New MCM8 mutation associated with premature ovarian insufficiency and chromosomal instability in a highly consanguineous Tunisian family

被引:59
作者
Bouali, Nouha [1 ]
Francou, Bruno [2 ,3 ]
Bouligand, Jerome [2 ,3 ]
Imanci, Dilek [3 ]
Dirnassi, Sarra [1 ]
Tosca, Lucie [4 ]
Zaouali, Mania [5 ]
Mougou, Soumaya [1 ]
Young, Jacques [2 ,6 ]
Saad, Ali [1 ]
Mantel, Anne Guiochon [2 ,3 ]
机构
[1] Farhat Hached Univ Hosp, Lab Human Cytogenet Mol Genet & Reprod Biol, St Ibn ELJAZZAR, Sousse 4000, Tunisia
[2] Univ Paris Saclay, Univ Paris Sud, Fac Med Paris Sud, Inserm UMRS 1185, Le Kremlin Bicetre, France
[3] Hop Bicetre, Assistance Publ Hop Paris, Serv Genet Mol Pharmacogenet & Hormonol, Le Kremlin Bicetre, France
[4] Hop Antoine Beclere, Serv Histol Embryol & Cytogenet, Clamart, France
[5] Farhat Hached Univ Hosp, Dept Physiol & Funct Explorat, Sousse, Tunisia
[6] Hop Bicetre, Assistance Publ Hop Paris, Serv Endocrinol & Malad Reprod, Le Kremlin Bicetre, France
关键词
MCM8; NOBOX; GDF9; next-generation sequencing (NGS); primary ovarian insufficiency (POI); HOMOLOGOUS RECOMBINATION; CANDIDATE-GENE; FAILURE; NOBOX; REPRODUCTION; PREMUTATION; DEFECTS; COHORT;
D O I
10.1016/j.fertnstert.2017.07.015
中图分类号
R71 [妇产科学];
学科分类号
100211 ;
摘要
Objective: To identify the gene(s) involved in the etiology of premature ovarian insufficiency in a highly consanguineous Tunisian family. Design: Genetic analysis of a large consanguineous family with several affected siblings. Setting: University hospital-based cytogenetics and molecular genetics laboratories. Patient(s): A highly consanguineous Tunisian family with several affected siblings born to healthy second-degree cousins. Intervention(s): None. Main Outcome Measure(s): Targeted exome sequencing was performed by next-generation sequencing for affected family members. Mutations were validated by Sanger sequencing. Functional experiments were performed to explore the deleterious effects of the identified mutation. DNA damage was induced by increasing mitomycin C (MMC) concentrations on cultured peripheral lymphocytes. Result(s): Analysis of the next-generation sequencing data revealed a new homozygous missense mutation in the minichromosome maintenance 8 gene (MCM8). This homozygous mutation (c.482A>C; p.His161Pro) was predicted to be deleterious and segregated with the disease in the family. MCM8 participates in homologous recombination during meiosis and DNA double-stranded break repair by dimerizing with MCM9. Mcm8 knock out results in an early block in follicle development and small gonads. Given this, we tested the chromosomal breakage repair capacity of homozygous and heterozygous MCM8 p.His161Pro mutation on cultured peripheral lymphocytes exposed to increasing MMC concentrations. We found that chromosomal breakage after MMC exposure was significantly higher in cells from homozygously affected individuals than in those from a healthy control. Conclusion(s): Our findings provide additional support to the view that MCM8 mutations are involved in the primary ovarian insufficiency phenotype. (C) 2017 by American Society for Reproductive Medicine.
引用
收藏
页码:694 / 702
页数:9
相关论文
共 21 条
[1]   Exome sequencing reveals MCM8 mutation underlies ovarian failure and chromosomal instability [J].
AlAsiri, Saleh ;
Basit, Sulman ;
Wood-Trageser, Michelle A. ;
Yatsenko, Svetlana A. ;
Jeffries, Elizabeth P. ;
Surti, Urvashi ;
Ketterer, Deborah M. ;
Afzal, Sibtain ;
Ramzan, Khushnooda ;
Faiyaz-Ul Haque, Muhammad ;
Jiang, Huaiyang ;
Trakselis, Michael A. ;
Rajkovic, Aleksandar .
JOURNAL OF CLINICAL INVESTIGATION, 2015, 125 (01) :258-262
[2]   Premature ovarian failure [J].
Beck-Peccoz, Paolo ;
Persani, Luca .
ORPHANET JOURNAL OF RARE DISEASES, 2006, 1 (1)
[3]   NOBOX is a strong autosomal candidate gene in Tunisian patients with primary ovarian insufficiency [J].
Bouali, N. ;
Francou, B. ;
Bouligand, J. ;
Lakhal, B. ;
Malek, I. ;
Kammoun, M. ;
Warszawski, J. ;
Mougou, S. ;
Saad, A. ;
Guiochon-Mantel, A. .
CLINICAL GENETICS, 2016, 89 (05) :608-613
[4]   Analysis of FMR1 gene premutation and X chromosome cytogenetic abnormalities in 100 Tunisian patients presenting premature ovarian failure [J].
Bouali, Nouha ;
Hmida, Dorra ;
Mougou, Soumaya ;
Bouligand, Jerome ;
Lakhal, Besma ;
Dimessi, Sarra ;
Francou, Bruno ;
Saad, Ghada ;
Trabelsi, Saoussen ;
Zaouali, Monia ;
Gribaa, Moez ;
Chaieb, Molka ;
Bibi, Mouhamed ;
Guiochon-Mantel, Anne ;
Saad, Ali .
ANNALES D ENDOCRINOLOGIE, 2015, 76 (06) :671-678
[5]   New NOBOX Mutations Identified in a Large Cohort of Women With Primary Ovarian Insufficiency Decrease KIT-L Expression [J].
Bouilly, Justine ;
Roucher-Boulez, Florence ;
Gompel, Anne ;
Bry-Gauillard, Helene ;
Azibi, Kemal ;
Beldjord, Cherif ;
Dode, Catherine ;
Bouligand, Jerome ;
Mantel, Anne Guiochon ;
Hecart, Annie-Claude ;
Delemer, Brigitte ;
Young, Jacques ;
Binart, Nadine .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2015, 100 (03) :994-1001
[6]   Novel NOBOX Loss-of-Function Mutations Account for 6.2% of Cases in a Large Primary Ovarian Insufficiency Cohort [J].
Bouilly, Justine ;
Bachelot, Anne ;
Broutin, Isabelle ;
Touraine, Philippe ;
Binart, Nadine .
HUMAN MUTATION, 2011, 32 (10) :1108-1113
[7]   The genetics of premature ovarian failure: current perspectives [J].
Chapman, Chevy ;
Cree, Lynsey ;
Shelling, Andrew N. .
INTERNATIONAL JOURNAL OF WOMENS HEALTH, 2015, 7 :799-810
[8]  
COULAM CB, 1986, OBSTET GYNECOL, V67, P604
[9]   MCM8 and MCM9 Nucleotide Variants in Women With Primary Ovarian Insufficiency [J].
Desai, Swapna ;
Wood-Trageser, Michelle ;
Matic, Jelena ;
Chipkin, Jaqueline ;
Jiang, Huaiyang ;
Bachelot, Anne ;
Dulon, Jerome ;
Sala, Cinzia ;
Barbieri, Caterina ;
Cocca, Massimiliano ;
Toniolo, Daniela ;
Touraine, Philippe ;
Witchel, Selma ;
Rajkovic, Aleksandar .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2017, 102 (02) :576-582
[10]   A non-sense MCM9 mutation in a familial case of primary ovarian insufficiency [J].
Fauchereau, F. ;
Shalev, S. ;
Chervinsky, E. ;
Beck-Fruchter, R. ;
Legois, B. ;
Fellous, M. ;
Caburet, S. ;
Veitia, R. A. .
CLINICAL GENETICS, 2016, 89 (05) :603-607