Efecto del tratamiento enzimático en el proceso de microfiltración

The fragile X syndrome is a relatively common cause o f mental handicap, and is due to expansion o f a polymorphic CGG trinucleotide repeat in the 5' untranslated region o f the F M R l gene at Xq27.3. N orm ally the number o f repeats is 5 -5 0 . Premutations have 50-200 repeats, and do not affect the synthesis o f the gene product FMRP. The fu ll Fragile X (F R A X A ) mutation o f greater than 200 repeats is associated w ith méthylation o f the promoter and silencing o f gene transcription (Fig. 2). Absence o f the gene product FMRP is associated w ith the clinical syndrome o f mental retardation.

Studies have demonstrated that 13-25% o f fragile X carriers experience POF (Allingham -Hawkins et a l , 1999; U zie lli et a l,

1999), and conversely 3 -1 5 % o f women w ith idiopathic POF harbour a fragile X premutation, compared w ith an expected prevalence o f 1:590 (Conway e ta l , 1998b; U zielli e ta l , 1999). Also, there were no fu ll mutations in the POF population confirm ing previous reports o f the association between F R A X A and POF being restricted to premutation carriers (Cronister

et a l, 1991; Schwartz et a l , 1994).

Interpretation o f this finding into a molecular mechanism is perplexing. When the F M R l gene is inactivated by méthylation as in the fu ll F R A X A mutation, there appears to be no detrimental effect on ovarian function. Protein studies have 1999 Blackwell Science Ltd, Clinical Endocrinology, 51, 673-679

The X chromosome and ovarian failure 677

been unable to detect a difference in the expression o f the F M R l protein from premutation alleles as compared with normal (Devys et a l, 1993; Feng et a l , 1995), and yet premutation alleles clearly have an adverse effect on ovarian function. One theory is that although the F M R l protein is absent in the fu ll mutation, a back up protein provides its function. In the case o f premutations however, where F M R l is expressed, the alternative mechanism fails to come into play and any adverse effect caused by the premutation is expressed.

Another possibility is that a particular isoform o f F M R l, crucial during oogenesis is less efficiently produced from premutation alleles. Murine studies have shown that F M R l is particularly strongly expressed during the mitotic phases o f oogenesis (Bachner et a l , 1993) and so any changes in expression at this critical time could dramatically reduce the number o f oocytes. Against this hypothesis are the results o f studies on at least 11 isoforms o f F M R l showing no differences between tissues o f normal compared with premutation alleles (Ashley et a l , 1993; Devys et a l , 1993; Khandjian et a l , 1995; Verheij et a l , 1995). In conclusion, there is an association between FR A X A premutations and POF but the exact role o f the F M R l gene in reproduction is as yet undetermined.

Conclusions

From studies o f X chromosome deletions it seems likely that many ovarian determining genes w ill be found on the X but as yet none has been sufficiently w ell characterized to claim this status. Here, we have reviewed the evidence that POF genes are concentrated on the X chromosome and have presented the case for eight obvious candidates. It seems likely that these eight genes are only a start. As the fu ll complement o f genes on the X chromosome emerges, the list o f ovarian determining genes w ill define the ’female sex chromosome’ .

References

A llingham-Hawkins, D.J., B abul-H itji, R., Chitayat, D., Holden, J.J., Yang, K.T., Lee, C., Hudson, R., G orw ill, H., Nolin, S.L., Glicksman, A., Jenkins, E.G., Brown, W.T., Howard-Peebles, P.N., Becchi, C., Cummings, E., Fallon, L., Seitz, S., Black, S.H., Vianna-Morgante, A .M ., Costa, S.S., Otto, P.A., Mingroni-Netto, R.C., Murray, A., Webb, J. & Vieri, F. (1999) Fragile X premutation is a significant risk factor fo r premature ovarian failure: the International Colla­ borative POF in Fragile X study — preliminary data. American Joum al o f Medicine Genetics, 83, 322-325.

Aittom aki, K. (1994) The genetics o f X X gonadal dysgenesis. American Joum al o f Human Genetics, 54, 844-851.

Aittom aki, K., Lucena, J.L., Pakarinen, P., Sistonen, P., Tapanainen, J., Gromoll, J., Kaskikari, R., Sankila, E.M., Lehvaslaiho, H. & Engel, A.R. (1995) Mutation in the follicle-stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure. CeU, 82, 959-968.

Aittom aki, K., Herva, R., Stenman, U.H., Juntunen, K., Ylostalo, P., Hovatta, O. & de la Chapelle, A. (1996) Clinical features o f primary ovarian failure caused by a point mutation in the follicle-stimulating hormone receptor gene. Joum al o f Clinical Endocrinology and Metabolism, 81, 3722-3726.

Ashley, C.T., Sutcliffe, J.S., Kunst, C.B., Leiner, H.A., Eichler, E.E., Nelson, D.L. & Warren, S.T. (1993) Human and murine FMR-1: alternative splicing and translational initiation downstream o f the CGG-repeat. Nature Genetics, 4, 244-251.

Bachner, D., Manca, A., Steinbach, P., Wohrle, D., Just, W., Vogel, W., Hameister, H. & Poustka, A. (1993) Enhanced expression o f the murine F M R l gene during germ cell proliferation suggests a special function in both the male and the female gonad. Human Molecular Genetics, 2, 2043-2050.

Banfi, S., Borsani, G., Bulfone, A. & Ballabio, A. (1997) Drosophila- related expressed sequences. Human Molecular Genetics, 6, 1745- 1753.

Bione, S., Sala, C., Manzini, C., Arrigo, G., Zuffardi, O., Banfi, S., Borsani, G., Jonveaux, P., Philippe, C., Zuccotti, M ., Ballabio, A. & Toniolo, D. (1998) A human homologue o f the Drosophila melanogaster diaphanous gene is disrupted in a patient with premature ovarian failure: evidence for conserved function in oogenesis and implications fo r human sterility. American Joumal o f Human Genetics, 62, 533-541.

Brown, C.J., Lafreniere, R.G., Powers, V.E., Sebastio, G., Ballabio, A., Pettigrew, A.L., Ledbetter, D.H., Levy, E., Craig, l.W . & W illard, H.F. (1991) Localization o f the X inactivation centre on the human X chromosome in Xq. Nature, 349, 82-84.

Brown, G.M., Furlong, R.A., Sargent, C.A., Erickson, R.P., Longepied, G., M itchell, M ., Jones, M .H., Hargreave, T.B., Cooke, H.J. & Affara, N.A. (1998) Characterisation o f the coding sequence andfine mapping o f the human DFFRY gene and comparative expression analysisand mapping to the Sxr-b interval o f the mouse Y chromosome o f theDffry gene. Hum Molecular Genetics, 7 ,97-107. Collignon, J., Sockanathan, S., Hacker, A., Cohem Tannoudji, M.,

Norris, D., Rastan, S., Stevanovic, M ., Goodfellow, P.N. & Lovell- Badge, R. (1996) A comparison o f the properties o f Sox-3 w ith Sry and two related genes, Sox-1 and Sox-2. Development, 122, 5 0 9 - 520.

Conway, G.S., Conway, E., Walker, C., Hoppner, W., GromoUi, J. & Simoni, M . (1998a) Mutation screening and isoform prevalence o f the FSH receptor gene in women with premature ovarian failure and PCOS. Clinical Endocrinology, 51, 97-99.

Conway, G.S., Payne, N., Webb, J., Murray, A. & Jacobs, P.A. (1998b) Fragile X screening in women w ith premature ovarian failure.

Human Reproduction, 13, 1184-1187.

Coulam, C.B., Stringfellow, S. & Hoefnagel, D. (1983) Evidence for a genetic factor in the etiology o f premature ovarian failure. Fertility and Sterility, 40, 693-695.

Cronister, A., Schreiner, R., Wittenberger, M ., A m iri, K., Harris, K. & Hagerman, R.J. (1991) Heterozygous fragile X female: historical, physical, cognitive, and cytogenetic features. American Joum al o f Human Genetics, 38, 269-274.

Daud, A.I., Bumpus, F.M. & Husain, A. (1988) Evidence for selective expression o f angiotensin 11 receptors on atretic follicles in the rat ovary: an autoradiographic study. Endocrinology, 122, 2727-2734. Davison, R.M., Quilter, C.R., Webb, J., Murray, A., Fishe, R.A.M.,

Valentine, A., Serhal, P. & Conway, G.S. (1998) A fam ilial case o f X chromosome deletion ascertained by cytogenetic screening o f women with premature ovarian failure (POF). Human Reproduction,

13,3039-3041.

678 R. M. Davison et al.

Devys, D., Lutz, Y., Rouyer, N., Bellocq, J.P. & Mandel, J.L. (1993) The FMR-1 protein is cytoplasmic, most abundant in neurons and appears normal in carriers o f a fragile X premutation. Nature Genetics, 4, 335-334.

Feng, Y., Lakkis, L., Devys, D. & Warren, S.T. (1995) Quantitative comparison o f F M R l gene expression in normal and premutation alleles. American Joum al o f Human Genetics, 56, 106-113. Fitch, N., de Saint Victor, J., Richer, C.L., Pinsky, L. & Sitahal, S.

(1982) Premature menopause due to a small deletion in the long arm o f the X chromosome: a report o f three cases and a review. American Joum al o f Obstetrics and Gynecolology, 142, 968-972.

Foster, J.W. & Graves, J.A. (1994) An SRY-related sequence on the marsupial X chromosome; implications fo r the evolution o f the mammalian testis-determining gene. Proceedings o f National Academy o f Sciences o f the U-S-A, 5, 1927-1931.

Grady, E.F., Sechi, L.A., G riffin, C.A., Schambelan, M . & Kalinyak, J.E. (1991) Expression o f A T 2 receptors in the developing rat fetus.

Joum al o f Clinical Investigation, 88, 921-933.

Hsueh, A.J., B illig , H. & Tsafriri, A. (1994) Ovarian fo llicle atresia: a hormonally controlled apoptotic process. Endocrine Reviews, 15, 707-724.

James, R.S., Coppin, B., Dalton, P., Dennis, N.R., M itchell, C., Sharp, A.J., Skuse, D.H., Thomas, N.S. & Jacobs, P.A. (1998) A study o f females w ith deletions o f the short arm o f the X chromosome. Human Genetics, 102, 507-516.

Jones, M .H., Furlong, R.A., Burkin, H., Chalmers, I.J., Brown, G.M., Khwaja & Affara, N.A. (1996) The Drosophila developmental gene fat facets has a human homologue in X p ll. 4 which escapes X - inactivation and has related sequences on Y q ll.2 . Human Molecular Genetics, 5, 1695-1701,.

Katsuya, T., Horiuchi, M., M inam i, S., Koike, G., Santoro, N.F., Hsueh, A.J. & Dzau, V.J. (1997) Genomic organization and polymorphism o f human angiotensin I I type 2 receptor: no evidence fo r its gene mutation in two families o f human premature ovarian failure syndrome. Molecular and Cell Endocrinology, 127, 221-228. Khandjian, E.W., Fortin, A., Thibodeau, A., Tremblay, S., Cote, F.,

Devys, D., Mandel, J.L. & Rousseau, F. (1995) A heterogeneous set o f F M R l proteins is widely distributed in mouse tissues and is modulated in cell culture. Human Molecular Genetics, 4, 783-789. Koike, G., Winer, E.S., Horiuchi, M ., Brown, D M ., Szpirer, C., Dzau,

V.J. & Jacob, H.J. (1995) Cloning, characterization, and genetic mapping o f the rat type 2 angiotensin U receptor gene. Hypertension,

26, 998-1002.

Krauss, C M ., Turksoy, R.N., Atkins, L., McLaughlin, C., Brown, L.G. & Page, D C. (1987) Fam ilial premature ovarian failure due to an interstitial deletion o f the long arm o f the X chromosome. New England Joum al o f Medicine, 317, 125-131.

Lahn, B.T. & Page, D C. (1997) Functional coherence o f the human Y chromosome. Science, 278, 675-680.

Layman, L.C., Made, S., Cohen, D.P., Jin, M . & Xie, J. (1998) The Finnish follicle-stimulating hormone receptor gene mutation is rare in North American women with 46,XX ovarian failure. Fertility and Sterility, 69, 300-302.

Luoh, S.W., Jegalian, K., Lee, A., Chen, E.Y., Ridley, A. & Page, D C. (1995) CpG islands in human ZFX and Z FY and mouse Z fx genes: sequence similarities and méthylation differences. Genomics, 29, 353-363.

Luoh, S.W., Bain, P.A., Polakiewicz, R.D., Goodheart, M .L., Gardner, H., Jaenisch, R. & Page, D C. (1997) Z fx mutation results in small animal size and reduced germ cell number in male and female mice.

Development, 124, 2275-2284.

Mattison, D R., Evans, M .I., Schwimmer, W.B., White, B.J., Jensen, B. & Schulman, J.D. (1984) Fam ilial premature ovarian failure.

American Joum al o f Human Genetics,36, 1341-1348.

Page, D.C., Mosher, R., Simpson, E.M., Fisher, E.M., Mardon, G., Pollack, J., McGiUivray, B., de la ChapeUe, A. & . & Brown, L.G. (1987) The sex-determining region o f the human Y chromosome encodes a finger protein. Cell,51, 1091-1104.

Page, D C., Disteche, C.M., Simpson, E.M., de la Chapelle, A., Andersson, M ., A litalo, T., Brown, L.G., Green, P. & Akots, G. (1990) Chromosomal localization o f Z F X — a human gene that escapes X inactivation — and its murine homologs. Genomics,7,3 7 - 46.

Panning, B. & Jaenisch, R. (1998) R N A and epigenetic regulation o f X chromosome inactivation. Cell,93, 305-308.

Penny, G.D., Kay, G.F., Sheardown, S.A., Rastan, S. & Brockdorff, N. (1996) Requirement fo r X ist in X chromosome inactivation. Nature,

379, 131-137.

Plenge, R.M., Hendrich, B.D., Schwartz, C., Arena, J.F., Naumova, A., Sapienza, C., Winter, R.M. & W illard, H.F. (1997) A promoter mutationin the XIST gene in two unrelated families with skewed X - chromosome inactivation. Nature Genetics,17, 353-356.

Portuondo, J.A., Neyro, J.L., De Benito, J.A., lo Rios, A. & Barrai, A. (1987) Fam ilial 46, X X gonadal dysgenesis. Intemational Joum al o f Fertility,32, 56-58.

Powell, C M ., Taggart, R.T., Drumheller, T.C., Wangsa, D., Qian, C., Nelson, L.M . & White, B.J. (1994) Molecular and cytogenetic studies o f an X ; autosome translocation in a patient with premature ovarian failure and review o f the literature. American Joum al o f Medical Genetics,52, 19-26.

Roberts, R.G., Kendall, E., Vetrie, D. & Bobrow, M . (1996) Sequence and chromosomal location o f a human homologue o f LR P R l, an FSH primary response gene. Genomics,37, 122-124.

Rousseau, F., Vincent, A., Rivella, S., Heitz, D., T riboli, C., Maestrini, E., Warren, S.T., Suthers, G., Goodfellow, P. & Mandel, J.L. (1991) Four chromosomal breakpoints and four new probes mark out a 10-cM region encompassing the fragile-X locus (FRAXA). American Joum al o f Human Genetics,48, 108-116.

Sala, C., Arrigo, G., Torri, G., Martinazzi, F., Riva, P., Larizza, L., Philippe, C., Jonveaux, P., Sloan, F., Labella, T. & Toniolo, D. (1997) Eleven X chromosome breakpoints associated with premature ovarian failure (POF) map to a 15-Mb Y A C contig spanning Xq21.

Genomics,40, 123-131.

Sarto, G.E., Therman, E. & . Patau, K. (1973) X inactivation in man; A woman with t (Xq; 12q-f). American Joum al o f Human Genetics,25, 262-270.

Schneider Gadicke, A., Beer, R.P., Brown, L.G., Nussbaum, R. & Page, D C. (1989) ZFX has a gene structure similar to ZFY, the putative human sex determinant, and escapes X inactivation. Cell,57, 1247- 1258.

Schwartz, C.E., Dean, J., Howard Peebles, P.N., Bugge, M ., Mikkelsen, M ., Tommerup, N., H ull, C., Hagerman, R., Holden, J.J. & Stevenson, R E. (1994) Obstetrical and gynecological complications in fragile X carriers: a multicenter study. American Joum al o f Human Genetics,51, 400-402.

Slegtenhorst-Eegdeman, K.E., Verhoef-Post, M ., Parvinen, M ., Groo­ tegoed, J.A. & Themmen, A.P. (1998) Differential regulation o f leucine-rich primary response gene 1 (LR P R l) m RNA expression in rat testis and ovary. Molecular Hum Reproduction,4, 649-656. Slegtenhorst-Eegdeman, K.E., Post, M ., Baarends, W .M ., Themmen,

A.P. & Grootegoed, J.A. (1995) Regulation o f gene expression in Sertoli cells by follicle-stimulating hormone (FSH): cloning and

The X chromosome and ovarian failure 679

characterization o f LR P R l, a primary response gene encoding a leucine-rich protein. Molecular and Cellular Endocrinology, 108, 115-24.

Stevanovic, M ., Lovell Badge, R., Collignon, J. & Goodfellow, P.N. (1993) S0X 3 is an X-linked gene related to SRY. Human Molecular Genetics, 2, 2013-2018.

Stratakis, C.A. & Rennet, O.M. (1994) Turner syndrome: molecular and cytogenetics, dysmorphology, endocrine and other clinical manifes­ tations and their treatment. Endocrinologist, 44, 442-453. Tanaka, M ., Ohnishi, J., Ozawa, Y., Sugimoto, M ., Usuki, S., Naruse,

M ., Murakami, K. & Miyazaki, H. (1995) Characterization o f angiotensin I I receptor type 2 during differentiation and apoptosis o f rat ovarian cultured granulosa cells. Biochemical and Biophysical Research Communications, 207, 593-598.

Tharapel, A T., Anderson, K.P., Simpson, J.L., Martens, P R., W ilroy, R.S. Jr, Llerena, J.C. Jr & Schwartz, C.E. (1993) Deletion (X) (q26.1—»q28) in a prohand and her mother: molecular characteriza­ tion and phenotypic-karyotypie deductions. American Joum al o f Human Genetics, 52, 463-471.

Therman, E., Laxova, R. & Susman, B. (1990) The critical region on the human Xq. effects caused by Xp and X q deletions in the human female: a hypothesis. Human Genetics, 85, 455-461.

U zielli, M L., Guarducci, S., Lapi, E., Cecconi, A., Ricci, U., Riccoti, G., Biondi, C., Scaselli, B., V ieri, P., Scamato, P., Gori, F. & Semi, A. (1999) Premature ovarian failure and fragile X premutation

females: from POF to fragile X carrier identification, from fragile X carrier diagnosis to POF association data. American Joum al o f Medical Genetics, 84, 300-303.

Vegetti, W., Grazia T ibiletti, M ., de Testa, G., Lauretis Yankowski, Alagna, P., Castoldi, E., Taborelli, M ., Motta, T., Bolis, P.P., Dalpra, L. & Crosignani, P.G. (1998) Inheritance in idiopathic premature ovarian failure: analysis o f 71 cases. Human Reproduction, 13 (7), 1796-1800.

Veneman, T.F., Beverstock, G.C., Exalto, N. & Mollevanger, P. (1991) Premature menopause because o f an inherited deletion in the long arm o f the X-chromosome. Fertility and Sterility, 55, 631-634. Verheij, C., de Graaff, E., Bakker, C.E., Willemsen, R., W illems, P.J.,

M eijer, N., Galjaard, H., Reuser, A.J., Oostra, B.A. & Hoogeveen, A T. (1995) Characterization o f F M R l proteins isolated from different tissues. Human Molecular Genetics, 4, 895-901. Whitney, E.A., Layman, L.C., Chan, P.J., Lee, A., Peak, D.B. &

McDonough, P.G. (1995) The follicle-stimulating hormone receptor gene is polymorphic in premature ovarian failure and normal controls. Fertility and Sterility, 64, 518-524.

Yamada, T., Horiuchi, M . & Dzau, V.J. (1995) Mitogen-activated protein kinase dephosphorylation by angiotensin 11 type 2 receptor induces apoptosis. Circulation, 92 (Suppl.), 1-489.

Yamada, T., Horiuchi, M . & Dzau, V.J. (1996) Angiotensin I I type 2 receptor mediates programmed cell death. Proceedings o f National Academy o f Sciences o f the U-S-A, 93, 156-160.

Molecular Human Reproduction vol.6 no.4 pp. 314-318, 2000

Mapping of the POF1 locus and identification of putative genes for