Cornelia de Lange syndrome and molecular implications of the cohesin complex: Abstracts from the 7th biennial scientific and educational symposium 2016

Kline, Antonie D.; Krantz, Ian D.; Deardorff, Matthew A.; Shirahige, Katsuhiko; Dorsett, Dale; Gerton, Jennifer L.; Wu, Meng; Mehta, Daryush D.; Mills, Jason A.; Carrico, Cheri S.; Noon, Sarah E.; Herrera, Pamela S.; Horsfield, Julia A.; Bettale, Chiara; Morgan, Jeremy P; Huisman, Sylvia; Moss, Joanna; McCleery, Joseph P.; Grados, Marco A.; Hansen, Blake D.; Srivastava, Siddharth; Taylor-Snell, Emily; Kerr, Lynne M.; Katz, Olivia; Calof, Anne L.; Musio, Antonio; Egense, Alena; Haaland, Richard E.

doi:10.1002/ajmg.a.38161

Cited by 13 publications

(10 citation statements)

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“…Whether the AD pathology is caused by cohesinopathy, centrosome defect, or the common consequence that is prolonged mitosis must be distinguished. Cohesinopathy in humans leads to diseases with cancer proneness, developmental malformation, and/or intellectual disability and behavioral issues, such as Cornelia de Lange syndrome or mutations in STAG1 or STAG2 (Kline et al., 2017; Kumar et al., 2015). The symptoms suggest that maintenance of chromosome cohesion may play a role more critical than previously anticipated in brain functions.…”

Section: Discussionmentioning

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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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: Discussionmentioning

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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“…Although SgoL1 mutation itself remains under-characterized in the human LOAD brain, many other causes, e.g. spindle checkpoint-activating events, such as the aneuploidy that is prevalent in aged brains [115] or dysfunction in mitosis-regulatory genes that also induce cohesinopathy (genes of cohesins or centrosome components), can produce prolonged mitosis in the human brain that results in the functional equivalent of Sgo1 mutation [74,[116][117][118][119] Implications of LOAD mouse model on AD drug research and development (R&D)…”

Section: Late-onset Accumulation Of Amyloid-beta In Sgo1 Brainmentioning

confidence: 99%

Critical role of mitosis in spontaneous late-onset Alzheimer’s disease; from a Shugoshin 1 cohesinopathy mouse model

et al. 2018

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From early-onset Alzheimer's disease (EOAD) studies, the amyloid-beta hypothesis emerged as the foremost theory of the pathological causes of AD. However, how amyloid-beta accumulation is triggered and progresses toward senile plaques in spontaneous late-onset Alzheimer's disease (LOAD) in humans remains unanswered. Various LOAD facilitators have been proposed, and LOAD is currently considered a complex disease with multiple causes. Mice do not normally develop LOAD. Possibly due to the multiple causes, proposed LOAD facilitators have not been able to replicate spontaneous LOAD in mice, representing a disease modeling issue. Recently, we reported spontaneous late-onset development of amyloid-beta accumulation in brains of Shugoshin 1 (Sgo1) haploinsufficient mice, a cohesinopathy-mediated chromosome instability model. The result for the first time expands disease relevance of mitosis studies to a major disease other than cancers. Reverse-engineering of the model would shed light on the process of late-onset amyloid-beta accumulation in the brain and spontaneous LOAD development, and contribute to development of interventions for LOAD. This review will discuss the Sgo1 model, our current "three-hit hypothesis" regarding LOAD development with an emphasis on critical role of prolonged mitosis in amyloid-beta accumulation, and implications for human LOAD intervention and treatment. Abbreviations: Alzheimer's disease (AD); Late-onset Alzheimer's disease (LOAD); Early-onset Alzheimer's disease (EOAD); Shugoshin-1 (Sgo1); Chromosome Instability (CIN); apolipoprotein (Apoe); Central nervous system (CNS); Amyloid precursor protein (APP); N-methyl-d-aspartate (NMDA); Hazard ratio (HR); Cyclin-dependent kinase (CDK); Chronic Atrial Intestinal Dysrhythmia (CAID); beta-secretase 1 (BACE); phosphor-Histone H3 (p-H3); Research and development (R&D); Non-steroidal anti-inflammatory drugs (NSAIDs); Brain blood barrier (BBB).

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“…Furthermore, short stature occurs proportionally and hypertrichosis is commonly observed. 3,4 Previous studies have shown that upper extremity defects ranging from clinodactyly to severe reduction defects of the forearms have been reported in approximately 30% of individuals with CdLS. Although, cardiac anomaly is not a major criterion of the disease, approximately 50% of CdLS patients presented with congenital heart defects.…”

Section: Introductionmentioning

confidence: 99%

“…Although, cardiac anomaly is not a major criterion of the disease, approximately 50% of CdLS patients presented with congenital heart defects. 4 5 Approximately 50% of individuals with CdLS have ocular anomalies with the most common being ptosis, myopia, nystagmus, and strabismus. Many individuals with CdLS demonstrate neuropsychiatric features including seizures, autistic behavior, and self-destructive tendencies.…”

Section: Introductionmentioning

confidence: 99%

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A Novel Mutation in NIPBL Gene with the Cornelia de Lange Syndrome and a 10q11.22-q11.23 Microdeletion in the Same Individual

et al. 2020

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The Cornelia de Lange syndrome (CdLS) is a genetic disorder characterized by multisystemic malformations. CdLS is due to mutations in one of the following genes: NIPBL, SMC1A, SMC3, RAD21, and HDAC8. On the other hand, 10q11.2 deletions cause a wide range of presentations in patients. Approximately 40 cases with variable deletions of 10q11.2 have been reported in literature. Some of the reported cases involve the coexistence of duplication or deletion affecting one copy of the chromosome. However, deletion of chromosome 10q11.22-q11.23 and CdLS syndrome caused by NIPBL gene mutations have not been reported previously. This report, therefore, is the first to report their coexistence together.

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Cornelia de Lange syndrome and molecular implications of the cohesin complex: Abstracts from the 7th biennial scientific and educational symposium 2016

Cited by 13 publications

References 0 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

Critical role of mitosis in spontaneous late-onset Alzheimer’s disease; from a Shugoshin 1 cohesinopathy mouse model

A Novel Mutation in NIPBL Gene with the Cornelia de Lange Syndrome and a 10q11.22-q11.23 Microdeletion in the Same Individual

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