PDF(Pubmed)
Abstract：
The human fovea is a specialized pit structure in the central retina. Foveal hypoplasia is a condition where the foveal pit does not fully develop, and it is associated with poor vision. Autosomal dominant isolated foveal hypoplasia (FVH1) is a rare condition of foveal hypoplasia (FH) that lacks any other ocular manifestations. FVH1 is associated with hypomorphic mutations in the PAX6 gene that encodes a sequence-specific DNA-binding transcription factor for morphogenesis and evolution of the eye. We report our findings in 17 patients with PAX6 mutations associated with FVH1 or FH with aniridia and corneal opacities. Patients with three mutations, p.V78E, p.V83F and p.R128H, in the C-terminal subdomain of the paired domain (CTS) consistently have severe FH. Luciferase assays for a single reporter containing a representative PAX6 binding site indicated that the transcriptional activities of these mutations were significantly reduced, comparable to that of the truncation mutation of p.G65Rfs*5. Patients with p.P20S in the N-terminal subdomain of the paired domain, and a patient with p.N365K in the proline-serine-threonine-rich domain (PSTD) had mild FH. A patient with p.Q255L in the homeodomain had severe FH. The P20S and Q255L mutants did not affect the transcriptional activity. Mutant N365K has a retained DNA-binding activity but a reduced transcriptional activity, due to a low PSTD transactivation. These findings demonstrated that mutations associated with FVH1 underlie a functional divergence between DNA-binding ability and transcriptional activity. We conclude that a wide range of mutations in the PAX6 gene is not limited to the CST region and are responsible for FVH1.
摘要：
人类中央凹是中央视网膜中的特殊凹坑结构。中心凹发育不全是指中心凹不完全发育的一种情况,它与视力不佳有关。常染色体显性遗传的孤立性中央凹发育不全（FVH1）是中央凹发育不全（FH）的罕见疾病，缺乏任何其他眼部表现。FVH1与PAX6基因中的低态突变有关，该基因编码序列特异性DNA结合转录因子，用于眼睛的形态发生和进化。我们报告了17例PAX6突变与FVH1或FH相关的无虹膜和角膜混浊患者的发现。有三个突变的病人,p.V78E,p.V83F和p.R128H，在配对结构域（CTS）的C端亚结构域中始终具有严重的FH。含有代表性PAX6结合位点的单个报道分子的荧光素酶测定表明，这些突变的转录活性显着降低，与p.G65Rfs*5的截短突变相当。p.P20S在配对结构域的N末端亚结构域的患者，并且在脯氨酸-丝氨酸-苏氨酸-富含结构域(PSTD)中具有p.N365K的患者具有轻度FH。同源结构域中p.Q255L的患者患有严重的FH。P20S和Q255L突变体不影响转录活性。突变体N365K具有保留的DNA结合活性，但转录活性降低，由于低的PSTD反式激活。这些发现表明，与FVH1相关的突变是DNA结合能力和转录活性之间功能差异的基础。我们得出的结论是，PAX6基因中的广泛突变不限于CST区域，并且是FVH1的原因。
