Section of Genetics, Department of Pediatrics, University of California-Davis, Sacramento, CA 95817, USA.
Hum Mutat. 2012 Dec;33(12):1626-9. doi: 10.1002/humu.22166. Epub 2012 Aug 13.
Craniosynostosis is the early fusion of one or more sutures of the infant skull and is a common defect occurring in approximately 1 of every 2,500 live births. Nonsyndromic craniosynostosis (NSC) accounts for approximately 80% of all cases and is thought to have strong genetic determinants that are yet to be identified. ALX4 is a homeodomain transcription factor with known involvement in osteoblast regulation. By direct sequencing of the ALX4 coding region in sagittal or sagittal-suture-involved nonsyndromic craniosynostosis probands, we identified novel, nonsynonymous, familial variants in three of 203 individuals with NSC. Using dual-luciferase assay we show that two of these variants (V7F and K211E) confer a significant gain-of-function effect on ALX4. Our results suggest that ALX4 variants may have an impact on the genetic etiology of NSC.
颅缝早闭是婴儿颅骨的一条或多条缝过早融合，是一种常见的缺陷，大约每 2500 例活产儿中就有 1 例。非综合征性颅缝早闭（NSC）约占所有病例的 80%，据认为具有尚未确定的强烈遗传决定因素。ALX4 是一种同源域转录因子，已知参与成骨细胞的调节。通过对 203 名 NSC 先证者的 ALX4 编码区进行直接测序，我们在 3 名患者中发现了新的、非同义的、家族性的变异。使用双荧光素酶测定法，我们证明其中两种变体（V7F 和 K211E）对 ALX4 具有显著的功能获得效应。我们的结果表明，ALX4 变体可能对 NSC 的遗传病因学有影响。
