Hyon C, Mansour-Hendili L, Chantot-Bastaraud S, Donadille B, Kerlan V, Dodé C, Jonard S, Delemer B, Gompel A, Reznik Y, Touraine P, Siffroi J P, Christin-Maitre S
Département de Génétique Médicale (C.H., L.M.H., S.C.B., J.P.S.), Assistance Publique-Hôpitaux de Paris (AP-HP), Groupe Hospitalier Universitaire de l'Est Parisien-Hôpital Armand Trousseau, 75012, Paris, France; Institut National de la Santé et de la Recherche Médicale (INSERM), UMRS 933, Physiopathologie des Maladies Génétiques d'Expression Pédiatrique (C.H., J.P.S., S.C.M.), Hôpital Armand Trousseau, 75012 Paris, France; Unité de Formation et de Recherche (UFR) de Médecine Pierre et Marie Curie, Université Pierre et Marie Curie (UPMC) Université Paris VI (C.H., J.P.S., S.C.M.), Paris, France; Service d'Endocrinologie et Médecine de la Reproduction-CRMERC (B.D., S.C.M.), AP-HP, Groupe Hospitalier Universitaire de l'Est Parisien-Hôpital St-Antoine, 75012 Paris, France; Service d'Endocrinologie, Diabétologie et Maladies Métaboliques (V.K.), Centre Hospitalier Universitaire de Brest, La Cavale Blanche, 29200, Brest, France; Département de Génétique et Développement (C.D.), Institut Cochin, INSERM U1016, Université Paris-Descartes, Paris, France; Service de Gynécologie Endocrinienne et Médecine de la Reproduction (S.J.), Hôpital Jeanne-de-Flandre, 59037 Lille, France; Service d'Endocrinologie-Diabète-Nutrition (B.D.), Centre Hospitalier Universitaire (CHU) de Reims-Hôpital Robert-Debré, 51092 Reims, France; Unité de Gynécologie Endocrinienne (A.G.), Université Paris Descartes, Hôpital Port Royal, Paris, France; Service d'Endocrinologie (Y.R.), Centre Hospitalier Universitaire Côte de Nacre, 14000 Caen, France; and Service Endocrinologie et Médecine de la Reproduction-CRMERC (P.T.), AP-HP, Groupe Hospitalier Pitié-Salpêtrière, 75013, Paris, France.
J Clin Endocrinol Metab. 2016 May;101(5):2099-104. doi: 10.1210/jc.2016-1291. Epub 2016 Mar 22.
Premature ovarian insufficiency (POI) may be secondary to chemotherapy, radiotherapy, or environmental factors. Genetic causes are identified in 20-25% of cases, but most POI cases remain idiopathic.
This study aimed to identify new genes involved in POI and to characterize the implication of CPEB1 gene in POI.
This was a case report and cohort study replicate conducted in academic medical centers.
A deletion including CPEB1 gene was first identified in a patient with primary amenorrhea. Secondly, 191 sporadic POI cases and 68 familial POI cases were included. For each patient, karyotype was normal and FMR1 premutation was excluded. Search for CPEB1 deletions was performed by quantitative multiplex PCR of short fluorescent fragments or DNA microarray analysis. Gene sequencing of CPEB1 was performed for 95 patients.
We identified three patients carrying a microdeletion in band 15q25.2. The proximal breakpoint, for the three patients, falls within a low-copy repeat region disrupting the CPEB1 gene, which represents a strong candidate gene for POI as it is known to be implicated in oocyte meiosis. No mutation was identified by sequencing CPEB1 gene. Therefore, heterozygous deletion of CPEB1 gene leading to haploinsufficiency could be responsible for POI in humans.
Microdeletions of CPEB1 were identified in 1.3% of patients with POI, whereas no mutation was identified. This microdeletion is rare but recurrent as it is mediated by nonallelic homologous recombination due to the existence of low-copy repeats in the region. This result demonstrates the importance of DNA microarray analysis in etiological evaluation and counseling of patients with POI.
卵巢早衰（POI）可能继发于化疗、放疗或环境因素。20%-25%的病例可确定遗传原因，但大多数POI病例仍为特发性。
本研究旨在鉴定参与POI的新基因，并描述CPEB1基因在POI中的作用。
这是一项在学术医学中心进行的病例报告和队列研究复现。
首先在一名原发性闭经患者中鉴定出一个包含CPEB1基因的缺失。其次，纳入191例散发性POI病例和68例家族性POI病例。对每位患者，核型正常且排除FMR1前突变。通过短荧光片段定量多重PCR或DNA微阵列分析寻找CPEB1缺失。对95例患者进行CPEB1基因测序。
我们鉴定出三名携带15q25.2带微缺失的患者。这三名患者的近端断点位于一个低拷贝重复区域内，该区域破坏了CPEB1基因，由于已知其与卵母细胞减数分裂有关，因此它是POI的一个强有力候选基因。通过对CPEB1基因测序未鉴定出突变。因此，CPEB1基因的杂合缺失导致单倍剂量不足可能是人类POI的原因。
在1.3%的POI患者中鉴定出CPEB1微缺失，而未鉴定出突变。这种微缺失罕见但会复发，因为它是由该区域存在的低拷贝重复介导的非等位基因同源重组引起的。这一结果证明了DNA微阵列分析在POI患者病因评估和咨询中的重要性。
