Unidad de Gestión Clínica de Genética, Reproducción y Medicina Fetal, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.
BMC Med Genet. 2011 Oct 13;12:138. doi: 10.1186/1471-2350-12-138.
RET is the major gene associated to Hirschsprung disease (HSCR) with differential contributions of its rare and common, coding and noncoding mutations to the multifactorial nature of this pathology. In the present study, we have performed a comprehensive study of our HSCR series evaluating the involvement of both RET rare variants (RVs) and common variants (CVs) in the context of the disease.
RET mutational screening was performed by dHPLC and direct sequencing for the identification of RVs. In addition Taqman technology was applied for the genotyping of 3 RET CVs previously associated to HSCR, including a variant lying in an enhancer domain within RET intron 1 (rs2435357). Statistical analyses were performed using the SPSS v.17.0 to analyze the distribution of the variants.
Our results confirm the strongest association to HSCR for the "enhancer" variant, and demonstrate a significantly higher impact of it in male versus female patients. Integration of the RET RVs and CVs analysis showed that in 91.66% of cases with both kinds of mutational events, the enhancer allele is in trans with the allele bearing the RET RV.
A gender effect exists on both the transmission and distribution of rare coding and common HSCR causing mutations. In addition, these RET CVs and RVs seem to act in a synergistic way leading to HSCR phenotype.
RET 是与先天性巨结肠（HSCR）相关的主要基因，其稀有和常见的、编码和非编码突变对该病理的多因素性质有不同的贡献。在本研究中，我们对我们的 HSCR 系列进行了全面研究，评估了 RET 稀有变异（RVs）和常见变异（CVs）在疾病背景下的参与情况。
通过 dHPLC 和直接测序对 RET 稀有变异（RVs）进行突变筛选，以确定 RVs。此外，应用 Taqman 技术对先前与 HSCR 相关的 3 个 RET CVs 进行基因分型，包括位于 RET 内含子 1 内增强子区域的一个变异（rs2435357）。使用 SPSS v.17.0 进行统计分析，以分析变异的分布。
我们的结果证实了“增强子”变异与 HSCR 的最强关联，并表明其在男性患者中比女性患者的影响更为显著。RET RVs 和 CVs 分析的整合表明，在 91.66%的同时存在这两种突变事件的病例中，增强子等位基因与携带 RET RV 的等位基因位于异源染色体上。
在稀有编码和常见的 HSCR 致病突变的传递和分布上存在性别效应。此外，这些 RET CVs 和 RVs 似乎以协同方式作用，导致 HSCR 表型。
