De Baere E, Dixon M J, Small K W, Jabs E W, Leroy B P, Devriendt K, Gillerot Y, Mortier G, Meire F, Van Maldergem L, Courtens W, Hjalgrim H, Huang S, Liebaers I, Van Regemorter N, Touraine P, Praphanphoj V, Verloes A, Udar N, Yellore V, Chalukya M, Yelchits S, De Paepe A, Kuttenn F, Fellous M, Veitia R, Messiaen L
Department of Medical Genetics, Ghent University Hospital, B-9000 Ghent, Belgium.
Hum Mol Genet. 2001 Jul 15;10(15):1591-600. doi: 10.1093/hmg/10.15.1591.
Mutations in FOXL2, a forkhead transcription factor gene, have recently been shown to cause blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) types I and II, a rare genetic disorder. In BPES type I a complex eyelid malformation is associated with premature ovarian failure (POF), whereas in BPES type II the eyelid defect occurs as an isolated entity. In this study, we describe the identification of novel mutations in the FOXL2 gene in BPES types I and II families, in sporadic BPES patients, and in BPES families where the type could not be established. In 67% of the patients studied, we identified a mutation in the FOXL2 gene. In total, 21 mutations (17 of which are novel) and one microdeletion were identified. Thirteen of these FOXL2 mutations are unique. In this study, we demonstrate that there is a genotype--phenotype correlation for either types of BPES by the finding that mutations predicted to result in a truncated protein either lacking or containing the forkhead domain lead to BPES type I. In contrast, duplications within or downstream of the forkhead domain, and a frameshift downstream of them, all predicted to result in an extended protein, cause BPES type II. In addition, in 30 unrelated patients with isolated POF no causal mutations were identified in FOXL2. Our study provides further evidence that FOXL2 haploinsufficiency may cause BPES types I and II by the effect of a null allele and a hypomorphic allele, respectively. Furthermore, we propose that in a fraction of the BPES patients the genetic defect does not reside within the coding region of the FOXL2 gene and may be caused by a position effect.
叉头转录因子基因FOXL2的突变最近被证明会导致I型和II型睑裂狭小-上睑下垂-内眦赘皮综合征（BPES），这是一种罕见的遗传疾病。在I型BPES中，复杂的眼睑畸形与卵巢早衰（POF）相关，而在II型BPES中，眼睑缺陷是一个孤立的症状。在本研究中，我们描述了在I型和II型BPES家族、散发的BPES患者以及无法确定类型的BPES家族中FOXL2基因新突变的鉴定情况。在67%的研究患者中，我们鉴定出FOXL2基因存在突变。总共鉴定出21种突变（其中17种是新突变）和1个微缺失。这些FOXL2突变中有13种是独特的。在本研究中，我们通过发现预测导致截短蛋白（缺失或含有叉头结构域）的突变会导致I型BPES，证明了两种类型的BPES均存在基因型-表型相关性。相比之下，叉头结构域内部或下游的重复以及它们下游的移码突变，均预测会导致蛋白质延长，从而引起II型BPES。此外，在30例孤立性POF的无关患者中，未在FOXL2中鉴定出致病突变。我们的研究进一步证明，FOXL2单倍体不足可能分别通过无效等位基因和亚效等位基因的作用导致I型和II型BPES。此外，我们提出，在一部分BPES患者中，遗传缺陷并不存在于FOXL2基因的编码区域内，可能是由位置效应引起的。
