Brémond-Gignac Dominique, Bitoun Pierre, Reis Linda M, Copin Henri, Murray Jeffrey C, Semina Elena V
Department of Pediatric Ophthalmology, St Victor University Hospital of Amiens, INSERM UMRS968, Vision Institute, Paris VI University, Amiens, France.
Mol Vis. 2010 Aug 22;16:1705-11.
Aniridia and congenital cataract represent rare but severe developmental ocular conditions. We examined 33 probands from France for mutations in several transcription factors associated with these phenotypes, the forkhead box E3 (FOXE3), paired box gene 6 (PAX6), paired-like homeodomain transcription factor 2 (PITX2), and paired-like homeodomain transcription factor 3 (PITX3) genes.
Out of 33 probands, 27 were affected with congenital cataract while the remaining six were affected with aniridia (with or without cataract). The coding regions of FOXE3, PAX6, PITX2, and PITX3 were examined by direct DNA sequencing of gene-specific PCR products.
A novel dominant mutation at the stop codon of FOXE3, c.959G>C (p.X320SerextX72), was identified in a patient with congenital cataract. Another novel FOXE3 sequence change, c.571-579dup (p.Tyr191_Pro193dup), was identified in a patient with aniridia, mild lens opacities, and some additional ocular defects; this patient was also found to carry a nonsense mutation in PAX6. PAX6 mutations were identified in two additional probands with aniridia and cataracts. None of the observed sequence alterations were found in normal controls. No mutations were identified in PITX2 or PITX3.
The p.X320SerextX72 mutation is only the fourth FOXE3 allele associated with a dominant phenotype since the majority of FOXE3 mutations appear to be recessive with no phenotype observed in heterozygous carriers. The encoded protein is predicted to contain a complete normal sequence followed by seventy-two erroneous amino acids; the position and effect of this mutation are similar to two of the previously reported dominant changes, suggesting a common mechanism for dominant alleles. The p.Tyr191_Pro193dup is predicted to result in an in-frame duplication of three amino acids; however, the contribution of this mutation to the phenotype is unclear since the affected patient also carries a nonsense mutation in PAX6 which acts upstream of FOXE3 in the molecular pathway. The identified PAX6 mutations correspond to the two most commonly observed mutant alleles and demonstrate phenotypes that are consistent with the previously reported spectrum.
无虹膜和先天性白内障是罕见但严重的眼部发育疾病。我们对来自法国的33名先证者进行了检测，以查找与这些表型相关的几种转录因子，即叉头框E3（FOXE3）、配对盒基因6（PAX6）、配对样同源结构域转录因子2（PITX2）和配对样同源结构域转录因子3（PITX3）基因中的突变。
在33名先证者中，27名患有先天性白内障，其余6名患有无虹膜（伴有或不伴有白内障）。通过对基因特异性PCR产物进行直接DNA测序，检测FOXE3、PAX6、PITX2和PITX3的编码区。
在一名先天性白内障患者中，发现了FOXE3终止密码子处的一个新的显性突变，即c.959G>C（p.X320SerextX72）。在一名患有无虹膜、轻度晶状体混浊和一些其他眼部缺陷的患者中，发现了另一个新的FOXE3序列变化，即c.571 - 579dup（p.Tyr191_Pro193dup）；该患者还被发现携带PAX6中的一个无义突变。在另外两名患有无虹膜和白内障的先证者中发现了PAX6突变。在正常对照中未发现所观察到的序列改变。在PITX2或PITX3中未发现突变。
p.X320SerextX72突变是与显性表型相关的第四个FOXE3等位基因，因为大多数FOXE3突变似乎是隐性的，杂合携带者未观察到表型。预测编码的蛋白质包含一个完整的正常序列，随后是72个错误的氨基酸；该突变的位置和效应与先前报道的两个显性变化相似，表明显性等位基因存在共同机制。p.Tyr191_Pro193dup预计会导致三个氨基酸的框内重复；然而，由于受影响的患者还携带PAX6中的一个无义突变，该突变在分子途径中位于FOXE3上游，因此该突变对表型的贡献尚不清楚。所鉴定的PAX6突变对应于两个最常观察到的突变等位基因，并表现出与先前报道的谱一致的表型。
