Zhong Xingwu, Chen Suqin, Huang Weijun, Yang Jun, Chen Xiaolian, Zhou Yan, Zhou Qiang, Wang Yiming
Zhongshan Ophthalmic Center and State Key laboratory of ophthalmology, Sun Yat-Sen University, Guangzhou, P.R.China.
Mol Vis. 2010 Feb 15;16:224-30.
To report novel transforming growth factor beta-induced (TGFBI) mutations responsible for lattice corneal dystrophy (LCD), the associated genotype-phenotype correlation, and structural changes in the mutant proteins in three Chinese families.
Three unrelated Chinese families were diagnosed as Type I LCD. Mutations in TGFBI were detected by sequencing all of the 17 exons and splice sites of the gene. Phenotype, including corneal erosions, and opacification in the families were compared. Structural changes of the mutant proteins were modeled. One hundred healthy volunteers were recruited as controls for sequence analysis of TGFBI.
Two novel mutations, c.(1702G>C and 1706T>A; p.Arg514Pro and Phe515Leu) in TGFBI were identified in Family 1. Two known hotspot mutations, c. 531C>T (p. Arg124Cys) and c.1876A>G (p.His572Arg), were revealed in Family 2 and Family 3, respectively. Sequence analysis in the 100 healthy control subjects, the unaffected members in Family 1, and evolutionary alignment showed that the novel mutations occurred in the conserved amino acids. Structural modeling revealed changes in the 2nd structure of the mutant proteins, but did not detect gross structural changes. Mutations c.(1702G>C and 1706T>A; p.Arg514Pro and Phe515Leu) and the c. 531C>T (p. Arg124Cys) were present in the corneas with sever opacification.
The novel mutations c.(1702G>C and 1706T>A; p.Arg514Pro and Phe515Leu), c. 531C>T (p. Arg124Cys), c.1876A>G (p.His572Arg) in TGFBI were responsible for LCD in the 3 families. Mutations c.(1702G>C and 1706T>A) (p.Arg514Pro and Phe515Leu) and the c. 531C>T (p. Arg124Cys) were associated with more severe LCD phenotypes in the families. These results provide more data for molecular diagnosis and prognosis of the disease.
报告导致格子状角膜营养不良（LCD）的新型转化生长因子β诱导（TGFBI）突变、相关的基因型-表型相关性以及三个中国家系中突变蛋白的结构变化。
三个无血缘关系的中国家系被诊断为I型LCD。通过对该基因的全部17个外显子和剪接位点进行测序来检测TGFBI中的突变。比较家系中的表型，包括角膜糜烂和混浊情况。对突变蛋白的结构变化进行建模。招募100名健康志愿者作为TGFBI序列分析的对照。
在家族1中鉴定出TGFBI的两个新突变，c.（1702G>C和1706T>A；p.Arg514Pro和Phe515Leu）。在家族2和家族3中分别发现了两个已知的热点突变，c.531C>T（p.Arg124Cys）和c.1876A>G（p.His572Arg）。对100名健康对照受试者、家族1中未受影响的成员进行的序列分析以及进化比对显示，新突变发生在保守氨基酸中。结构建模揭示了突变蛋白二级结构的变化，但未检测到总体结构变化。突变c.（1702G>C和1706T>A；p.Arg514Pro和Phe515Leu）以及c.531C>T（p.Arg124Cys）存在于混浊严重的角膜中。
TGFBI中的新突变c.（1702G>C和1706T>A；p.Arg514Pro和Phe515Leu）、c.531C>T（p.Arg124Cys）、c.1876A>G（p.His572Arg）导致了这3个家系中的LCD。突变c.（1702G>C和1706T>A）（p.Arg514Pro和Phe515Leu）以及c.531C>T（p.Arg124Cys）与家系中更严重的LCD表型相关。这些结果为该疾病的分子诊断和预后提供了更多数据。
