Variants in TRIM44 Cause Aniridia by Impairing PAX6 Expression
Variants in TRIM44 Cause Aniridia by Impairing PAX6 Expression
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TRIM44 的变异体通过损害 PAX6 表达导致无虹膜
DOI：
10.1002/humu.22907
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发表时间：
2015-12-01
期刊：
影响因子：
3.9
通讯作者：
Yu, Ling
中科院分区：
文献类型：
--
作者：
Zhang, Xibo;Qin, Gang;Yu, Ling
先天性无虹膜是一种遗传性疾病，表现为虹膜发育不全和其他相关的眼部并发症。PAX 6基因突变被认为是无虹膜的主要原因。在这项研究中，我们从一个四代中国家系中鉴定了四种仅存在于无虹膜患者中的突变，包括PAX 6的3′UTR中的两个单核苷酸取代（NM_000280. 4：c. [* 76 G>A; * 2977 C>A]）和含有44的三联基序中的两个错义突变（TRIM 44，NM_017583.4：c. [191C>A; 463 G>A]），其分别导致氨基酸改变p.S64Y和p.G155R。生物信息学分析表明，PAX 6的两个3′UTR突变破坏了野生型3′UTR序列中的microRNA结合基序。荧光素酶报告基因检测和Western blotting分析表明，这两个3′UTR突变对PAX 6的表达量无影响或仅增加。因此，它们不会是PAX 6缺乏导致的无虹膜的原因。相反，我们发现TRIM 44的过表达显著降低人透镜上皮细胞中PAX 6的表达，并且p.G155 R突变体表现出比野生型形式强得多的作用。我们的结论是突变TRIM 44抑制PAX 6的表达是一种新的无虹膜的致病机制。
Congenital aniridia is a genetic disorder that manifests as iris hypoplasia and other associated ocular complications. Mutations in the paired box 6 (PAX6) gene are considered the major cause of aniridia. In this study, we identified four mutations exclusively presented in aniridia patients from a four‐generation Chinese pedigree, including two single nucleotide substitutions in the 3′UTR of PAX6 (NM_000280.4:c.[*76G>A; *2977C>A]) and two missense mutations in tripartite motif containing 44 (TRIM44, NM_017583.4:c.[191C>A; 463G>A]), which lead to amino acid changes p.S64Y and p.G155R, respectively. Bioinformatic analyses revealed that the two 3′UTR mutations of PAX6 disrupted microRNA binding motifs in the wildtype 3′UTR sequence. Luciferase reporter assay and Western blotting with predicted microRNAs showed that the two 3′UTR mutations could only increase or have no effect on the expression of PAX6. Therefore, they would not be the cause of aniridia that resulted from PAX6 deficiency. Instead, we found that overexpression of TRIM44 significantly reduced the expression of PAX6 in human lens epithelial cells, and the p.G155R mutant exhibited much stronger effect than the wildtype form. We conclude that inhibition of PAX6 expression by mutant TRIM44 is a novel pathogenic mechanism for aniridia.