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Preliminary molecular genetic analysis of the Receptor Interacting Protein 140 (RIP140) in women affected by endometriosis
Journal of Experimental & Clinical Assisted Reproduction volume 2, Article number: 11 (2005)
Endometriosis is a complex disease affecting 10–15% of women at reproductive age. Very few genes are known to be altered in this pathology. RIP140 protein is an important cofactor of oestrogen receptor and many other nuclear receptors. Targeting disruption experiments of nrip1 gene in mice have demonstrated that nuclear receptor interacting protein 1 gene (nrip1), the gene encoding for rip140 protein, is essential for female fertility. Specifically, mice null for nrip1 gene are viable, but females are infertile because of complete failure of mature follicles to release oocytes at ovulation stage. The ovarian phenotype observed in mice devoid of rip140 closely resembles the luteinized unruptured follicle (LUF) syndrome that is observed in a high proportion of women affected of endometriosis or idiopathic infertility. Here we present a preliminary work that analyses the role of NRIP1 gene in humans.
We have sequenced the complete coding region of NRIP1 gene in 20 unrelated patients affected by endometriosis. We have performed genetic association studies by using the DNA variants identified during the sequencing process.
We identified six DNA variants within the coding sequence of NRIP1 gene, and five of them generated amino acid changes in the protein. We observed that three of twenty sequenced patients have specific combinations of amino-acid variants within the RIP140 protein that are poorly represented in the control population (p = 0.006). Moreover, we found that Arg448Gly, a common polymorphism located within NRIP1 gene, is associated with endometriosis in a case-control study (59 cases and 141 controls, pallele positivity test = 0.027).
Our results suggest that NRIP1 gene variants, separately or in combinations, might act as predisposing factors for human endometriosis.
Bulum SE, Zeitoun KM, Takayama K, Sasano H: Estrogen biosynthesis in endometriosis: molecular basis and clinical relevance. J Mol Endocrinol. 2000, 25: 35-42. 10.1677/jme.0.0250035.
Donnez J, Thomas K: Incidence of luteinized unruptured follicle syndrome in fertile women and women with endometriosis. Eur J Obstet Gynecol Reprod Biol. 1982, 14: 187-190. 10.1016/0028-2243(82)90095-8.
White R, Leonardsson G, Rosewell I, Ann Jacobs M, Milligan S, Parker M: The nuclear receptor co-repressor Nrip1 (RIP140) is essential for female fertility. Nat Med. 2000, 6: 1368-1374. 10.1038/82183.
García-Velasco JA, Arici A: Is the endometrium or oocyte/embryo affected in endometriosis?. Hum Reprod. 1999, 2: 77-89.
Vercammen EE, D'Hooghe TM: Endometriosis and recurrent pregnancy loss. Semin Reprod Med. 2000, 18: 363-368. 10.1055/s-2000-13726.
Leonardsson G, Steel JH, Christian M, Pocock V, Milligan S, Bell J, So PW, Medina-Gomez G, Vidal-Puig A, White R, Parker MG: Nuclear receptor corepressor RIP140 regulates fat accumulation. Proc Natl Acad Sci U S A. 2004, 101: 8437-42. 10.1073/pnas.0401013101.
American Society for Reproductive Medicine: Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril. 1997, 67: 817-821. 10.1016/S0015-0282(97)81391-X.
Cavailles V, Dauvois S, L'Horset F, Lopez G, Hoare S, Kushner PJ, Parker MG: Nuclear factor RIP140 modulates transcriptional activation by the estrogen receptor. EMBO J. 1995, 14: 3741-3751.
den Dunnen JT, Antonarakis SE: Nomenclature for the description of human sequence variations. Hum Genet. 2001, 109: 121-124. 10.1007/s004390100505.
Gonzalez A, Abril E, Roca A, Aragon MJ, Figueroa MJ, Velarde P, Royo JL, Real LM, Ruiz A: CAPN10 alleles are associated with polycystic ovary syndrome. J Clin Endocrinol Metab. 2002, 87: 3971-3976. 10.1210/jc.87.8.3971.
Sasieni PD: From genotypes to genes: doubling the sample size. Biometrics. 1997, 53: 1253-1261.
Georgiou I, Syrrou M, Bouba I, Dalkalitsis N, Paschopoulos M, Navrozoglou I, Lolis D: Association of estrogen receptor gene polymorphisms with endometriosis. Fertil Steril. 1999, 72: 64-66. 10.1016/S0015-0282(99)00198-3.
Kado N, Kitawaki J, Obayashi H, Ishihara H, Koshiba H, Kusuki I, Tsukamoto K, Hasegawa G, Nakamura N, Yoshikawa T, Honjo H: Association of the CYP17 gene and CYP19 gene polymorphisms with risk of endometriosis in Japanese women. Hum Reprod. 2002, 17: 897-902. 10.1093/humrep/17.4.897.
Wieser F, Schneeberger C, Tong D, Tempfer C, Huber JC, Wenzl R: PROGINS receptor gene polymorphism is associated with endometriosis. Fertil Steril. 2002, 77: 309-312. 10.1016/S0015-0282(01)02984-3.
Dogan S, Machicao F, Wallwiener D, Haering HU, Diedrich K, Hornung D: Association of peroxisome proliferator-activated receptor gamma 2 Pro-12-Ala polymorphism with endometriosis. Fertil Steril. 2004, 81: 1411-1413. 10.1016/j.fertnstert.2003.10.026.
Baranova H, Canis M, Ivaschenko T, Albuisson E, Bothorishvilli R, Baranov V, Malet P, Bruhat MA: Possible involvement of arylamine N-acetyltransferase 2, glutathione S-transferases M1 and T1 genes in the development of endometriosis. Mol Hum Reprod. 1999, 5: 636-641. 10.1093/molehr/5.7.636.
Arvanitis DA, Goumenou AG, Matalliotakis IM, Koumantakis EE, Spandidos DA: Low-penetrance genes are associated with increased susceptibility to endometriosis. Fertil Steril. 2001, 76: 1202-1206. 10.1016/S0015-0282(01)02865-5.
Arvanitis DA, Koumantakis GE, Goumenou AG, Matalliotakis IM, Koumantakis EE, Spandidos DA: CYP1A1, CYP19, and GSTM1 polymorphisms increase the risk of endometriosis. Fertil Steril. 2003, 702-709. 10.1016/S0015-0282(02)04817-3. Suppl 1
Moutsatsou P, Sekeris CE: Steroid receptors in the uterus: implications in endometriosis. Ann N Y Acad Sci. 2003, 997: 209-222. 10.1196/annals.1290.024.
Kitawaki J, Kado N, Ishihara H, Koshiba H, Kitaoka Y, Honjo H: Endometriosis: the pathophysiology as an estrogen-dependent disease. J Steroid Biochem Mol Biol. 2002, 83: 149-155. 10.1016/S0960-0760(02)00260-1.
Kastner P, Mark M, Leid M, Gansmuller A, Chin W, Grondona JM, Decimo D, Krezel W, Dierich A, Chambon P: Abnormal spermatogenesis in RXR beta mutant mice. Genes Dev. 1996, 10: 80-92.
Dupont S, Krust A, Gansmuller A, Dierich A, Chambon P, Mark M: Effect of single and compound knockouts of estrogen receptors alpha (ERalpha) and beta (ERbeta) on mouse reproductive phenotypes. Development. 2000, 127: 4277-4291.
Cui Y, Miyoshi K, Claudio E, Siebenlist UK, Gonzalez FJ, Flaws J, Wagner KU, Hennighausen L: Loss of the peroxisome proliferation-activated receptor gamma (PPARgamma) does not affect mammary development and propensity for tumor formation but leads to reduced fertility. J Biol Chem. 2002, 17: 17830-17835. 10.1074/jbc.M200186200.
Nakamura T, Yao R, Ogawa T, Suzuki T, Ito C, Tsunekawa N, Inoue K, Ajima R, Miyasaka T, Yoshida Y, Ogura A, Toshimori K, Noce T, Yamamoto T, Noda T: Oligo-astheno-teratozoospermia in mice lacking Cnot7, a regulator of retinoid X receptor beta. Nat Genet. 2004, 36: 528-533. 10.1038/ng1344.
Hoh J, Ott J: Genetic dissection of diseases: design and methods. Curr Opin Genet Dev. 2004, 14: 229-232. 10.1016/j.gde.2004.04.006.
Lohnes D, Kastner P, Dierich A, Mark M, LeMeur M, Chambon P: Function of retinoic acid receptor gamma in the mouse. Cell. 1993, 21: 643-658. 10.1016/0092-8674(93)90246-M.
Dufour JM, Vo MN, Bhattacharya N, Okita J, Okita R, Kim KH: Peroxisome proliferators disrupt retinoic acid receptor alpha signaling in the testis. Biol Reprod. 2003, 68: 1215-1224. 10.1095/biolreprod.102.010488.
Cohen JC, Kiss RS, Pertsemlidis A, Marcel YL, McPherson R, Hobbs HH: Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science. 2004, 305: 869-872. 10.1126/science.1099870.
Lohmueller KE, Pearce CL, Pike M, Lander ES, Hirschhorn JN: Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet. 2003, 33: 177-182. 10.1038/ng1071.
Zilliacus J, Holter E, Wakui H, Tazawa H, Treuter E, Gustafsson JA: Regulation of glucocorticoid receptor activity by 14-3-3-dependent intracellular relocalization of the corepressor RIP140. Mol Endocrinol. 2001, 15: 501-511. 10.1210/me.15.4.501.
Ohtake F, Takeyama K, Matsumoto T, Kitagawa H, Yamamoto Y, Nohara K, Tohyama C, Krust A, Mimura J, Chambon P, Yanagisawa J, Fujii-Kuriyama Y, Kato S: Modulation of oestrogen receptor signalling by association with the activated dioxin receptor. Nature. 2003, 423: 545-550. 10.1038/nature01606.
Kumar MB, Tarpey RW, Perdew GH: Differential recruitment of coactivator RIP140 by Ah and estrogen receptors. Absence of a role for LXXLL motifs. J Biol Chem. 1999, 274: 22155-22164. 10.1074/jbc.274.32.22155.
Peters GA, Khan SA: Estrogen receptor domains E and F: role in dimerization and interaction with coactivator RIP-140. Mol Endocrinol. 1999, 13: 286-296. 10.1210/me.13.2.286.
Galan JJ, Buch B, Cruz N, Segura A, Moron FJ, Bassas L, Martinez-Pineiro L, Real LM, Ruiz A: Multilocus analyses of estrogen-related genes reveal the involvement of ESR1 gene in male infertility and the polygenic nature of the pathology. Fertil Steril.
We are deeply grateful to patients and controls for participation in this study. Funded by the Ministerio de Ciencia y Tecnología (MCYT, Spain, grant numbers FIT-010000-2003-36, FIT-010000-2003-89, FIT-010000-2003-70, PTQ2002-0206) and Organón Española S.A. (BCN, Spain).
The author(s) declare that they have not competing interests.
VC, JAS, MC, MAL, FC and VL carried out the recruitment and classification of patients and controls and the biological samples management. RR and JJG carried out the molecular genetic studies and participate in the analysis and interpretation of data. LMR and AR carried out the design of the study, performed the statistical analyses and the interpretation of data.
All authors have been involved in drafting the article or revising it critically for important intellectual content and have given final approval of the version to be published.
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Caballero, V., Ruiz, R., Sainz, J.A. et al. Preliminary molecular genetic analysis of the Receptor Interacting Protein 140 (RIP140) in women affected by endometriosis . J Exp Clin Assist Reprod 2, 11 (2005). https://doi.org/10.1186/1743-1050-2-11