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| Status |
Public on Feb 04, 2020 |
| Title |
BubR1 allelic effects drive phenotypic heterogeneity in MVA progeria syndrome [3 month old RNA-seq] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
Skeletal muscle (skM, gastrocnemius) from 3-month-old wildtype and two BubR1 MVA allele carriers, BubR1+/L1002P and BubR1+/X753 were collected and harvested from naturally aged mice, euthanized at 3 months of age. RNA was extracted from tissues and was used for RNA sequencing.
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| Contributor(s) |
van Deursen J, Li H |
| Citation(s) |
31738183 |
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| Submission date |
Jul 24, 2019 |
| Last update date |
Feb 04, 2020 |
| Contact name |
Hu Li |
| E-mail(s) |
li.hu@mayo.edu
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| Organization name |
Mayo Clinic
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| Department |
Molecular Pharmacology & Experimental Therapeutics
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| Lab |
Systems Biology and Pharmacology
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| Street address |
200 First Street, Gonda Building G19-408
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| City |
Rochester |
| State/province |
MN |
| ZIP/Postal code |
55904 |
| Country |
USA |
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| Platforms (1) |
| GPL21103 |
Illumina HiSeq 4000 (Mus musculus) |
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| Samples (9)
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| Relations |
| BioProject |
PRJNA556410 |
| SRA |
SRP216223 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE134781_counts.txt.gz |
343.8 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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