Familial Cancer Clinical Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
General Surgery Service, Hospital 12 de Octubre, Madrid, Spain.
Eur J Hum Genet. 2014 Mar;22(3):423-6. doi: 10.1038/ejhg.2013.146. Epub 2013 Jul 10.
Truncating mutations in the AXIN2 gene, a key regulator of β-catenin degradation in the Wnt pathway, have been reported in three families with gastrointestinal adenomatous polyposis and features of ectodermal dysplasia. However, the role of AXIN2 in familial adenomatous polyposis (FAP) syndrome is not completely understood. We performed an in-depth study of APC and MUTYH, and ruled out their implication in 23 FAP families. We then investigated the role of other genes involved in the Wnt pathway, including AXIN2, and identified a novel missense variant in AXIN2 in one family with attenuated FAP. Carriers of the variant exhibited a variable number of polyps but none showed any sign of ectodermal dysplasia. We have demonstrated the pathogenicity of this novel variant by establishing its low frequency in controls as well as by LOH analysis, a segregation study, and immunofluorescent staining of AXIN2 and β-catenin proteins. This report expands the phenotype known to be related to AXIN2 alterations and raises the question of whether to screen AXIN2 in FAP cases negative for alterations in APC and MUTYH.
AXIN2 基因是 Wnt 通路中 β-连环蛋白降解的关键调节因子，其截断突变已在三个具有胃肠道腺瘤性息肉病和外胚层发育不良特征的家族中报道。然而，AXIN2 在家族性腺瘤性息肉病（FAP）综合征中的作用尚不完全清楚。我们对 APC 和 MUTYH 进行了深入研究，并排除了它们在 23 个 FAP 家族中的影响。然后，我们研究了其他参与 Wnt 通路的基因的作用，包括 AXIN2，并在一个具有减轻的 FAP 的家族中发现了 AXIN2 的一种新的错义变异。该变异的携带者表现出可变数量的息肉，但均未出现外胚层发育不良的任何迹象。我们通过证明该变体在对照中的低频率以及通过 LOH 分析、分离研究以及 AXIN2 和 β-连环蛋白蛋白的免疫荧光染色，证明了该新型变体的致病性。该报告扩展了已知与 AXIN2 改变相关的表型，并提出了是否要在 APC 和 MUTYH 改变阴性的 FAP 病例中筛查 AXIN2 的问题。
