University Clermont, UFR Médecine, Histologie Embryologie Cytogénétique, CHU Clermont-Ferrand, France.
Fetal Diagn Ther. 2010;28(3):129-39. doi: 10.1159/000313331. Epub 2010 May 26.
BACKGROUND/OBJECTIVES: Although there is strong evidence implicating genetic factors in congenital diaphragmatic hernia (CDH) pathogenesis, few causal genes have been identified. Many studies suggest that early disruption of the retinoid signaling pathway during gestation may contribute to CDH etiology. Chromosome abnormalities are detected in 10-20% of CDH cases. Chromosomal regions that are involved in balanced translocations or are recurrently deleted or duplicated in patients with CDH are of particular interest to researchers because they are more likely to harbor genes that cause or predispose one to the development of CDH. The aim of this review was to select chromosome loci which have been shown to be associated with CDH and to investigate if these loci contain candidate genes involved in the retinoic signaling pathway.
We have re-examined the known CDH-critical chromosomal loci and searched in available databases, such as the UCSC Genome Browser and OMIM, to see whether candidate genes related to the retinoid pathway were present within these loci.
Twelve retinoid-related genes have been proposed as potential candidates. Among them, COUP-TFII, FOG2 and GATA4 have already been well studied, especially in animal models. We propose other candidates such as STRA6, LRAT, CRBP1, CRBP2 and CRABP1 are directly implicated in retinoic acid metabolism.
The identification of CDH-related genes and pathways affecting a normal diaphragm will contribute to the understanding of the pathophysiology of this severe embryopathy and might help to facilitate prenatal management and devise more individual treatment strategies. Further studies are necessary to screen large cohorts of patients with CDH for microimbalances or de novo mutations in these candidate genes. Moreover, functional analyses are needed to establish their exact role in CDH etiology.
背景/目的：虽然有强有力的证据表明遗传因素与先天性膈疝（CDH）的发病机制有关，但已确定的致病基因很少。许多研究表明，妊娠期间视黄酸信号通路的早期中断可能导致 CDH 的发病机制。在 10-20%的 CDH 病例中检测到染色体异常。在 CDH 患者中涉及平衡易位或经常缺失或重复的染色体区域特别引起研究人员的兴趣，因为它们更有可能包含导致或易患 CDH 发展的基因。本综述的目的是选择已显示与 CDH 相关的染色体基因座，并研究这些基因座是否包含参与视黄酸信号通路的候选基因。
我们重新检查了已知的 CDH 关键染色体基因座，并在可用的数据库（如 UCSC 基因组浏览器和 OMIM）中进行了搜索，以查看这些基因座中是否存在与视黄酸通路相关的候选基因。
已经提出了 12 个与视黄酸相关的候选基因。其中，COUP-TFII、FOG2 和 GATA4 已经得到了很好的研究，尤其是在动物模型中。我们还提出了其他候选基因，如 STRA6、LRAT、CRBP1、CRBP2 和 CRABP1，它们直接参与视黄酸代谢。
确定与 CDH 相关的基因和影响正常膈肌的途径将有助于理解这种严重的胚胎病的病理生理学，并可能有助于促进产前管理和制定更个体化的治疗策略。需要进一步研究以筛选大量 CDH 患者这些候选基因中的微不平衡或新生突变。此外，需要进行功能分析以确定它们在 CDH 发病机制中的确切作用。
