Involvement of the WNT and FGF signaling pathways in non-isolated anorectal malformations: Sequencing analysis of WNT3A, WNT5A, WNT11, DACT1, FGF10, FGFR2 and the T gene
Involvement of the WNT and FGF signaling pathways in non-isolated anorectal malformations: Sequencing analysis of WNT3A, WNT5A, WNT11, DACT1, FGF10, FGFR2 and the T gene
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DOI：
10.3892/ijmm.2012.1124
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发表时间：
2012-12-01
影响因子：
5.4
通讯作者：
Ludwig, Michael
中科院分区：
文献类型：
--
作者：
Draaken, Markus;Prins, Wiebke;Ludwig, Michael
肛门直肠畸形（ARM）包括一系列的异常，包括肛门闭锁，先天性肛瘘和泄殖腔的持久性。研究表明，遗传因素在ARM的发展中起着重要作用。然而，很少有遗传变异被发现。胚胎发生是由无翅型MMTV整合位点家族（WNT）和成纤维细胞生长因子（FGF）信号通路的串扰协调的，该过程涉及几个细胞内级联反应。对小鼠的研究表明，这些途径中的几个基因与ARMs的病因有关。我们对78例ARMs患者的7个先前报道的基因进行了测序分析，这些患者至少有一个额外的先天性异常。未发现与WNT 3A、WNT 5A、WNT 11、DACT 1、FGF 10或T基因变异相关。在FGFR 2基因中，鉴定了三个新的杂合核苷酸取代。进一步的研究，包括对家族成员的研究，显示这些变异与当前ARM队列中的表型没有因果关系。尽管如此，在极少数情况下，七个研究基因的突变可能是ARMs的原因。然而.进一步的研究应该考虑编码WNT/FGF信号通路中其他蛋白质的基因作为可能的候选者。
Anorectal malformations (ARMs) comprise a broad spectrum of anomalies, including anal atresia, congenital anal fistula and persistence of the cloaca. Research suggests that genetic factors play an important role in ARM development. However, few genetic variants have been identified. Embryogenesis is orchestrated by crosstalk of the wingless-type MMTV integration site family (WNT) and fibroblast growth factor (FGF) signaling pathways in a process that involves several intracellular cascades. Studies in mice have implicated several genes from these pathways in the etiology of ARMs. We performed sequencing analysis of seven of these previously reported genes in 78 patients with ARMs occurring within the context of at least one additional congenital anomaly. No associations were identified with variants in WNT3A, WNT5A,WNT11, DACT1, FGF10 or the T gene. In the FGFR2 gene, three novel heterozygous nucleotide substitutions were identified. Further investigations, including the study of family members, revealed that these variants were not causally related to the phenotype in the present ARM cohort. Mutations in the seven investigated genes may nonetheless be a cause of ARMs in rare cases. However. further studies should consider genes encoding other proteins in the WNT/FGF signaling pathways as possible candidates.