title: The combination of polyalanine expansion mutation and a novel missense substitution in transcription factor FOXL2 leads to different ovarian phenotypes in blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) patients.
abstract: OBJECTIVE
  What are the implications of multiple alterations of the forkhead box L2 (FOXL2) gene in blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) patients?
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  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.
  
  
  METHODS
  In this study, patients from seven BPES families and six sporadic cases were included.
  
  
  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.
  
  
  RESULTS
  We 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.
  
  
  CONCLUSIONS
  The multi-mutation of FOXL2 was detected in one BPES family and it needs to be validated further by more BPES subjects.
  
  
  CONCLUSIONS
  The results of our study contribute new insights into the research field of BPES caused by the multi-mutation of FOXL2.
  
  
  BACKGROUND
  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.
authors.affiliation: Department of Ophthalmology,  Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, NO.639 Zhi Zao Ju Road, Shanghai 200011,  P. R. China.
authors.forename: Jiayan
authors.initials: J
authors.lastname: Fan
authors.forename: Yixiong
authors.initials: Y
authors.lastname: Zhou
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Huang
authors.forename: Leilei
authors.initials: L
authors.lastname: Zhang
authors.forename: Yuting
authors.initials: Y
authors.lastname: Yao
authors.forename: Xin
authors.initials: X
authors.lastname: Song
authors.forename: Junzhao
authors.initials: J
authors.lastname: Chen
authors.forename: Jifan
authors.initials: J
authors.lastname: Hu
authors.forename: Shengfang
authors.initials: S
authors.lastname: Ge
authors.forename: Huaidong
authors.initials: H
authors.lastname: Song
authors.forename: Xianqun
authors.initials: X
authors.lastname: Fan
mesh_terms: D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution; D016569:Blepharophimosis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D002681:China; D005260:Female; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D056726:Genetic Association Studies; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D016254:Mutagenesis, Insertional; D009154:Mutation; D020125:Mutation, Missense; D010053:Ovary / Q000503:physiopathology*; D010375:Pedigree; D021381:Protein Transport; D059370:RNA Folding; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012720:Severity of Illness Index; D012868:Skin Abnormalities / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D014564:Urogenital Abnormalities
chemical_list: C421604:FOXL2 protein, human; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors; D011994:Recombinant Proteins