Modifiers and Mediators of Craniosynostosis Severity Revealed by Differential Gene Expression
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA601128 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10883825_1.fastq.gz | Fastqsanger.gz | |||
| SRR10883825_2.fastq.gz | Fastqsanger.gz | |||
| SRR10883826_1.fastq.gz | Fastqsanger.gz | |||
| SRR10883826_2.fastq.gz | Fastqsanger.gz | |||
| SRR10883827_1.fastq.gz | Fastqsanger.gz |
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Project description:Severity of craniosynostosis in humans varies widely even in patients with identical genetic mutations, and severity corresponds with morbidity. In this study we compared RNA sequencing data from cranial tissues of a severe form of Crouzon craniosynostosis syndrome (C57BL/6 FGFR2C342Y/+ mice) with those of a less severe form of Crouzon craniosynostosis (BALB/c FGFR2C342Y/+ mice) to identify genetic modifiers that influence craniosynostosis phenotype severity. Comparison of the mice revealed neonatal onset of coronal suture fusion in the form of suture obliteration in C57BL/6 mice (88% incidence, p<.001 between genotypes) in C57BL/6 mice. Coronal suture fusion in the form of point fusions across the suture occurred at approximately 4 weeks after birth, with less severe skull shape abnormalities, in BALB/c mice. Substantially fewer genes were differentially expressed in BALB/c FGFR2+/+ vs. FGFR2C342Y/+ mice (87 out of 15,893 expressed genes) than in C57BL/6 FGFR2C+/+ vs. FGFR2C342Y/+ mice (2,043 out of 19,097 expressed genes). Further investigation of the gene expression data revealed differential expression of coronal suture associated genes, eph/ephrin boundary genes, cell proliferation genes and osteoblast differentiation genes, among others. The most striking pattern in the data was the minimal change in gene expression seen in BALB/c FGFR2+/+ vs. FGFR2C342Y/+ mice. Analysis of protein processing and lysosomal components support the hypothesis that the craniosynostosis phenotype is less severe in BALB/c mice because the mutant FGFR2C342Y protein is not expressed to the same extent as that seen in C57BL/6 mice. Together, these results suggest that a strategy aimed at increasing degradation of the mutant receptor could lead to diminished phenotype severity.
2020-01-15 | GSE143628 | GEO
Project description:Craniosynostosis severity varies in patients with identical genetic mutations. To understand causes of this phenotypic variation, we backcrossed the FGFR2+/C342Y mouse model of Crouzon syndrome onto congenic C57BL/6 and BALB/c backgrounds. Coronal suture fusion was observed in C57BL/6 (88% incidence, p < .001 between genotypes) but not in BALB/c FGFR2+/C342Y mutant mice at 3 weeks after birth, establishing that that the two models differ in phenotype severity. To begin identifying pre-existing modifiers of craniosynostosis severity, we compared transcriptome signatures of cranial tissues from C57BL/6 vs. BALB/c FGFR2+/+ mice. We separately analyzed frontal bone with coronal suture tissue from parietal bone with sagittal suture tissues because the coronal suture but not the sagittal suture fuses in FGFR2+/C342Y mice. The craniosynostosis associated Twist and En1 transcription factors were down-regulated, while Runx2 was up-regulated, in C57BL/6 compared to BALB/c tissues, which could predispose to craniosynostosis. Transcriptome analyses under the GO term MAPK cascade revealed that genes associated with calcium ion channels, angiogenesis, protein quality control and cell stress response were central to transcriptome differences associated with genetic background. FGFR2 and HSPA2 protein levels plus ERK1/2 activity were higher in cells isolated from C57BL/6 than BALB/c cranial tissues. Notably, the HSPA2 protein chaperone is central to craniofacial genetic epistasis, and we find that FGFR2 protein is abnormally processed in primary cells from FGFR2+/C342Y but not FGFR2+/+ mice. Therefore, we propose that differences in protein quality control responses may contribute to genetic background influences on craniosynostosis phenotype severity.
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Project description:Modifiers of Disease Severity and Progression in Cerebral Cavernous Malformation - BVMC 6201
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Project description:Modifiers of Disease Severity and Progression in Cerebral Cavernous Malformation - BVMC 6201
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Project description:Comparison of four craniosynostosis disease groups of 10 samples each: Apert syndrome (AS), Muenke syndrome (MS), Saetre-Chotzen syndrome (SCS), and non-syndromic craniosynostosis (NSS).
2009-07-06 | E-MEXP-2236 | biostudies-arrayexpress
Project description:Autosomal recessive polycystic kidney disease (ARPKD) is caused by mutations in the PKHD1 gene in both humans and the orthologous PCK rat model. Although ARPKD results solely from PKHD1 mutations, the disease onset and severity are highly variable, indicating that other unknown genetic risk factor(s) modify ARPKD-associated phenotypes. To identify genetic modifiers of ARPKD severity, we created two genetically distinct Pkhd1 congenic rat strains on the Fawn-Hooded Hypertensive (FHH) and the Dahl S (SS) rat backgrounds (denoted FHH.Pkhd1 and SS.Pkhd1, respectively) that harbor the PCK-derived Pkhd1 allele. The FHH.Pkhd1 and SS.Pkhd1 strains had lower renal cyst formation at 30 days-of-age (5±2% and 8±2% cystic, respectively; P<0.001) compared to the PCK kidneys (26±4% cystic), which coincided with significantly reduced kidney weights in the FHH.Pkhd1 and SS.Pkhd1. Liver cyst formation and liver weight did not differ between PCK, FHH.Pkhd1, and SS.Pkhd1. These data indicated that the PCK genome harbors genetic modifier(s) of ARPKD severity that are not present in the FHH and SS genomes. Using high density SNP array genotyping and microarray expression analysis, we identified 50 potential modifiers of ARPKD severity in the PCK rat. Of these candidates, a damaging nonsynonymous variant in Nphp4 stood out as the most likely candidate based on variant segregation, protein modeling, network analysis, and gene ontology. Nphp4 is widely associated with the autosomal recessive cilliopathy and nephronopthisis, but had not been previously implicated in the molecular or cellular pathophysiology of ARPKD. Collectively, these data provide genetic evidence of disease modifier(s) in the PCK model of ARPKD and prioritized multiple candidates, including NPHP4, for further investigation in ARPKD pathogenesis. In this study, we used microarray to analyze transcript expression in the kidneys of 30 day old SD (n=4), PCK (n=4), FHH (n=4), FHH.Pkhd1 (n=4), SS (n=4), and SS.Pkhd1 (n=4). Samples were pooled and the pooled samples were run in triplicate. The 30 day timepoint was chosen because the differences in renal cyst formation between PCK, FHH.Pkhd1, and SS.Pkhd1 were greatest at this timepoint. To account for genetic strain differences that do not contribute to ARPKD severity, gene expression of each cystic rat strain was compared to its parental strain.
2015-06-06 | E-GEOD-58229 | biostudies-arrayexpress
Project description:Mutations within FGFR2 are causative for various craniosynostosis syndromes. The mandibular dysmorphogenesis in these syndromes has rarely been quantitatively characterized prenatally and the cellular and molecular mechanism involved is unclear. To investigate the effects of FGFR2 mutations on development of the mandible, micro-computed tomography (μCT) images were acquired using newborn mice of three Fgfr2-mutant lines associated with Apert and Crouzon craniosynostosis syndromes. Euclidean Distance Matrix Analysis and analysis of relative bone mineral density (BMD) of 3D μCT images revealed differences in mandible morphology and BMD between the mice carrying the Fgfr2 mutations and their unaffected littermates. We further investigated the mechanism for mandibular dysgenesis in the Fgfr2+/S252W (Fgfr2S252W) mouse model that showed the most severe phenotypes. At E16.5, Fgfr2S252W embryos showed an increase in the size of the osteogenic anlagen and Meckel’s cartilage (MC) and altered microarchitecture and mineralization in the mandible relative to unaffected littermates. Laser capture microdissection and RNA-Seq analysis revealed transcriptomic changes in the mandibular bone, highlighting increased expression of genes undergoing osteoclast differentiation and dysregulated genes active in bone mineralization. Increased osteoclastic activity in the mandible of Fgfr2S252W embryos was confirmed and elevated inorganic pyrophosphate concentration was identified due to upregulated expression of Enpp1 and Ank. In contrast, increased proliferation in MC was observed at E12.5. These findings provide evidence that gain-of-function mutations in FGFRs differentially affect intramembranous ossification of dermal bone and cartilage formation contributing to mandibular dysmorphogenesis in craniosynostosis syndromes.
2018-11-07 | GSE121780 | GEO
Project description:Autosomal recessive polycystic kidney disease (ARPKD) is caused by mutations in the PKHD1 gene in both humans and the orthologous PCK rat model. Although ARPKD results solely from PKHD1 mutations, the disease onset and severity are highly variable, indicating that other unknown genetic risk factor(s) modify ARPKD-associated phenotypes. To identify genetic modifiers of ARPKD severity, we created two genetically distinct Pkhd1 congenic rat strains on the Fawn-Hooded Hypertensive (FHH) and the Dahl S (SS) rat backgrounds (denoted FHH.Pkhd1 and SS.Pkhd1, respectively) that harbor the PCK-derived Pkhd1 allele. The FHH.Pkhd1 and SS.Pkhd1 strains had lower renal cyst formation at 30 days-of-age (5±2% and 8±2% cystic, respectively; P<0.001) compared to the PCK kidneys (26±4% cystic), which coincided with significantly reduced kidney weights in the FHH.Pkhd1 and SS.Pkhd1. Liver cyst formation and liver weight did not differ between PCK, FHH.Pkhd1, and SS.Pkhd1. These data indicated that the PCK genome harbors genetic modifier(s) of ARPKD severity that are not present in the FHH and SS genomes. Using high density SNP array genotyping and microarray expression analysis, we identified 50 potential modifiers of ARPKD severity in the PCK rat. Of these candidates, a damaging nonsynonymous variant in Nphp4 stood out as the most likely candidate based on variant segregation, protein modeling, network analysis, and gene ontology. Nphp4 is widely associated with the autosomal recessive cilliopathy and nephronopthisis, but had not been previously implicated in the molecular or cellular pathophysiology of ARPKD. Collectively, these data provide genetic evidence of disease modifier(s) in the PCK model of ARPKD and prioritized multiple candidates, including NPHP4, for further investigation in ARPKD pathogenesis.
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Project description:We report on explant osteoblast cultures from human patients, demonstrating that there are at least three sub-types of non-syndromic craniosynostosis defined by similarity of gene expression profiles. Osteoblast growth in culture, 23 craniosynostosis skull samples (7 metopic; 8 coronal; 3 lambdoid; 5 sagittal) and 8 normal (4 cranial bones and 4 long bones)
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