Mutations in SGOL1 cause a novel cohesinopathy affecting heart and gut rhythm. Nat Genet 2014 Nov;46(11):1245-9
Date
10/06/2014Pubmed ID
25282101DOI
10.1038/ng.3113Scopus ID
2-s2.0-84908684632 (requires institutional sign-in at Scopus site) 94 CitationsAbstract
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.
Author List
Chetaille P, Preuss C, Burkhard S, Côté JM, 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, FORGE Canada Consortium, Zhan SH, Shen Y, Jomphe M, Jones SJ, Bakkers J, Andelfinger GMESH terms used to index this publication - Major topics in bold
Abnormalities, MultipleAnimals
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