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Unique sex-based approach identifies transcriptomic biomarkers associated with non-syndromic craniosynostosis.

Stamper BD, Park SS, Beyer RP, Bammler TK, Cunningham ML - Gene Regul Syst Bio (2012)

Bottom Line: Population-based epidemiological studies have found that the birth prevalence of single-suture craniosynostosis is both suture- and sex-dependent.Transcriptomic data from 199 individuals with isolated sagittal (n = 100), unilateral coronal (n = 50), and metopic (n = 49) synostosis were compared against a control population (n = 50) to identify transcripts accounting for the different sex-based frequencies observed in this disease.Differential sex-based gene expression was classified as either gained (divergent) or lost (convergent) in affected individuals to identify transcripts related to disease predilection.

View Article: PubMed Central - PubMed

Affiliation: Center for Tissue and Cell Sciences, Seattle Children's Research Institute, Seattle, WA 98101, USA.

ABSTRACT

Background: The premature fusion of one cranial suture, also referred to as non-syndromic craniosynostosis, most commonly involves premature fusion of the sagittal, coronal, or metopic sutures, in that order. Population-based epidemiological studies have found that the birth prevalence of single-suture craniosynostosis is both suture- and sex-dependent.

Methods: Transcriptomic data from 199 individuals with isolated sagittal (n = 100), unilateral coronal (n = 50), and metopic (n = 49) synostosis were compared against a control population (n = 50) to identify transcripts accounting for the different sex-based frequencies observed in this disease.

Results: Differential sex-based gene expression was classified as either gained (divergent) or lost (convergent) in affected individuals to identify transcripts related to disease predilection. Divergent expression was dependent on synostosis sub-type, and was extensive in metopic craniosynostosis specifically. Convergent microarray-based expression was independent of synostosis sub-type, with convergent expression of FBN2, IGF2BP3, PDE1C and TINAGL1 being the most robust across all synostosis sub-types.

Conclusions: Analysis of sex-based gene expression followed by validation by qRT-PCR identified that concurrent upregulation of FBN2 and IGF2BP3, and downregulation of TINAGL1 in craniosynostosis cases were all associated with increased RUNX2 expression and may represent a transcriptomic signature that can be used to characterize a subset of single-suture craniosynostosis cases.

No MeSH data available.


Related in: MedlinePlus

Comparative approach used to identify transcripts that may predispose individuals to non-syndromic craniosynostosis based on sex.Notes: Sex-based differences associated with affected individuals and not seen in controls are contained within the divergent gene set, whereas sex-based differences unique to the control population and not seen in affected individuals are contained within the convergent gene set. Those transcripts contained within the shared gene set are sex-based differences associated with both controls and affected craniosynostosis cases. Once identified, gene expression considered divergent or convergent was reanalyzed by comparing affected individuals to their respective sex-matched controls.
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f1-grsb-6-2012-081: Comparative approach used to identify transcripts that may predispose individuals to non-syndromic craniosynostosis based on sex.Notes: Sex-based differences associated with affected individuals and not seen in controls are contained within the divergent gene set, whereas sex-based differences unique to the control population and not seen in affected individuals are contained within the convergent gene set. Those transcripts contained within the shared gene set are sex-based differences associated with both controls and affected craniosynostosis cases. Once identified, gene expression considered divergent or convergent was reanalyzed by comparing affected individuals to their respective sex-matched controls.

Mentions: To this end, transcriptomic arrays from a large cohort of individuals with non-syndromic craniosynostosis were analyzed in order to identify sex-related changes in gene expression that predispose individuals to developing this disease. First, differential gene expression between control males and females was compared against differential gene expression between males and females with craniosynostosis in order to create divergent and convergent gene sets. Sex related expression was defined as divergent in craniosynostosis cases when sex differences were not observed in controls and convergent when sex differences present in controls were absent in cases (Fig. 1). Next, the divergent and convergent gene expression of affected male and female cases was compared directly against sex-matched controls to confirm that the gain or loss of transcript expression was significantly different (Fig. 1). Results from these comparisons identified sex-dependant disturbances to genes involved in Ca2+-mediated phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling as key targets that predispose females to craniosynostosis, whereas TINAGL1 expression plays a more important role in predisposing males to the disease by potentially disrupting TGF-β activity. More importantly, differential expression of genes related to these pathways can be directly linked to increased RUNX2 activity, a mechanism known to cause premature fusion of calvarial sutures.


Unique sex-based approach identifies transcriptomic biomarkers associated with non-syndromic craniosynostosis.

Stamper BD, Park SS, Beyer RP, Bammler TK, Cunningham ML - Gene Regul Syst Bio (2012)

Comparative approach used to identify transcripts that may predispose individuals to non-syndromic craniosynostosis based on sex.Notes: Sex-based differences associated with affected individuals and not seen in controls are contained within the divergent gene set, whereas sex-based differences unique to the control population and not seen in affected individuals are contained within the convergent gene set. Those transcripts contained within the shared gene set are sex-based differences associated with both controls and affected craniosynostosis cases. Once identified, gene expression considered divergent or convergent was reanalyzed by comparing affected individuals to their respective sex-matched controls.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3362332&req=5

f1-grsb-6-2012-081: Comparative approach used to identify transcripts that may predispose individuals to non-syndromic craniosynostosis based on sex.Notes: Sex-based differences associated with affected individuals and not seen in controls are contained within the divergent gene set, whereas sex-based differences unique to the control population and not seen in affected individuals are contained within the convergent gene set. Those transcripts contained within the shared gene set are sex-based differences associated with both controls and affected craniosynostosis cases. Once identified, gene expression considered divergent or convergent was reanalyzed by comparing affected individuals to their respective sex-matched controls.
Mentions: To this end, transcriptomic arrays from a large cohort of individuals with non-syndromic craniosynostosis were analyzed in order to identify sex-related changes in gene expression that predispose individuals to developing this disease. First, differential gene expression between control males and females was compared against differential gene expression between males and females with craniosynostosis in order to create divergent and convergent gene sets. Sex related expression was defined as divergent in craniosynostosis cases when sex differences were not observed in controls and convergent when sex differences present in controls were absent in cases (Fig. 1). Next, the divergent and convergent gene expression of affected male and female cases was compared directly against sex-matched controls to confirm that the gain or loss of transcript expression was significantly different (Fig. 1). Results from these comparisons identified sex-dependant disturbances to genes involved in Ca2+-mediated phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling as key targets that predispose females to craniosynostosis, whereas TINAGL1 expression plays a more important role in predisposing males to the disease by potentially disrupting TGF-β activity. More importantly, differential expression of genes related to these pathways can be directly linked to increased RUNX2 activity, a mechanism known to cause premature fusion of calvarial sutures.

Bottom Line: Population-based epidemiological studies have found that the birth prevalence of single-suture craniosynostosis is both suture- and sex-dependent.Transcriptomic data from 199 individuals with isolated sagittal (n = 100), unilateral coronal (n = 50), and metopic (n = 49) synostosis were compared against a control population (n = 50) to identify transcripts accounting for the different sex-based frequencies observed in this disease.Differential sex-based gene expression was classified as either gained (divergent) or lost (convergent) in affected individuals to identify transcripts related to disease predilection.

View Article: PubMed Central - PubMed

Affiliation: Center for Tissue and Cell Sciences, Seattle Children's Research Institute, Seattle, WA 98101, USA.

ABSTRACT

Background: The premature fusion of one cranial suture, also referred to as non-syndromic craniosynostosis, most commonly involves premature fusion of the sagittal, coronal, or metopic sutures, in that order. Population-based epidemiological studies have found that the birth prevalence of single-suture craniosynostosis is both suture- and sex-dependent.

Methods: Transcriptomic data from 199 individuals with isolated sagittal (n = 100), unilateral coronal (n = 50), and metopic (n = 49) synostosis were compared against a control population (n = 50) to identify transcripts accounting for the different sex-based frequencies observed in this disease.

Results: Differential sex-based gene expression was classified as either gained (divergent) or lost (convergent) in affected individuals to identify transcripts related to disease predilection. Divergent expression was dependent on synostosis sub-type, and was extensive in metopic craniosynostosis specifically. Convergent microarray-based expression was independent of synostosis sub-type, with convergent expression of FBN2, IGF2BP3, PDE1C and TINAGL1 being the most robust across all synostosis sub-types.

Conclusions: Analysis of sex-based gene expression followed by validation by qRT-PCR identified that concurrent upregulation of FBN2 and IGF2BP3, and downregulation of TINAGL1 in craniosynostosis cases were all associated with increased RUNX2 expression and may represent a transcriptomic signature that can be used to characterize a subset of single-suture craniosynostosis cases.

No MeSH data available.


Related in: MedlinePlus