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Ovarian Failure Related to Eukaryotic Initiation Factor 2B Mutations

2003; Elsevier BV; Volume: 72; Issue: 6 Linguagem: Inglês

10.1086/375404

1537-6605

Anne Fogli, Diana Rodriguez, Eléonore Eymard‐Pierre, Françoise Bouhour, Pierre Labauge, Brandon Meaney, Susan Zeesman, Christine R. Kaneski, Raphael Schiffmann, Odile Boespflug‐Tanguy,

Sperm and Testicular Function

Ovarian failure (OF) at age <40 years occurs in ∼1% of all women. Other than karyotype abnormalities, very few genes are known to be associated with this ovarian dysfunction. We studied eight patients who presented with premature OF and white-matter abnormalities on magnetic resonance imaging. Neurological signs may be absent or present after OF. In seven patients, we report for the first time mutations in three of the five EIF2B genes (EIF2B2, -4, and -5) that were recently shown to cause childhood ataxia with central nervous system hypomyelination/vanishing white-matter disease leukodystrophy. The correlation we observed between the age at onset of the neurological deterioration and the severity of OF suggests a common pathophysiological pathway. Ovarian failure (OF) at age 6 mo, associated with elevated gonadotrophin levels at age <40 years. Premature OF affects 1% of all women and occurs in 0.1% at age <30 years (Coulam et al. Coulam et al., 1986Coulam CB Adamson SC Annegers JF Incidence of premature ovarian failure.Obstet Gynecol. 1986; 67: 604-606PubMed Google Scholar). OF has been associated with karyotype abnormalities, including various X chromosome aberrations (POFX [MIM 147380]) (Shelling et al. Shelling et al., 2000Shelling AN Burton KA Chand AL van Ee CC France JT Farquhar CM Milsom SR Love DR Gersak K Aittomaki K Winship IM Inhibin: a candidate gene for premature ovarian failure.Hum Reprod. 2000; 15: 2644-2649Crossref PubMed Scopus (144) Google Scholar, Shelling, 2000Shelling AN X chromosome defects and premature ovarian failure.Aust N Z J Med. 2000; 30: 5-7Crossref PubMed Scopus (23) Google Scholar), the follicle-stimulating hormone receptor (FSHR; MIM 136435) (Aittomäki et al. Attomäki et al., 1995Attomäki K Lucena JL Pakarinen P Sistonen P Tapanainen J Gromoll J Kaskikari R Sankila EM Lahvaslaiho H Engel AR Mutation in the follicle-stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure.Cell. 1995; 82: 959-968Abstract Full Text PDF PubMed Scopus (777) Google Scholar), the luteinizing hormone/choriogonadotrophin receptor (LHCGR [MIM 152790]) (Latronico et al. Latronico et al., 1996Latronico AC Anasti J Arnhold IJ Rapaport R Mendonca BB Bloise W Castro M Tsigos C Chrousos GP Brief report: testicular and ovarian resistance to luteinizing hormone caused by inactivating mutations of the luteinizing hormone-receptor gene.N Engl J Med. 1996; 334: 507-512Crossref PubMed Scopus (284) Google Scholar), and the forkhead transcription factor 2 (FOXL2 [MIM 605597]) (Harris et al. Harris et al., 2002Harris SE Chand AL Winship IM Gersak K Aittomäki K Shelling AN Identification of novel mutations in FOXL2 associated with premature ovarian failure.Mol Hum Reprod. 2002; 8: 729-733Crossref PubMed Scopus (144) Google Scholar). In FOXL2 mutations, OF is associated with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES [MIM 110100]) (Harris et al. Harris et al., 2002Harris SE Chand AL Winship IM Gersak K Aittomäki K Shelling AN Identification of novel mutations in FOXL2 associated with premature ovarian failure.Mol Hum Reprod. 2002; 8: 729-733Crossref PubMed Scopus (144) Google Scholar). Mutations in these various genes are present in 30 years, with subsequent neurological deterioration, white-matter abnormalities (detected during cerebral MRI), and pigmentary orthochromatic leukodystrophy (observed at autopsy) (Verghese et al. Verghese et al., 2002Verghese J Weidenheim K Malik S Rapin I Adult onset pigmentary orthochromatic leukodystrophy with ovarian dysgenesis.Eur J Neurol. 2002; 9: 663-670Crossref PubMed Scopus (17) Google Scholar). The upper limit of reproductive life span is predetermined at birth, because all of the follicles that a woman will have in adult life are formed in utero. The number of primordial follicles reaches a maximum of 7 million at 5 mo gestation, whereas it declines to ∼2 million at birth and to ∼400,000 at puberty (Christin-Maitre et al. Christin-Maitre et al., 1998Christin-Maitre S Vasseur C Portnoi MF Bouchard P Genes and premature ovarian failure.Mol Cell Endocrinol. 1998; 145: 75-80Crossref PubMed Scopus (63) Google Scholar). That pool supplies the ovulatory follicles after menarche and is depleted until it falls below a threshold value of 1,000 follicles, and menopause ensues (Faddy Faddy, 2000Faddy MJ Follicle dynamics during ovarian ageing.Mol Cell Endocrinol. 2000; 163: 43-48Crossref PubMed Scopus (204) Google Scholar). Therefore, >99% of the follicles from the initial pool will undergo atresia, with apoptosis being the most important phenomenon controlling this atresia (Christin-Maitre et al. Christin-Maitre et al., 1998Christin-Maitre S Vasseur C Portnoi MF Bouchard P Genes and premature ovarian failure.Mol Cell Endocrinol. 1998; 145: 75-80Crossref PubMed Scopus (63) Google Scholar). Premature OF could result from a decrease in the number of follicles formed, an increase in the rate of follicle loss, an alteration in the recruitment of the follicle, or an interruption in the maturation of the follicle. In BPES due to FOXL2 mutation, the ovarian dysfunction and the eyelid phenotype can be explained by the restricted expression of the mutated FOXL2 gene in these cell types during development (Crisponi et al. Crisponi et al., 2001Crisponi L Deiana M Loi A Chiappe F Uda M Amati P Bisceglia L Zelante L Nagaraja R Porcu S Ristaldi MS Marzella R Rocchi M Nicolino M Lienhardt-Roussie A Nivelon A Verloes A Schlessinger D Gasparini P Bonneau D Cao A Pilia G The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome.Nat Genet. 2001; 27: 159-166Crossref PubMed Scopus (764) Google Scholar). Although eIF2B is a ubiquitous protein, its mutations, for still unexplained reasons, seem to affect only the CNS and ovary in the patients we have reported here. The correlation observed between the age at onset of the neurological deterioration and the severity of OF suggests a common pathophysiological pathway. The potential role of eIF2B in the formation of follicles and glial cells has not yet been reported. In both tissues, successive programmed cell death occurs during development, and defects in regulation of intracellular death effectors, such as caspase-2, can affect both tissues (Bergeron et al. Bergeron et al., 1998Bergeron L Perez GI Macdonald G Shi L Sun Y Jurisicova A Varmuza S Latham KE Flaws JA Salter JCM Hara H Moskowitz MA Li E Greenberg A Tilly JL Yuan J Defects in regulation of apoptosis in caspase-2–deficient mice.Genes Dev. 1998; 12: 1304-1314Crossref PubMed Scopus (584) Google Scholar). The role of eIF2B in apoptosis is presently unknown. However, in the brains of patients with CACH/VWM, apoptosis of mature oligodendrocytes, as determined by use of morphological criteria, has been reported only once (Brück et al. Brück et al., 2001Brück W Herms J Brockmann K Schulz-Schaeffer W Hanefeld F Myelinopathia centralis diffusa (VWM disease): evidence of apoptotic oligodendrocyte degeneration in early lesion development.Ann Neurol. 2001; 50: 532-536Crossref PubMed Scopus (35) Google Scholar), whereas an increase in the number of mature oligodendocytes that have foamy aspects but lack apoptotic features has been frequently reported (Rodriguez et al. Rodriguez et al., 1999Rodriguez D Gelot A della Gaspera B Robain O Ponsot G Sarliève LL Ghandour S Pompidou A Dautigny A Aubourg P Pham-Dinh D Increased density of oligodendrocytes in childhood ataxia with diffuse central hypomyelination (CACH) syndrome: neuropathological and biochemical study of two cases.Acta Neuropathol. 1999; 97: 469-480Crossref PubMed Scopus (72) Google Scholar; Wong et al. Wong et al., 2000Wong K Armstrong RC Gyure KA Morrison AL Rodriguez D Matalon R Johnson AB Wollmann R Gilbert E Le TQ Bradley CA Crutchfield K Schiffmann R Foamy cells with oligodendroglial phenotype in childhood ataxia with diffuse central nervous system hypomyelination syndrome.Acta Neuropathol. 2000; 100: 635-646Crossref PubMed Scopus (80) Google Scholar). In addition, in a particularly severe form of CACH/VWM, no abnormalities have been found by use of TUNEL and P53 labeling (Francalanci et al. Francalanci et al., 2001Francalanci P Eymard-Pierre E Dionisi-Vici C Boldrini R Piemonte F Virgili R Fariello G Bosman C Santorelli FM Boespflug-Tanguy O Bertini E Fatal infantile leukodystrophy, a severe variant of CACH/VWM syndrome, allelic to chromosome 3q27.Neurology. 2001; 57: 265-270Crossref PubMed Scopus (49) Google Scholar). eIF2B is an important regulatory pathway for the prevention of synthesis of denatured proteins during cellular stress, and it functions in parallel with the production of heat shock proteins (Proud et al. Proud, 2001Proud CG Regulation of eukaryotic initiation factor eIF2B.Prog Mol Subcell Biol. 2001; 26: 95-114Crossref PubMed Scopus (65) Google Scholar). In patients with eIF2B mutations, a high susceptibility to cellular stress is suggested by the acute phase of neurological deterioration observed after minor head trauma or common viral infections. Knockout mice for the heat shock factor 2 (Hsf2), a transcriptional regulator of heat shock gene expression, are infertile because of the increased apoptosis of ovarian follicles that is associated with brain abnormalities, an observation suggestive of defects in glial cell development (Kallio et al. Kallio et al., 2002Kallio M Chang Y Manuel M Alastalo TP Rallu M Gitton Y Pirkkala L Loones MT Paslaru L Larney S Hiard S Morange M Sistonen L Mezger V Brain abnormalities, defective meiotic chromosome synapsis and female subfertility in HSF2 null mice.EMBO J. 2002; 21: 2591-2601Crossref PubMed Scopus (126) Google Scholar). Similarly, eIF2B dysfunction in humans may be responsible for increased apoptosis of ovarian follicles (leading to OF) and for a defect in glial cell development (causing abnormal formation of white-matter structures). This abnormal CNS development would increase susceptibility of eIF2B-mutated cells to cellular stress, with subsequent progressive neurological deterioration and white-matter cavitation. Estrogen deprivation due to OF may accelerate this deterioration by increasing the vulnerability of neurons to injury (Liu et al. Liu et al., 2001Liu Z Gastard M Verina T Bora S Mouton PR Koliatsos VE Estrogens modulate experimentally induced apoptosis of granule cells in the adult hippocampus.J Comp Neurol. 2001; 441: 1-8Crossref PubMed Scopus (51) Google Scholar). In conclusion, we report an association of white-matter disease with OF in seven patients with mutations in the EIF2B genes. Further investigation may show that defects in this gene are the basis of some cases of OF of unknown cause. The correlation we observed between the age at onset of the neurological deterioration and the severity of the OF suggests a common pathophysiological pathway in these two tissue types that is mediated by eIF2B and result from dysgenesis during development and/or abnormal response to stress in the adult. We gratefully acknowledge the participation of the patients' families and the patient referral by Dr. Mark Lipson. We thank Dr. S. Matsuzaki for her comments on this manuscript. We also thank P. Combes, F. Gauthier, and G. Giraud for technical help in processing blood samples and in sequencing. This work was supported by grants from the European Leukodystrophy Association, the Fondation pour la Recherche Médicale (grant ARS 2000), and the Jean Pierre and Nancy Boespflug Myopathic Research Foundation.