Abstract
The blepharophimosis syndrome (BPES) is an autosomal dominant developmental disorder in which craniofacial/eyelid malformations are associated (type I) or not (type II) with premature ovarian failure (POF). Mutations in the FOXL2 gene, encoding a forkhead transcription factor, are responsible for both types of BPES. Heterozygous polyalanine expansions of +10 residues (FOXL2–Ala24) account for 30% of FOXL2 mutations and are fully penetrant for the eyelid phenotype. Here we describe the first homozygous FOXL2 mutation leading to a polyalanine expansion of +5 residues (FOXL2–Ala19). This novel mutation segregates in an Indian family where heterozygous mutation carriers are unaffected whereas homozygous individuals have the typical BPES phenotype, with proven POF in one female. Expression of the FOXL2–Ala19 protein in COS-7 cells revealed a significantly higher cytoplasmic retention compared to the wild-type protein. This is the first study providing genetic evidence for a recessive inheritance of BPES associated with ovarian dysfunction.
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Acknowledgments
RAV is supported by the INSERM and the University Paris VII. PS is supported by the Aravind Medical Research Foundation, Aravind Eye Hospital, Madurai, Tamilnadu, India. EDB is supported by the Fund for Scientific Research (FWO) (post-doctoral fellowship; KAN N° 1.5.244.05; mobility grant 1M84304N). DB is supported by Bijzonder Onderzoeksfonds of the Ghent University (BOZF N° BOF2002/DRMAN/047). JN has been supported by a Sandwich Fellowship from the French Embassy in India. We thank the patients involved in this study for their cooperation and two anonymous reviewers for their helpful and constructive criticisms.
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Periasamy Sundaresan and Reiner A. Veitia contributed equally to the development of this work and are listed alphabetically.
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Nallathambi, J., Moumné, L., De Baere, E. et al. A novel polyalanine expansion in FOXL2: the first evidence for a recessive form of the blepharophimosis syndrome (BPES) associated with ovarian dysfunction. Hum Genet 121, 107–112 (2007). https://doi.org/10.1007/s00439-006-0276-0
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DOI: https://doi.org/10.1007/s00439-006-0276-0