Yang Xiao-Wen, He Wen-Bin, Gong Fei, Li Wen, Li Xiu-Rong, Zhong Chang-Gao, Lu Guang-Xiu, Lin Ge, Du Juan, Tan Yue-Qiu
Institute of Reproductive and Stem Cell Engineering, Central South University, Changsha, Hunan, China.
Reproductive and Genetic Hospital of Citic-Xiangya, Changsha, Hunan, China.
Mol Genet Genomic Med. 2018 Mar;6(2):261-267. doi: 10.1002/mgg3.366. Epub 2018 Jan 29.
Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a malformation of the eyelids. Forkhead Box L2 (FOXL2) is the only gene known to be associated with BPES.
We identified two Han Chinese BPES families with premature ovarian insufficiency (POI). Sanger sequencing and in vitro functional analysis were performed to identify the genetic cause.
Sanger sequencing identified two novel mutations (c.462_468del, c.988_989insG) in FOXL2, one in each family. The in vitro functional analysis confirmed that both novel mutations were associated with impaired transactivation of downstream genes. Specifically, the single-base insertion, c.988_989insG, led to subcellular mislocalization and aggregation of the encoded protein, which validated the hypothesis that the two novel FOXL2 mutations are deleterious and associated with POI in the two BPES families.
The novel mutations identified in the present study will enhance the present knowledge of the mutation spectrum of FOXL2. The in vitro experiments provide further insights into the molecular mechanism by which the two new variants mediate disease pathogenesis and may contribute to elucidating the genotype-phenotype correlation between the two novel FOXL2 mutations and POI.
睑裂狭小-上睑下垂-内眦赘皮综合征（BPES）是一种眼睑畸形。叉头框L2（FOXL2）是已知与BPES相关的唯一基因。
我们鉴定了两个患有卵巢早衰（POI）的汉族BPES家系。进行了桑格测序和体外功能分析以确定遗传病因。
桑格测序在FOXL2中鉴定出两个新突变（c.462_468del，c.988_989insG），每个家系各一个。体外功能分析证实这两个新突变均与下游基因的转录激活受损有关。具体而言，单碱基插入c.988_989insG导致编码蛋白的亚细胞定位错误和聚集，这证实了以下假设：这两个新的FOXL2突变是有害的，并且与两个BPES家系中的POI相关。
本研究中鉴定出的新突变将增进我们对FOXL2突变谱的现有认识。体外实验进一步深入了解了这两个新变体介导疾病发病机制的分子机制，并可能有助于阐明这两个新的FOXL2突变与POI之间的基因型-表型相关性。
