Functional study on new FOXL2 mutations found in Chinese patients with blepharophimosis, ptosis, epicanthus inversus syndrome

Lu Zhou,Jiaqi Wang,Tailing Wang

doi:10.1186/s12881-018-0631-8

Abstract

BackgroundBlepharophimosis, ptosis, epicanthus inversus syndrome (BPES) is a rare inheritable disease that mainly affects eyelid development associated with (type I) or without (type II) ovarian dysfunction, resulting in premature ovarian failure (POF). Mutations in the gene forkhead box L2 (FOXL2) have been shown to be responsible for BPES. The aim of this study was to determine and functionally validate the FOXL2 mutation in a Chinese BPES family.MethodsTwelve individuals including five BPES patients from a Chinese family were enrolled. Genomic DNA was extracted from peripheral blood of enrolled subjects. The coding region of the FOXL2 gene was amplified and mutations were determined by sequencing analyses. Functional analysis was carried out to study changes in expression and transcriptional activity of the mutant FOXL2 protein.ResultsA novel mutation in the FOXL2 gene (c.931C > T) was detected in all five BPES patients, which converts a histidine residue into a tyrosine (p.H311Y) in the FOXL2 protein. Functional analysis revealed that this point mutation reduces FOXL2 protein expression, concomitant with decreased transcriptional activity on the steroidogenic acute regulatory (StAR) gene promotor.ConclusionsOur results expand the mutational spectrum of the FOXL2 gene and provide additional insights to the research on the molecular pathogenesis of FOXL2 in BPES.

Highlights

Blepharophimosis, ptosis, epicanthus inversus syndrome (BPES) is a rare inheritable disease that mainly affects eyelid development associated with or without ovarian dysfunction, resulting in premature ovarian failure (POF)
Genetic findings Sequencing analysis of the forkhead box L2 (FOXL2) locus from the affected individuals revealed a heterozygous missense mutation c.931C > T (p.H311Y) (Fig. 1c), which has never been reported in familial BPES and is absent in the 100 ethnically matched control chromosomes
The histidine 311 residue of FOXL2 protein is highly conserved across species (Fig. 1d) while the Grantham distance score (83) between histidine and tyrosine is high [20], suggesting this amino acid substitution might have a functional impact on FOXL2 protein and subsequently the pathogenesis of BPES

Summary

Introduction

Blepharophimosis, ptosis, epicanthus inversus syndrome (BPES) is a rare inheritable disease that mainly affects eyelid development associated with (type I) or without (type II) ovarian dysfunction, resulting in premature ovarian failure (POF). Blepharophimosis, ptosis, epicanthus inversus syndrome (BPES, OMIM # 110100) is a rare genetic disorder with an estimated incidence of 1 in 50,000 births [1] It can occur sporadically or associate with autosomal dominant mutations. BPES patients are classified into two different groups, with type I patients having POF while type II referring to those with normal ovarian function [3] Both types of BPES are widely recognized to result predominantly from mutations in the forkhead transcriptional factor-2 (FOXL2) gene that is involved in palpebral and ovarian development [4]

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