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Gene expression changes between patent and fused cranial sutures in a nonsyndromic craniosynostosis population.

Potter AB, Rhodes JL, Vega RA, Ridder T, Shiang R - Eplasty (2015)

Bottom Line: SFRP2 (secreted frizzled-related protein 2) demonstrated the largest decrease in fused sutures.SPHKAP (sphingosine kinase type 1-interacting protein), a modulator of TGFβ signaling, was significant in the sagittal subset.Genes having significant roles in osteoblastogenesis as negative regulators of canonical Wnt pathway were significantly downregulated.

View Article: PubMed Central - PubMed

Affiliation: Integrated Genomics Laboratory, Oregon Health & Science University, Portland.

ABSTRACT

Objective: Craniosynostosis is a premature fusion of 1 or more cranial sutures. It may occur with additional morphological abnormalities (syndromic) or in isolation. Studies suggest that dysregulation of normal cell proliferation, differentiation, and migration has a role in isolated or nonsyndromic craniosynostosis but the molecular mechanisms remain unknown. The aim of this research is to identify genes differentially expressed in prematurely fused human suture compared to patent suture in nonsyndromic craniosynostosis.

Methods: Bone fragments from synostosed and patent sutures of 7 infants with nonsyndromic craniosynostosis were collected during surgical release of fused sutures. RNA was isolated from the fragments (7 patent and 7 fused) and global gene expression profiled using the Illumina WGE-DASL assay and HumanRef 8.0 Beadchip.

Results: Comparison of mRNA expression in fused and patent suture identified 68 genes significantly differentially expressed and having fold changes ≤ -2.0 and ≥ 2.0 with a false discovery rate adjusted P value at .10 and 136 with adjusted P value of 0.15. SFRP2 (secreted frizzled-related protein 2) demonstrated the largest decrease in fused sutures. Analysis including only sagittal fused sutures revealed a set of 35 overlapping genes that may be involved in suture patency over all suture types. SPHKAP (sphingosine kinase type 1-interacting protein), a modulator of TGFβ signaling, was significant in the sagittal subset.

Conclusion: Differentially expressed genes were identified in fused suture relative to patent in a nonsyndromic craniosynostosis population. SFRP2 is likely important in suture patency. Genes having significant roles in osteoblastogenesis as negative regulators of canonical Wnt pathway were significantly downregulated.

No MeSH data available.


Related in: MedlinePlus

Venn diagram. Overlap of the number of genes identified as significantly differentially expressed (FDR 0.15) in this study and other studies.7-9
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Figure 5: Venn diagram. Overlap of the number of genes identified as significantly differentially expressed (FDR 0.15) in this study and other studies.7-9

Mentions: To determine whether our gene list corroborates previous studies, we compared the gene list from this study with genes identified in 3 previous human studies (Fig 5). First, we compared our gene list with study results of differentially expressed genes between fused sutures and suture tissue that were dedifferentiated in culture.7 There was no overlap with our most relaxed gene list (FDR 0.15) with the top-50 genes from that study. A large number of differentially expressed genes were identified in that study (∼2000) so the genes identified from this study could have overlapped with the genes in the larger list. The second list was of single sutures with tissue also grown in tissue culture and compared to a set of unrelated controls.9 Again, only the top genes from that study were analyzed (47 genes) and 2 genes overlap with our FDR 0.15 gene list, GEM, MAB21L2 (P = .007) (Fig 5). Interestingly, comparing the gene list from this study with a much smaller list of significantly differentially expressed genes (28 genes) using primary suture tissue, 6 genes in common were identified with the FDR 0.10 list and include FBLN1, FMOD, MFAP4, MN1, RBP4, SPON1 (P < .0001) (data not shown).8 One additional gene can be included using a more relaxed FDR 0.15 (PDZRN3) (P < .0001) (Fig 5). Our study identifies 25% of their significantly changed genes, which supports the importance of these genes in suture patency and that these downstream changes seem to be irrespective of the primary cause of craniosynostosis in these cases (Fig 5). There was no overlap between gene lists between any of the previously published studies.


Gene expression changes between patent and fused cranial sutures in a nonsyndromic craniosynostosis population.

Potter AB, Rhodes JL, Vega RA, Ridder T, Shiang R - Eplasty (2015)

Venn diagram. Overlap of the number of genes identified as significantly differentially expressed (FDR 0.15) in this study and other studies.7-9
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4401998&req=5

Figure 5: Venn diagram. Overlap of the number of genes identified as significantly differentially expressed (FDR 0.15) in this study and other studies.7-9
Mentions: To determine whether our gene list corroborates previous studies, we compared the gene list from this study with genes identified in 3 previous human studies (Fig 5). First, we compared our gene list with study results of differentially expressed genes between fused sutures and suture tissue that were dedifferentiated in culture.7 There was no overlap with our most relaxed gene list (FDR 0.15) with the top-50 genes from that study. A large number of differentially expressed genes were identified in that study (∼2000) so the genes identified from this study could have overlapped with the genes in the larger list. The second list was of single sutures with tissue also grown in tissue culture and compared to a set of unrelated controls.9 Again, only the top genes from that study were analyzed (47 genes) and 2 genes overlap with our FDR 0.15 gene list, GEM, MAB21L2 (P = .007) (Fig 5). Interestingly, comparing the gene list from this study with a much smaller list of significantly differentially expressed genes (28 genes) using primary suture tissue, 6 genes in common were identified with the FDR 0.10 list and include FBLN1, FMOD, MFAP4, MN1, RBP4, SPON1 (P < .0001) (data not shown).8 One additional gene can be included using a more relaxed FDR 0.15 (PDZRN3) (P < .0001) (Fig 5). Our study identifies 25% of their significantly changed genes, which supports the importance of these genes in suture patency and that these downstream changes seem to be irrespective of the primary cause of craniosynostosis in these cases (Fig 5). There was no overlap between gene lists between any of the previously published studies.

Bottom Line: SFRP2 (secreted frizzled-related protein 2) demonstrated the largest decrease in fused sutures.SPHKAP (sphingosine kinase type 1-interacting protein), a modulator of TGFβ signaling, was significant in the sagittal subset.Genes having significant roles in osteoblastogenesis as negative regulators of canonical Wnt pathway were significantly downregulated.

View Article: PubMed Central - PubMed

Affiliation: Integrated Genomics Laboratory, Oregon Health & Science University, Portland.

ABSTRACT

Objective: Craniosynostosis is a premature fusion of 1 or more cranial sutures. It may occur with additional morphological abnormalities (syndromic) or in isolation. Studies suggest that dysregulation of normal cell proliferation, differentiation, and migration has a role in isolated or nonsyndromic craniosynostosis but the molecular mechanisms remain unknown. The aim of this research is to identify genes differentially expressed in prematurely fused human suture compared to patent suture in nonsyndromic craniosynostosis.

Methods: Bone fragments from synostosed and patent sutures of 7 infants with nonsyndromic craniosynostosis were collected during surgical release of fused sutures. RNA was isolated from the fragments (7 patent and 7 fused) and global gene expression profiled using the Illumina WGE-DASL assay and HumanRef 8.0 Beadchip.

Results: Comparison of mRNA expression in fused and patent suture identified 68 genes significantly differentially expressed and having fold changes ≤ -2.0 and ≥ 2.0 with a false discovery rate adjusted P value at .10 and 136 with adjusted P value of 0.15. SFRP2 (secreted frizzled-related protein 2) demonstrated the largest decrease in fused sutures. Analysis including only sagittal fused sutures revealed a set of 35 overlapping genes that may be involved in suture patency over all suture types. SPHKAP (sphingosine kinase type 1-interacting protein), a modulator of TGFβ signaling, was significant in the sagittal subset.

Conclusion: Differentially expressed genes were identified in fused suture relative to patent in a nonsyndromic craniosynostosis population. SFRP2 is likely important in suture patency. Genes having significant roles in osteoblastogenesis as negative regulators of canonical Wnt pathway were significantly downregulated.

No MeSH data available.


Related in: MedlinePlus