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

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

doi:10.1038/ng.3113

Cited by 106 publications

(114 citation statements)

References 48 publications

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“…In humans, the homolog SgoL1 is frequently mutated or abnormally expressed in cancers, affecting the mitotic process (Iwaizumi et al., 2009; Kahyo et al., 2011; Matsuura et al., 2013; Wang et al., 2015). Congenital mutations in human SgoL1 lead to chronic atrial and intestinal dysrhythmia syndrome, affecting the heart and gut rhythm (Chetaille et al., 2014). However, whether the mutations affect AD is unknown.…”

Section: Introductionmentioning

confidence: 99%

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Spontaneous development of Alzheimer's disease‐associated brain pathology in a Shugoshin‐1 mouse cohesinopathy model

et al. 2018

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SummarySpontaneous late‐onset Alzheimer's disease (LOAD) accounts for more than 95% of all human AD. As mice do not normally develop AD and as understanding on molecular processes leading to spontaneous LOAD has been insufficient to successfully model LOAD in mouse, no mouse model for LOAD has been available. Existing mouse AD models are all early‐onset AD (EOAD) models that rely on forcible expression of AD‐associated protein(s), which may not recapitulate prerequisites for spontaneous LOAD. This limitation in AD modeling may contribute to the high failure rate of AD drugs in clinical trials. In this study, we hypothesized that genomic instability facilitates development of LOAD and tested two genomic instability mice models in the brain pathology at the old age. Shugoshin‐1 (Sgo1) haploinsufficient (∓) mice, a model of chromosome instability (CIN) with chromosomal and centrosomal cohesinopathy, spontaneously exhibited a major feature of AD pathology; amyloid beta accumulation that colocalized with phosphorylated Tau, beta‐secretase 1 (BACE), and mitotic marker phospho‐Histone H3 (p‐H3) in the brain. Another CIN model, spindle checkpoint‐defective BubR1−/+ haploinsufficient mice, did not exhibit the pathology at the same age, suggesting the prolonged mitosis‐origin of the AD pathology. RNA‐seq identified ten differentially expressed genes, among which seven genes have indicated association with AD pathology or neuronal functions (e.g., ARC, EBF3). Thus, the model represents a novel model that recapitulates spontaneous LOAD pathology in mouse. The Sgo1−/+ mouse may serve as a novel tool for investigating mechanisms of spontaneous progression of LOAD pathology, for early diagnosis markers, and for drug development.

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Section: Introductionmentioning

confidence: 99%

“…Chetaille et al. (2014) originally reported only 17 patients. The disease‐associated SgoL1 missense mutation was found in <1% in public database.…”

Section: Introductionmentioning

confidence: 99%

Spontaneous development of Alzheimer's disease‐associated brain pathology in a Shugoshin‐1 mouse cohesinopathy model

et al. 2018

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“…This rapid expansion and migration gave rise to regional populations with genetic features that can be explained by founder effects (Bherer et al 2011;Gauvin et al 2014;Moreau et al 2011a;Roy-Gagnon et al 2011). Geneticists have taken advantage of this genetic homogeneity in the French-Canadian founder population of Quebec to map genes involved in rare and common human diseases (Chami et al 2014;Chetaille et al 2014;Laprise 2014;Scriver 2001). To date, however, no WGS project has explored the pattern of rare genetic variation in French Canadians from Quebec, as well as its contribution to disease aetiology.…”

Section: Introductionmentioning

confidence: 99%

Whole-genome sequencing in French Canadians from Quebec

Low‐Kam

Rhainds

et al. 2016

Hum Genet

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Genome-wide association studies (GWAS) have had a tremendous success in the identification of common DNA sequence variants associated with complex human diseases and traits. However, because of their design, GWAS are largely inappropriate to characterize the role of rare and low-frequency DNA variants on human phenotypic variation. Rarer genetic variation is geographically more restricted, supporting the need for local whole-genome sequencing (WGS) efforts to study these variants in specific populations. Here, we present the first large-scale low-pass WGS of the French-Canadian population. Specifically, we sequenced at ~5.6× coverage the whole genome of 1970 French Canadians recruited by the Montreal Heart Institute Biobank and identified 29 million bi-allelic variants (31 % novel), including 19 million variants with a minor allele frequency (MAF) <0.5 %. Genotypes from the WGS data are highly concordant with genotypes obtained by exome array on the same individuals (99.8 %), even when restricting this analysis to rare variants (MAF <0.5, 99.9 %) or heterozygous sites (98.9 %). To further validate our data set, we showed that we can effectively use it to replicate several genetic associations with myocardial infarction risk and blood lipid levels. Furthermore, we analyze the utility of our WGS data set to generate a French-Canadian-specific imputation reference panel and to infer population structure in the Province of Quebec. Our results illustrate the value of low-pass WGS to study the genetics of human diseases in the founder French-Canadian population.

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“…Notably, other disorders have been identified to be caused by mutations in proteins that regulate the complex [8][9][10][11], but the CdLS spectrum is by far the most prevalent disorder recognized to date [58 •• ].…”

Section: Cdls and Cohesinmentioning

confidence: 99%

“…In addition to improving our understanding of CdLS over recent years, mutations in additional cohesin regulatory proteins [8][9][10][11] have been described to cause clinical presentations markedly different from CdLS. Since the term ''cohesinopathy'' does not accurately clarify this distinction, and may lead to confusion in the context of CdLS, the term ''Cornelia de Lange syndrome spectrum disorder'' has recently been proposed [12, 13 •• ].…”

Section: Introductionmentioning

confidence: 99%

Cornelia de Lange Syndrome: A Variable Disorder of Cohesin Pathology

Kline

Deardorff

2015

Curr Genet Med Rep

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Cornelia de Lange syndrome (CdLS) is a rare multiple malformation syndrome including small stature, distinctive craniofacial features, limb anomalies, neurodevelopmental and behavioral abnormalities, and other organ system pathology. Recent literature has demonstrated that typical CdLS and related overlapping disorders display a broad range of severity and pleiotropy, suggesting that considering these diagnoses as a spectrum may be more appropriate. A molecular basis has been identified in many individuals, with mutations in five genes primarily responsible. These genes encode structural or regulatory proteins of the cohesin protein complex, important in chromatid division, cell cycle function, DNA repair, and epigenetic control. This review summarizes clinical findings, current management recommendations, and recent advances in understanding the underlying biologic mechanisms of these overlapping disorders of cohesin pathology.

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

Cited by 106 publications

References 48 publications

Spontaneous development of Alzheimer's disease‐associated brain pathology in a Shugoshin‐1 mouse cohesinopathy model

Spontaneous development of Alzheimer's disease‐associated brain pathology in a Shugoshin‐1 mouse cohesinopathy model

Whole-genome sequencing in French Canadians from Quebec

Cornelia de Lange Syndrome: A Variable Disorder of Cohesin Pathology

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