Interdepartment of Biomedical Sciences, Faculty of Graduate School, Chulalongkorn University, Bangkok, Thailand.
Eur J Hum Genet. 2012 Oct;20(10):1058-62. doi: 10.1038/ejhg.2012.55. Epub 2012 Apr 4.
Isolated cleft palate (CP) is common in humans and has complex genetic etiologies. Many genes have been found to contribute to CP, but the full spectrum of genes remains unknown. PCR-sequencing of the entire coding regions and the 3' untranslated region (UTR) of the platelet-derived growth factor receptor alpha (PDGFRa) and the microRNA (miR), miR-140 identified seven novel single base-pair substitutions in the PDGFRa in 9/102 patients with CP (8.8%), compared with 5/500 ethnic-matched unaffected controls (1%) (the two-tailed P-value<0.0001). Of these seven, four were missense mutations in the coding regions and three in the 3'UTR. Frequencies of four changes (three in coding, one in 3'UTR) were statistically different from those of controls (P-value<0.05). The c.*34G>A was identified in 1/102 cases and 0/500 controls. This position is conserved in primates and located 10 bp away from a predicted binding site for the miR-140. Luciferase assay revealed that, in the presence of miR-140, the c.*34G>A significantly repressed luciferase activity compared with that of the wild type, suggesting functional significance of this variant. This is the first study providing evidence supporting a role of PDGFRa in human CP.
孤立性腭裂（CP）在人类中很常见，具有复杂的遗传病因。许多基因已被发现与 CP 有关，但完整的基因谱仍不清楚。对血小板衍生生长因子受体α（PDGFRa）和 microRNA（miR）的全长编码区和 3'非翻译区（UTR）进行 PCR 测序，在 102 名 CP 患者中的 9 名（8.8%）中鉴定出 PDGFRa 中的 7 个新的单碱基对取代，而在 500 名种族匹配的无影响对照者中只有 5 名（1%）（双侧 P 值<0.0001）。这七个中的四个是编码区的错义突变，三个是 3'UTR 的错义突变。四个变化（三个在编码区，一个在 3'UTR）的频率与对照组统计学上不同（P 值<0.05）。在 102 例中有 1 例和 500 例对照中有 0 例发现 c.*34G>A。该位置在灵长类动物中保守，位于预测与 miR-140 结合的位点 10 bp 之外。荧光素酶测定显示，在存在 miR-140 的情况下，c.*34G>A 与野生型相比显著抑制荧光素酶活性，表明该变体具有功能意义。这是第一个提供证据支持 PDGFRa 在人类 CP 中作用的研究。
