BubR1 allelic effects drive phenotypic heterogeneity in MVA progeria syndrome [10 month old RNA-seq]
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ABSTRACT:
PROVIDER: PRJNA556413 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9822920_1.fastq.gz | Fastqsanger.gz | |||
| SRR9822920_2.fastq.gz | Fastqsanger.gz | |||
| SRR9822930_1.fastq.gz | Fastqsanger.gz | |||
| SRR9822930_2.fastq.gz | Fastqsanger.gz | |||
| SRR9822940_1.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:Mosaic-variegated aneuploidy (MVA) syndrome is a rare childhood disorder characterized by biallelic BUBR1, CEP57, or TRIP13 aberrations, increased chromosome missegregation, and a broad spectrum of clinical features, including various cancers, congenital defects, and progeroid pathologies. To investigate the mechanisms underlying this disorder and its phenotypic heterogeneity, we mimicked the BUBR1L1012P mutation in mice (BubR1L1002P) and combined it with two other MVA variants, BUBR1X753 and BUBR1H, generating a truncated protein and low amounts of wildtype protein, respectively. Whereas, BubR1X753/L1002P and BubR1H/X753 mice die prematurely, BubR1H/L1002P mice are viable and exhibit many MVA features, including cancer predisposition and various progeroid phenotypes, including short lifespan, dwarfism, lipodystrophy, sarcopenia, and low cardiac stress tolerance. Strikingly, although these mice had a similar reduction in total BubR1 and spectrum of MVA phenotypes as BubR1H/H mice, several progeroid pathologies were attenuated in severity, which in skeletal muscle coincided with reduced senescence-associated secretory phenotype (SASP) complexity. Additionally, mice harboring heterozygous BUBR1 MVA variants developed mild MVA pathologies later in life, with alleles conferring unique phenotypic profiles. Together, these data demonstrate that subtle BUBR1 allelic effects contribute to disease heterogeneity in both MVA patients and heterozygous carriers of MVA mutations, independent of aneuploidy rates and BUBR1 protein levels.
2020-02-04 | GSE134781 | GEO
Project description:Mosaic-variegated aneuploidy (MVA) syndrome is a rare childhood disorder characterized by biallelic BUBR1, CEP57, or TRIP13 aberrations, increased chromosome missegregation, and a broad spectrum of clinical features, including various cancers, congenital defects, and progeroid pathologies. To investigate the mechanisms underlying this disorder and its phenotypic heterogeneity, we mimicked the BUBR1L1012P mutation in mice (BubR1L1002P) and combined it with two other MVA variants, BUBR1X753 and BUBR1H, generating a truncated protein and low amounts of wildtype protein, respectively. Whereas, BubR1X753/L1002P and BubR1H/X753 mice die prematurely, BubR1H/L1002P mice are viable and exhibit many MVA features, including cancer predisposition and various progeroid phenotypes, including short lifespan, dwarfism, lipodystrophy, sarcopenia, and low cardiac stress tolerance. Strikingly, although these mice had a similar reduction in total BubR1 and spectrum of MVA phenotypes as BubR1H/H mice, several progeroid pathologies were attenuated in severity, which in skeletal muscle coincided with reduced senescence-associated secretory phenotype (SASP) complexity. Additionally, mice harboring heterozygous BUBR1 MVA variants developed mild MVA pathologies later in life, with alleles conferring unique phenotypic profiles. Together, these data demonstrate that subtle BUBR1 allelic effects contribute to disease heterogeneity in both MVA patients and heterozygous carriers of MVA mutations, independent of aneuploidy rates and BUBR1 protein levels.
2020-02-04 | GSE134780 | GEO
Project description:BubR1 allelic effects drive phenotypic heterogeneity in MVA progeria syndrome [3 month old RNA-seq]
| PRJNA556410 | ENA
Project description:BubR1 allelic effects drive phenotypic heterogeneity in MVA progeria syndrom
| PRJEB33810 | ENA
Project description:Congenital heart defects (CHDs) are the most common type of congenital defects in humans and have consequences across the lifespan. Mutations in BubR1 cause mosaic variegated aneuploidy (MVA) syndrome in which patients develop CHDs such as atrial and ventricular septal defects. We observed that cardiac-specific BubR1 deletion causes embryonic lethality due to defects at the structural and cellular defects. We conducted single cell RNA sequencing (ScRNA-seq) to determine the defects that occur in the absence of BubR1 at the molecular level in the developing myocardium.
2025-02-18 | GSE270226 | GEO
Project description:Chromosome aneuploidy increases in oocytes with maternal age, and is considered the leading cause for the increased incidence of infertility, miscarriage, and birth defects. Using mRNA-Sequencing of oocytes from 12 month old mouse versus 3 month young mouse, we identified a spindle assembly checkpoint gene, BubR1, whose expression was significantly decreased. We employed a mRNA microinjection based approach to increase BubR1 expression in aging oocytes. We find that increased expression of BubR1 protects against aneuploidy and chromosome misalignment in aging oocytes. After in vitro fertilization, the embryos derived from BubR1 increased expression aging oocytes exhibited chromosome stability as robust as those of the young ones. Furthermore, following embryo transfer, these embryos showed greatly improved developmental competency, with comparable levels of full-term development to those of the young ones. These results indicate that the decline in oocyte quality may be reversible and could lead to treatments that prolong female fertility. Examination of the effect of maternal aging on the mRNA expression in the mature oocytes of the female mice. Naturally ovulated mature oocytes (MII stage) were collected from 6 young (3 month) and 6 aging (12 month) female mice (3 oocytes per mice, 18 oocytes for each group).
2014-05-10 | E-GEOD-57482 | biostudies-arrayexpress
Project description:Chromosome aneuploidy increases in oocytes with maternal age, and is considered the leading cause for the increased incidence of infertility, miscarriage, and birth defects. Using mRNA-Sequencing of oocytes from 12 month old mouse versus 3 month young mouse, we identified a spindle assembly checkpoint gene, BubR1, whose expression was significantly decreased. We employed a mRNA microinjection based approach to increase BubR1 expression in aging oocytes. We find that increased expression of BubR1 protects against aneuploidy and chromosome misalignment in aging oocytes. After in vitro fertilization, the embryos derived from BubR1 increased expression aging oocytes exhibited chromosome stability as robust as those of the young ones. Furthermore, following embryo transfer, these embryos showed greatly improved developmental competency, with comparable levels of full-term development to those of the young ones. These results indicate that the decline in oocyte quality may be reversible and could lead to treatments that prolong female fertility.
2014-05-10 | GSE57482 | GEO
Project description:Mosaic-variegated aneuploidy (MVA) syndrome is a rare childhood disorder characterized by biallelic BUBR1, CEP57, or TRIP13 aberrations; increased chromosome missegregation; and a broad spectrum of clinical features, including various cancers, congenital defects, and progeroid pathologies. To investigate the mechanisms underlying this disorder and its phenotypic heterogeneity, we mimicked the BUBR1L1012P mutation in mice (BubR1L1002P) and combined it with 2 other MVA variants, BUBR1X753 and BUBR1H, generating a truncated protein and low amounts of wild-type protein, respectively. Whereas BubR1X753/L1002P and BubR1H/X753 mice died prematurely, BubR1H/L1002P mice were viable and exhibited many MVA features, including cancer predisposition and various progeroid phenotypes, such as short lifespan, dwarfism, lipodystrophy, sarcopenia, and low cardiac stress tolerance. Strikingly, although these mice had a reduction in total BUBR1 and spectrum of MVA phenotypes similar to that of BubR1H/H mice, several progeroid pathologies were attenuated in severity, which in skeletal muscle coincided with reduced senescence-associated secretory phenotype complexity. Additionally, mice carrying monoallelic BubR1 mutations were prone to select MVA-related pathologies later in life, with predisposition to sarcopenia correlating with mTORC1 hyperactivity. Together, these data demonstrate that BUBR1 allelic effects beyond protein level and aneuploidy contribute to disease heterogeneity in both MVA patients and heterozygous carriers of MVA mutations.
| S-EPMC6934189 | biostudies-literature
Project description:Mosaic Variegated Aneuploidy (MVA) syndrome is a rare autosomal recessive disorder characterized by inaccurate chromosome segregation and high rates of near-diploid aneuploidy. Children with MVA syndrome die at an early age, are cancer prone, and have progeroid features like facial dysmorphisms, short stature, and cataracts. The majority of MVA cases are linked to mutations in BUBR1, a mitotic checkpoint gene required for proper chromosome segregation. Affected patients either have bi-allelic BUBR1 mutations, with one allele harboring a missense mutation and the other a nonsense mutation, or mono-allelic BUBR1 mutations combined with allelic variants that yield low amounts of wild-type BubR1 protein. Parents of MVA patients that carry single allele mutations have mild mitotic defects, but whether they are at risk for any of the pathologies associated with MVA syndrome is unknown. To address this, we engineered a mouse model for the nonsense mutation 2211insGTTA (referred to as GTTA) found in MVA patients with bi-allelic BUBR1 mutations. Here we report that both the median and maximum lifespans of the resulting BubR1(+/GTTA) mice are significantly reduced. Furthermore, BubR1(+/GTTA) mice develop several aging-related phenotypes at an accelerated rate, including cataract formation, lordokyphosis, skeletal muscle wasting, impaired exercise ability, and fat loss. BubR1(+/GTTA) mice develop mild aneuploidies and show enhanced growth of carcinogen-induced tumors. Collectively, these data demonstrate that the BUBR1 GTTA mutation compromises longevity and healthspan, raising the interesting possibility that mono-allelic changes in BUBR1 might contribute to differences in aging rates in the general population.
| S-EPMC3531486 | biostudies-literature
Project description:Aging is a major risk factor for cardiovascular diseases, including heart failure, and contributes to pathological changes such as hypertrophy, fibrosis, and cellular senescence in the heart. BubR1, a critical regulator of the spindle assembly checkpoint, has been linked to various aging phenotypes, though its specific role in the heart remains largely unexplored. In this study, we examined the effects of BubR1 insufficiency in hypomorphic mice, revealing significant cardiac hypertrophy, fibrosis, and increased markers of cellular senescence. Transcriptomic analysis demonstrated that BubR1 insufficiency triggers molecular changes in the heart similar to those seen in aged hearts. Likewise, comparisons with end-stage heart failure patients showed that BubR1 deficiency mirrors transcriptomic alterations characteristic of heart failure. Importantly, our results indicate that heart failure is associated with reduced BubR1 levels, which also naturally declines with age in the heart. Our findings suggest that BubR1, traditionally known for its mitotic functions, plays a crucial role in maintaining the structure and function of the post-mitotic heart.
2025-09-17 | GSE277997 | GEO