Center for Developmental Biology & Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA 98101, USA.
Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
Int J Mol Sci. 2023 Mar 10;24(6):5353. doi: 10.3390/ijms24065353.
Craniosynostosis is a birth defect where calvarial sutures close prematurely, as part of a genetic syndrome or independently, with unknown cause. This study aimed to identify differences in gene expression in primary calvarial cell lines derived from patients with four phenotypes of single-suture craniosynostosis, compared to controls. Calvarial bone samples (N = 388 cases/85 controls) were collected from clinical sites during reconstructive skull surgery. Primary cell lines were then derived from the tissue and used for RNA sequencing. Linear models were fit to estimate covariate adjusted associations between gene expression and four phenotypes of single-suture craniosynostosis (lambdoid, metopic, sagittal, and coronal), compared to controls. Sex-stratified analysis was also performed for each phenotype. Differentially expressed genes (DEGs) included 72 genes associated with coronal, 90 genes associated with sagittal, 103 genes associated with metopic, and 33 genes associated with lambdoid craniosynostosis. The sex-stratified analysis revealed more DEGs in males (98) than females (4). There were 16 DEGs that were homeobox (HOX) genes. Three TFs (SUZ12, EZH2, AR) significantly regulated expression of DEGs in one or more phenotypes. Pathway analysis identified four KEGG pathways associated with at least one phenotype of craniosynostosis. Together, this work suggests unique molecular mechanisms related to craniosynostosis phenotype and fetal sex.
颅缝早闭是一种颅缝过早闭合的先天缺陷，可能是遗传综合征的一部分，也可能是独立发生的，其病因未知。本研究旨在比较四种单缝颅缝早闭表型（人字缝、矢状缝、冠状缝和额缝）患者与对照组的原发性颅骨细胞系中的基因表达差异。在颅骨重建手术期间，从临床部位采集颅骨骨样本（N = 388 例/85 例对照）。然后从组织中提取原代细胞系并进行 RNA 测序。通过线性模型估计基因表达与四种单缝颅缝早闭表型（人字缝、矢状缝、冠状缝和额缝）与对照组之间的协变量调整关联。还对每个表型进行了性别分层分析。差异表达基因（DEGs）包括 72 个与冠状缝相关的基因、90 个与矢状缝相关的基因、103 个与额缝相关的基因和 33 个与人字缝相关的基因。性别分层分析显示，男性（98 个）比女性（4 个）有更多的 DEGs。有 16 个 DEGs 是同源盒（HOX）基因。三个 TF（SUZ12、EZH2、AR）显著调节了一个或多个表型中 DEGs 的表达。通路分析确定了四个与至少一种颅缝早闭表型相关的 KEGG 通路。总之，这项工作表明与颅缝早闭表型和胎儿性别相关的独特分子机制。
