Mutations in SGOL1 Cause a Novel Cohesinopathy Affecting Heart and Gut Rhythm

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • SGO1 protein, human
  • Transforming Growth Factor beta
  • cohesins