Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid and CIBER de Enfermedades Raras (CIBERER), Madrid, Spain.
Hum Mutat. 2009 Dec;30(12):1667-75. doi: 10.1002/humu.21117.
Autosomal recessive Ellis-van Creveld syndrome and autosomal dominant Weyer acrodental dysostosis are allelic conditions caused by mutations in EVC or EVC2. We performed a mutation screening study in 36 EvC cases and 3 cases of Weyer acrodental dysostosis, and identified pathogenic changes either in EVC or in EVC2 in all cases. We detected 40 independent EVC/EVC2 mutations of which 29 were novel changes in Ellis-van Creveld cases and 2 were novel mutations identified in Weyer pedigrees. Of interest one EvC patient had a T>G nucleotide substitution in intron 7 of EVC (c.940-150T>G), which creates a new donor splice site and results in the inclusion of a new exon. The T>G substitution is at nucleotide +5 of the novel 5' splice site. The three Weyer mutations occurred in the final exon of EVC2 (exon 22), suggesting that specific residues encoded by this exon are a key part of the protein. Using murine versions of EVC2 exon 22 mutations we demonstrate that the expression of a Weyer variant, but not the expression of a truncated protein that mimics an Ellis-van Creveld syndrome mutation, impairs Hedgehog signal transduction in NIH 3T3 cells in keeping with its dominant effect.
常染色体隐性埃利斯-范科尼综合征和常染色体显性韦耶牙-指（趾）发育不良是由 EVC 或 EVC2 基因突变引起的等位基因疾病。我们对 36 例 EVC 病例和 3 例韦耶牙-指（趾）发育不良进行了突变筛查研究，在所有病例中均发现了 EVC 或 EVC2 中的致病性变化。我们检测到 40 个独立的 EVC/EVC2 突变，其中 29 个是埃利斯-范科尼病例中的新变化，2 个是在韦耶家系中发现的新突变。有趣的是，一位 EVC 患者在 EVC 的内含子 7 中有一个 T>G 核苷酸取代（c.940-150T>G），这创建了一个新的供体位点，并导致一个新外显子的包含。T>G 取代位于新的 5' 剪接位点的+5 位核苷酸。三个韦耶突变发生在 EVC2 的最后一个外显子（外显子 22）中，这表明该外显子编码的特定残基是蛋白的关键部分。使用 EVC2 外显子 22 的鼠类突变版本，我们证明了韦耶变体的表达，但不是模拟埃利斯-范科尼综合征突变的截断蛋白的表达，会损害 NIH 3T3 细胞中的 Hedgehog 信号转导，符合其显性效应。
