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,

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgaveArtikelWetenschappelijkpeer review

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)1245-9
Aantal pagina's5
TijdschriftNature Genetics
Volume46
Nummer van het tijdschrift11
DOI's
StatusGepubliceerd - nov 2014

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