多聚丙氨酸延展突变和转录因子FOXL2的一种新错义置换共同引起睑裂狭小、倒转型内眦赘皮和上睑下垂综合征(BPES)患者的不同卵巢表型

Study Question What are the implications of multiple alterations of the forkhead box L2 (FOXL2) gene in blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) patients? Summary Answer A multi-mutation of FOXL2, consisting of the expansion of the polyalanine tract from 14 to 24 residues (FOXL2-Ala24), an novel Y186C substitution from c.557A>G, and a synonymous variant (c.505G>A), had a cumulative effect on ovarian phenotypes in BPES patients. What is Known Already Mutations in FOXL2, a gene encoding a forkhead transcription factor cause BPES. Overall, the expansion of the polyalanine tract of FOXL2 from 14 to 24 residues (FOXL2-Ala24) accounts for 30 of intragenic mutations. Study Design, Size, Duration In this study, patients from seven BPES families and six sporadic cases were included. Participants/Materials, Setting , Methods We conducted an extensive clinical, hormonal and functional study in 20 patients carrying the expansion of the polyalanine tract of FOXL2 associated with BPES. A multi-mutation of FOXL2 was detected in one BPES family that showed more severe BPES symptoms. Subcellular localization and transactivation studies were performed for the constructs of FOXL2-Ala24, Y186C and FOXL2-Ala24-Y186C.MAIN RESULTSWe described the first multi-mutation of FOXL2 (c. [672-701dup30; 557A>G]) that leads to the polyalanine expansion of 10 residues (FOXL2-Ala24) combined with an Y186C substitution and a synonymous variant in a Chinese BPES family. This multi-mutation genotype was associated with more serious BPES clinical manifestations and the development of esotropia in the right eye. In in vitro studies, the multi-mutation affected the function of FOKL2 on the StAR promoter and DK3, and induced more aggressive aggregation and mislocalization of FOXL2 protein. The synonymous variant, while not affecting amino acid coding, causes a change in the RNA stem-loop structure. Limitations, Reasons for Caution The multi-mutation of FOXL2 was detected in one BPES family and it needs to be validated further by more BPES subjects. Wider Implications of The Findings The results of our study contribute new insights into the research field of BPES caused by the multi-mutation of FOXL2. Study Funding/Competing Interest s This study was supported by Shanghai Leading Academic Discipline Project (Grant number S30205) and Shanghai Jiao Tong University School of Medicine Doctor Innovation Fund (Grant number 201131). The authors have no competing interests to declare. © 2012 The Author.

Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, NO.639 Zhi Zao Ju Road, Shanghai 200011, China