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

被引：90

作者：

Chetaille, Philippe ^{[1
]}

Preuss, Christoph ^{[2
]}

Burkhard, Silja ^{[3
,4
]}

Cote, Jean-Marc ^{[1
]}

Houde, Christine ^{[1
]}

Castilloux, Julie ^{[1
]}

Piche, Jessica ^{[2
]}

Gosset, Natacha ^{[2
]}

Leclerc, Severine ^{[2
]}

Wuennemann, Florian ^{[2
]}

Thibeault, Maryse ^{[2
]}

Gagnon, Carmen ^{[2
]}

Galli, Antonella ^{[5
]}

Tuck, Elizabeth ^{[5
]}

Hickson, Gilles R. ^{[6
]}

El Amine, Nour ^{[6
]}

Boufaied, Ines ^{[6
]}

Lemyre, Emmanuelle ^{[6
]}

Barbara, Pascal de Santa ^{[7
]}

Faure, Sandrine ^{[7
]}

Jonzon, Anders ^{[8
]}

Cameron, Michel ^{[2
]}

Dietz, Harry C. ^{[9
]}

Gallo-McFarlane, Elena ^{[9
]}

Benson, D. Woodrow ^{[10
]}

Moreau, Claudia ^{[6
]}

Labuda, Damian ^{[6
]}

Zhan, Shing H. ^{[11
]}

Shen, Yaoqing ^{[11
]}

Jomphe, Michele ^{[12
]}

Jones, Steven J. M. ^{[11
]}

Bakkers, Jeroen

Andelfinger, Gregor ^{[2
,13
]}

机构：

[1] Ctr Hosp Univ CHU Quebec, Ctr Mere Enfants Soleil, Dept Pediat, Quebec City, PQ, Canada

[2] Univ Montreal, Dept Pediat, Ctr Hosp Univ St Justine Res Ctr, Montreal, PQ H3C 3J7, Canada

[3] Royal Netherlands Acad Arts & Sci KNAW, Hubrecht Inst, Utrecht, Netherlands

[4] Univ Med Ctr Utrecht, Utrecht, Netherlands

[5] Wellcome Trust Sanger Inst, Hinxton, Cambs, England

[6] Univ Montreal, Dept Pediat, Montreal, PQ H3C 3J7, Canada

[7] INSERM U1046, Montpellier, France

[8] Uppsala Univ, Astrid Lindgrens Childrens Hosp, Sect Pediat, Dept Womens & Childrens Hlth, Uppsala, Sweden

[9] Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21205 USA

[10] Med Coll Wisconsin, Dept Pediat, Milwaukee, WI 53226 USA

[11] BC Canc Agcy, Michael Smith Genome Sci Ctr, Vancouver, BC, Canada

[12] Univ Quebec Chicoutimi, Projet BALSAC, Chicoutimi, PQ, Canada

[13] Univ Montreal, Dept Biochem, Montreal, PQ H3C 3J7, Canada

来源：

NATURE GENETICS | 2014年 / 46卷 / 11期

基金：

加拿大健康研究院;

关键词：

DE-LANGE-SYNDROME; IDIOPATHIC INTESTINAL PSEUDOOBSTRUCTION; SICK SINUS SYNDROME; CARDIAC-ARRHYTHMIA;

D O I：

10.1038/ng.3113

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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-beta 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.

引用

页码：1245 / 1249

页数：5

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