Settas Nikolaos, Anapliotou Margarita, Kanavakis Emmanuel, Fryssira Helen, Sofocleous Christalena, Dacou-Voutetakis Catherine, Chrousos George P, Voutetakis Antonis
1First Department of Pediatrics, School of Medicine, University of Athens, "Aghia Sophia" Children's Hospital, Athens, Greece 2Department of Medical Genetics, School of Medicine, University of Athens, "Aghia Sophia" Children's Hospital, Athens, Greece 3Private Practice, Athens, Greece 4Research Institute for the Study of Genetic and Malignant Diseases of Childhood, "Aghia Sophia" Children's Hospital, Athens, Greece.
Menopause. 2015 Nov;22(11):1264-8. doi: 10.1097/GME.0000000000000473.
This study aims to search for mutations in relevant genes in a woman with primary ovarian insufficiency (POI) and blepharophimosis-ptosis-epicanthus inversus syndrome (BPES).
This study reports on the case of a woman with POI, BPES, and autoimmune endocrine disorder. Bidirectional sequencing of the coding regions and intron/exon boundaries of FOXL2 and BMP15 genes and hormonal assays for the measurement of follicle-stimulating hormone, luteinizing hormone, estradiol, testosterone, Δ4-androstenedione, and dehydroepiandrosterone sulfate were employed.
A novel de novo heterozygous deletion (p.K150Rfs*121) in the FOXL2 gene was identified to coexist with two BMP15 gene variants located in the same allele (c.-9C>G; p.N103S).
The novel, de novo FOXL2 gene mutation (p.K150Rfs*121) expands the spectrum of molecular defects identified in women with BPES. Coexisting gene variants in POI-related genes, such as BMP15, may act synergistically and explain the observed phenotypic variability in women with BPES (ie, BPES with or without POI). The concept of digenic inheritance suggested herein has been previously introduced for other nosologies such as hypogonadotrophic hypogonadism. Endocrine autoimmunity might also contribute to the POI phenotype.
本研究旨在探寻一名患有原发性卵巢功能不全（POI）和睑裂狭小-上睑下垂-内眦赘皮综合征（BPES）的女性相关基因中的突变。
本研究报告了一名患有POI、BPES和自身免疫性内分泌疾病的女性病例。采用对FOXL2和BMP15基因的编码区及内含子/外显子边界进行双向测序，以及检测促卵泡生成素、促黄体生成素、雌二醇、睾酮、Δ4-雄烯二酮和硫酸脱氢表雄酮的激素测定方法。
在FOXL2基因中鉴定出一种新的新生杂合缺失（p.K150Rfs*121），并与位于同一等位基因中的两个BMP15基因变异（c.-9C>G；p.N103S）共存。
新的新生FOXL2基因突变（p.K150Rfs*121）扩展了在BPES女性中鉴定出的分子缺陷谱。POI相关基因（如BMP15）中共存的基因变异可能具有协同作用，并解释了BPES女性中观察到的表型变异性（即伴有或不伴有POI的BPES）。本文提出的双基因遗传概念此前已被引入其他疾病分类，如低促性腺激素性性腺功能减退。内分泌自身免疫也可能导致POI表型。
