在一大群原发性卵巢功能不全女性中鉴定出的新的NOBOX突变会降低KIT-L的表达。
New NOBOX mutations identified in a large cohort of women with primary ovarian insufficiency decrease KIT-L expression.
作者信息
Bouilly Justine, Roucher-Boulez Florence, Gompel Anne, Bry-Gauillard Hélène, Azibi Kemal, Beldjord Cherif, Dodé Catherine, Bouligand Jérôme, Mantel Anne Guiochon, Hécart Annie-Claude, Delemer Brigitte, Young Jacques, Binart Nadine
机构信息
Inserm U693 (J.B., J.B., A.G.M., J.Y., N.B.), Le Kremlin-Bicêtre, F-94276, France; Université Paris-Sud (J.B., J.Y., N.B.), Faculté de Médecine Paris-Sud, Le Kremlin-Bicêtre, F-94276, France; Service d'Hormonologie, d'Endocrinologie Moléculaire et Des Maladies Rares (F.R.-B.), Centre De Biologie et Pathologie Est, Université Lyon 1, 69677 Bron, France; Unité de Gynécologie Endocrinienne (A.G.), Université Paris-Descartes, l'Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Centre, 75014 Paris, France; l'Assistance Publique-Hôpitaux de Paris (H.B-G., J.Y., N.B.), Hôpital de Bicêtre, Service d'Endocrinologie et des Maladies de la Reproduction, Le Kremlin-Bicêtre, F-94276, France; Centre d'Aide Médicale à la Procréation (H.B-G.), CHI 94000 Créteil, France; Service de Biochimie et Génétique Moléculaire (K.A., C.B., C.D.), Hôpital Cochin, l'Assistance Publique-Hôpitaux de Paris Université Paris-Descartes, 75006 Paris, France; l'Assistance Publique-Hôpitaux de Paris (J.B., A.G.M.), Service de Génétique Moléculaire, Pharmacogénétique et Hormonologie, Le Kremlin-Bicêtre, F-94276, France; and Service d'Endocrinologie-Diabète-Nutrition (A.-C.H., B.D.), Centre Hospitalier Universitaire de Reims-Hôpital Robert-Debré, 51092 Reims, France.
出版信息
J Clin Endocrinol Metab. 2015 Mar;100(3):994-1001. doi: 10.1210/jc.2014-2761. Epub 2014 Dec 16.
CONTEXT
Primary ovarian insufficiency (POI) is a major cause of anovulation and infertility in women. This disease affects 1% of women before 40 years, and several genetic causes have been reported.
OBJECTIVE
The aim of the study was to evaluate the prevalence of NOBOX mutations in a new large cohort of women with POI and to characterize these variants and identify a NOBOX novel target gene.
PATIENTS AND METHODS
A total of 213 unrelated patients with POI were screened for NOBOX mutations, and luciferase reporter assays were performed for the mutations identified.
RESULTS
We reported 3 novel and 2 recurrent heterozygous missense NOBOX rare variants found in 12 patients but not in 724 alleles from ethnic-matched individual women with occurrence of menopause at a normal age. Their functional impact had been tested on the classic growth differentiation factor-9 (GDF9) promoter and on KIT-L, a new NOBOX target gene. The p.Gly91Thr, p.Gly111Arg, p.Arg117Trp, p.Lys371Thr, and p.Pro619Leu mutations were deleterious for protein function.
CONCLUSIONS
In our series, 5.6% of the patients with POI displayed heterozygous NOBOX mutations. We demonstrate that KIT-L could be now a direct NOBOX target. These findings replicate the high prevalence of the association between the NOBOX rare variants and POI.
背景
原发性卵巢功能不全（POI）是女性无排卵和不孕的主要原因。该疾病影响1%的40岁前女性，并且已报道了多种遗传病因。
目的
本研究旨在评估一个新的大型POI女性队列中NOBOX突变的患病率，对这些变异进行特征分析，并鉴定一个NOBOX新的靶基因。
患者和方法
对总共213例无亲缘关系的POI患者进行NOBOX突变筛查，并对鉴定出的突变进行荧光素酶报告基因检测。
结果
我们报告了在12例患者中发现的3个新的和2个复发性杂合错义NOBOX罕见变异，而在年龄正常绝经的种族匹配个体女性的724个等位基因中未发现。已在经典的生长分化因子9（GDF9）启动子和一个新的NOBOX靶基因KIT-L上测试了它们的功能影响。p.Gly91Thr、p.Gly111Arg、p.Arg117Trp、p.Lys371Thr和p.Pro619Leu突变对蛋白质功能有害。
结论
在我们的系列研究中，5.6%的POI患者存在杂合性NOBOX突变。我们证明KIT-L现在可能是一个直接的NOBOX靶标。这些发现重复了NOBOX罕见变异与POI之间关联的高患病率。
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