Identification of two novel LRP5 mutations in families with familial exudative vitreoretinopathy
Identification of two novel LRP5 mutations in families with familial exudative vitreoretinopathy
复制标题
家族性渗出性玻璃体视网膜病变家族中两种新的 LRP5 突变的鉴定
作者：
Yao, Quanyao;Li, Jing;Zhao, Peiquan;Yang, Zhenglin
目的探讨两个家族性渗出性玻璃体视网膜病变（FEVR）家系的临床特征及致病基因突变。方法收集FEVR患者的临床资料和基因组DNA。用PCR扩增FZD 4、LRP 5、TSPAN 12和NDP的编码外显子和相邻内含子区，并用桑格测序分析所得扩增子。通过荧光素酶报告基因测定法测定野生型和突变型LRP 5蛋白的Norrin/β-连环蛋白途径。结果在两个家系中发现了两个新的LRP 5基因杂合突变：p.A422T和p.L540P。2例患者及患病父母均出现典型的FEVR眼底改变和轻度骨密度降低。在荧光素酶研究中，p.A422T和p.L540P突变体在SuperTopFlash（STF）细胞中响应Norrin显示荧光素酶活性的显著降低（p.A422T降低87%，p.L540P降低97%）。两名患者都有额外的LRP 5序列变化（患者1中来自未受影响母亲的p.Q816P和患者2中的p.T852M被证实为新突变）。荧光素酶分析显示p.Q816P没有减少，而新突变p.T852M减少了94.9%，这表明p.Q816P可能不是致病性的，而p.T852M可能是致病性的。结论我们的研究结果证实了两个新的LRP 5突变在中国FEVR和轻度BMD降低患者中的存在。他们强调FEVR突变和表型的复杂性。
Purpose To investigate the clinical features and disease-causing mutations in two Chinese families with familial exudative vitreoretinopathy (FEVR). Methods Clinical data and genomic DNA were collected for patients with FEVR. The coding exons and adjacent intronic regions of FZD4, LRP5, TSPAN12, and NDP were amplified with PCR, and the resulting amplicons were analyzed with Sanger sequencing. Wild-type and mutant LRP5 proteins were assayed for the Norrin/β-catenin pathway by luciferase reporter assays. Results Two novel heterozygous mutations in the LRP5 gene were identified in two relatives—p.A422T and p.L540P. Typical FEVR fundus change and mild reduced bone mineral density (BMD) was found in the two patients and the affected parent. In the luciferase studies, both p.A422T and p.L540P mutants displayed a significant reduction of the luciferase activity in SuperTopFlash (STF) cells in response to Norrin (87% reduction for p.A422T and 97% reduction for p.L540P). Both patients had an additional LRP5 sequence change (p.Q816P in Patient 1 from the unaffected mother and p.T852M in Patient 2 verified as a new mutation). Luciferase assay showed no reduction for p.Q816P and 94.9% reduction for the new mutation p.T852M, suggesting that p.Q816P may be not pathogenic and p.T852M may be pathogenic. Conclusions Our findings demonstrated two new novel LRP5 mutations in Chinese patients with FEVR and mild reduced BMD. They emphasize the complexity of FEVR mutations and phenotypes.
登录
查看更多内容
影响因子：
64.8
作者：
Wehrli, M;Dougan, ST;DiNardo, S
通讯作者：
DiNardo, S
影响因子：
9.8
作者：
Ai, MR;Heeger, S;Schelling, DK
通讯作者：
Schelling, DK
影响因子：
13.7
作者：
Fatson Liche;Ajit B Majji
通讯作者：
Fatson Liche;Ajit B Majji
影响因子：
3.9
作者：
Nikopoulos, Konstantinos;Venselaar, Hanka;Cremers, Frans P. M.
通讯作者：
Cremers, Frans P. M.
影响因子：
9.8
作者：
Jiao, XD;Ventruto, V;Hejtmancik, JF
通讯作者：
Hejtmancik, JF