-9. https://doi.org/10.1038/ng.3113

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AU - Chetaille, Philippe

AU - Preuss, Christoph

AU - Burkhard, Silja

AU - Côté, Jean-Marc

AU - Houde, Christine

AU - Castilloux, Julie

AU - Piché, Jessica

AU - Gosset, Natacha

AU - Leclerc, Séverine

AU - Wünnemann, Florian

AU - Thibeault, Maryse

AU - Gagnon, Carmen

AU - Galli, Antonella

AU - Tuck, Elizabeth

AU - Hickson, Gilles R

AU - El Amine, Nour

AU - Boufaied, Ines

AU - Lemyre, Emmanuelle

AU - de Santa Barbara, Pascal

AU - Faure, Sandrine

AU - Jonzon, Anders

AU - Cameron, Michel

AU - Dietz, Harry C

AU - Gallo-McFarlane, Elena

AU - Benson, D Woodrow

AU - Moreau, Claudia

AU - Labuda, Damian

AU - Zhan, Shing H

AU - Shen, Yaoqing

AU - Jomphe, Michèle

AU - Jones, Steven J M

AU - Bakkers, Jeroen

AU - Andelfinger, Gregor

PY - 2014/11

Y1 - 2014/11

N2 - 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.

AB - 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.

KW - Abnormalities, Multiple

KW - Animals

KW - Arrhythmias, Cardiac

KW - Cell Cycle

KW - Cell Cycle Proteins

KW - Chromosomal Proteins, Non-Histone

KW - Enteric Nervous System

KW - Fibroblasts

KW - Founder Effect

KW - Gastrointestinal Tract

KW - Gene Knockdown Techniques

KW - Humans

KW - Intestinal Diseases

KW - Karyotyping

KW - Muscle Contraction

KW - Muscle, Smooth, Vascular

KW - Mutation

KW - Quebec

KW - Signal Transduction

KW - Syndrome

KW - Transforming Growth Factor beta

KW - Zebrafish

U2 - 10.1038/ng.3113

DO - 10.1038/ng.3113

M3 - Article

C2 - 25282101

SN - 1061-4036

VL - 46

SP - 1245

EP - 1249

JO - Nature Genetics

JF - Nature Genetics

IS - 11

ER -

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

Abstract

Keywords

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