Detailed Ophthalmologic Evaluation of 43 Individuals with PAX6 Mutations
Detailed Ophthalmologic Evaluation of 43 Individuals with PAX6 Mutations
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DOI：
10.1167/iovs.08-2827
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发表时间：
2009-06-01
影响因子：
4.4
通讯作者：
van Heyningen, Veronica
中科院分区：
文献类型：
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作者：
Hingorani, Melanie;Williamson, Kathleen A.;van Heyningen, Veronica
目的. PAX 6基因的杂合突变导致多种眼部畸形，最著名的是无虹膜（虹膜缺失）。对43例无虹膜或与之密切相关的眼部异常患者进行了突变分析和详细的临床评价，以研究表型是否与突变类型相关。审查病例记录和医疗记录，必要时对患者进行复查。变性高效液相色谱（DHPLC）分析和PAX 6编码区的测序进行了个体的突变是未知的。最常见的PAX 6突变是提前终止突变，氨基酸取代和C-末端延伸。报告了六种新的突变。一个拷贝的基因突变通常会导致严重的表型，包括中央凹发育不全，明显的虹膜异常和严重的视力障碍。错义突变，所有影响不变的氨基酸配对结构域，导致较温和的表型在这个队列中，与较低的发生率，黄斑中心凹发育不全和较轻的视力丧失。C-末端延伸突变引起相对严重的异常和视力明显下降。两例C端延伸病例患有单侧渗出性视网膜病变，类似于科茨病，此前尚未报道过与PAX 6突变相关的情况。结论。PAX 6突变导致全眼畸形，其模式和严重程度差异很大。在我们的队列中，虹膜发育不全、眼球震颤和中心凹发育不全是最常见的，白内障、角膜异常和高度屈光不正也经常观察到。在该队列中，发现功能丧失和C末端延伸突变比错义突变引起更严重的表型。（Invest Ophthalmol维斯科学。2009; 50：2581-2590）DOI：10.1167/iovs.08-2827
PURPOSE. Heterozygous mutations of the PAX6 gene cause a variety of ocular malformations, the best known being aniridia (absence of the iris). Mutation analyses and detailed clinical evaluations were performed in 43 individuals with aniridia or closely related ocular anomalies, to investigate whether phenotype correlates with mutation type.METHODS. Case notes and medical records were reviewed and patients were reexamined when necessary. Denaturing high-performance liquid chromatography (DHPLC) analysis and sequencing of the PAX6 coding region was performed in individuals whose mutation was unknown.RESULTS. The most common PAX6 mutations identified were premature termination mutations, amino acid substitutions, and C-terminal extensions. Six novel mutations are reported. Mutations that inactivate one copy of the gene typically caused a severe phenotype including foveal hypoplasia, marked iris anomalies, and severe visual impairment. Missense mutations, all affecting invariant amino acids in the paired domain, caused milder phenotypes in this cohort, with a lower incidence of foveal hypoplasia and less severe visual loss. C-terminal extension mutations caused relatively severe anomalies and marked reduction in vision. Two C-terminal extension cases had a unilateral exudative retinopathy, resembling Coats' disease, which has not previously been reported in association with PAX6 mutation.CONCLUSIONS. PAX6 mutations cause panocular malformations that vary considerably in pattern and severity. In our cohort, iris hypoplasia, nystagmus, and foveal hypoplasia were most common, with cataracts, corneal anomalies, and high refractive errors also frequently observed. In this cohort, loss-of-function and C-terminal extension mutations were found to cause more severe phenotypes than missense mutations. (Invest Ophthalmol Vis Sci. 2009; 50: 2581-2590) DOI:10.1167/iovs.08-2827