Functional study on a novel missense mutation of the transcription factor FOXL2 causes blepharophimosis-ptosis-epicanthus inversus syndrome (BPES)

• Published in: Mutagenesis 2011-03, Vol.26 (2), p.283-289
• Main Authors: FAN, Jia-Yan, BING HAN, JIE QIAO, LIU, Bing-Li, JI, Yong-Rong, GE, Sheng-Fang, SONG, Huai-Dong, FAN, Xian-Qun
• Format: Article
• Language: English
• Subjects: Adult; Amino Acid Sequence; Amino Acid Substitution; Amino acids; Biological and medical sciences; Blepharophimosis - genetics; Blepharoptosis - genetics; Complex syndromes; Female; Forkhead Box Protein L2; Forkhead Transcription Factors - chemistry; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Fundamental and applied biological sciences. Psychology; Humans; Intracellular Space - metabolism; Male; Medical genetics; Medical sciences; Membrane Transport Proteins - genetics; Middle Aged; Molecular and cellular biology; Molecular genetics; Molecular Sequence Data; Mutagenesis. Repair; Mutation, Missense; Pedigree; Promoter Regions, Genetic - genetics; Protein Structure, Tertiary; Protein Transport; Sequence Alignment; Syndrome; Transcription Factors - chemistry; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 0267-8357; 1464-3804
• DOI: 10.1093/mutage/geq086

Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a rare autosomal dominant disease caused by FOXL2 gene mutations. However, only one missense mutation has been found in family with BPES type I. Here, we report a novel missense mutation in the forkhead domain of the FOXL2 gene (c.340A > G, NM_023067) resulted in the replacement of lysine by glutamic acid at amino acid position 114 of the FOXL2 protein (p.K114E, NP_075555) that was identified in a Chinese family with BPES type I, members of which displayed clinical symptoms such as shortened palpebral fissures, drooping eyelids, a vertical skin fold arising from the lower eyelid, and premature ovarian failure (POF) in affected females. Based on the patients' clinical features and computational analysis of this missense mutation in a three-dimensional structural model, we hypothesised that the mutation might disturb the intermolecular contacts between FOXL2 and the StAR gene. The disturbance of this interaction might contribute to the POF observed in BPES type I patients. We performed subcellular localisation and functional studies and as expected, observed significant nuclear aggregation and cytoplasmic mislocalization of the mutant type protein and loss-of-function was confirmed by electrophoretic mobility shift assays, transcriptional activity assays and quantitative real-time polymerase chain reaction. This functional study on a novel missense mutation has important implications for the molecular analysis of this gene.