Artículos de revistas
The Novel P.cys65tyr Mutation In Nr5a1 Gene In Three 46,xy Siblings With Normal Testosterone Levels And Their Mother With Primary Ovarian Insufficiency
Registro en:
Bmc Medical Genetics. , v. 15, n. 1, p. - , 2014.
14712350
10.1186/1471-2350-15-7
2-s2.0-84892421279
Autor
Fabbri H.C.
de Andrade J.G.R.
Soardi F.C.
de Calais F.L.
Petroli R.J.
Maciel-Guerra A.T.
Guerra-Junior G.
de Mello M.P.
Institución
Resumen
Background: Disorders of sex development (DSD) is the term used for congenital conditions in which development of chromosomal, gonadal, or phenotypic sex is atypical. Nuclear receptor subfamily 5, group A, member 1 gene (NR5A1) encodes steroidogenic factor 1 (SF1), a transcription factor that is involved in gonadal development and regulates adrenal steroidogenesis. Mutations in the NR5A1 gene may lead to different 46,XX or 46,XY DSD phenotypes with or without adrenal failure. We report a Brazilian family with a novel NR5A1 mutation causing ambiguous genitalia in 46,XY affected individuals without Müllerian derivatives and apparently normal Leydig function after birth and at puberty, respectively. Their mother, who is also heterozygous for the mutation, presents evidence of primary ovarian insufficiency.Case presentation: Three siblings with 46,XY DSD, ambiguous genitalia and normal testosterone production were included in the study. Molecular analyses for AR, SRD5A2 genes did not reveal any mutation. However, NR5A2 sequence analysis indicated that all three siblings were heterozygous for the p.Cys65Tyr mutation which was inherited from their mother. In silico analysis was carried out to elucidate the role of the amino acid change on the protein function. After the mutation was identified, all sibs and the mother had been reevaluated. Basal hormone concentrations were normal except that ACTH levels were slightly elevated. After 1 mcg ACTH stimulation test, only the older sib showed subnormal cortisol response.Conclusion: The p.Cys65Tyr mutation located within the second zinc finger of DNA binding domain was considered deleterious upon analysis with predictive algorithms. The identification of heterozygous individuals with this novel mutation may bring additional knowledge on structural modifications that may influence NR5A1 DNA-binding ability, and may also contribute to genotype-phenotype correlations in DSD. The slightly elevated ACTH basal levels in all three patients with 46,XY DSD and the subnormal cortisol response after 1 mcg ACTH stimulation in the older sib indicate that a long-term follow-up for adrenal function is important for these patients. Our data reinforce that NR5A1 analysis must also be performed in 46,XY DSD patients with normal testosterone levels without AR mutations. © 2014 Fabbri et al.; licensee BioMed Central Ltd. 15 1
Luo, X., Ikeda, Y., Parker, K.L., A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation (1994) Cell, 77, pp. 481-490. , 10.1016/0092-8674(94)90211-9, 8187173 Lin, L., Achermann, J.C., Steroidogenic factor-1 (SF-1, Ad4BP, NR5A1) and disorders of testis development (2008) Sex Dev, 2, pp. 200-209. , 10.1159/000152036, 2645687, 18987494 Wong, M., Ramayya, M.S., Chrousos, G.P., Driggers, P.H., Parker, K.L., Cloning and sequence analysis of the human gene encoding steroidogenic factor 1 (1996) J Mol Endocrinol, 17, pp. 139-147. , 10.1677/jme.0.0170139, 8938589 Kimura, R., Yoshii, H., Nomura, M., Kotomura, N., Mukai, T., Ishihara, S., Ohba, K., Morohashi, K., Identification of novel first exons in Ad4BP/SF-1 (NR5A1) gene and their tissue- and species-specific usage (2000) Biochem Biophys Res Commun, 278 (SUPPL 1), pp. 63-71 Hoivik, E.A., Lewis, A.E., Aumo, L., Bakke, M., Molecular aspects of steroidogenic factor 1 (SF-1) (2010) Mol Cell Endocrinol, 315 (1-2 SUPPL), pp. 27-39 Ohno, C.K., Petkovich, M., FTZ-F1 beta, a novel member of the Drosophila nuclear receptor family (1993) Mech Dev, 40, pp. 13-24. , 10.1016/0925-4773(93)90084-B, 8382937 Parker, K.L., Rice, D.A., Lala, D.S., Ikeda, Y., Luo, X., Wong, M., Bakke, M., Schimmer, B.P., Steroidogenic factor 1: an essential mediator of endocrine development (2002) Recent Prog Horm Res, 57, pp. 19-36. , 10.1210/rp.57.1.19, 12017543 Zhao, H., Li, Z., Cooney, A.J., Lan, Z.J., Orphan nuclear receptor function in the ovary (2007) Front Biosci, 12, pp. 3398-3405. , 10.2741/2321, 17485308 Buaas, F.W., Gardiner, J.R., Clayton, S., Val, P., Swain, A., In vivo evidence for the crucial role of SF1 in steroid-producing cells of the testis, ovary and adrenal gland (2012) Development, 139, pp. 4561-4570. , 10.1242/dev.087247, 3509722, 23136395 Büdefeld, T., Tobet, S.A., Majdic, G., Steroidogenic factor 1 and the central nervous system (2012) J Neuroendocrinol, 24, pp. 225-235. , 10.1111/j.1365-2826.2011.02174.x, 21668533 Hughes, I.A., Houk, C., Ahmed, S.F., Lee, P.A., Group, L.C., Group, E.C., Consensus statement on management of intersex disorders (2006) Arch Dis Child, 91, pp. 554-563. , 2082839, 16624884 Nabhan, Z.M., Lee, P.A., Disorders of sex development (2007) Curr Opin Obstet Gynecol, 19, pp. 440-445. , 10.1097/GCO.0b013e3282eeb13d, 17885459 Achermann, J.C., Ito, M., Hindmarsh, P.C., Jameson, J.L., A mutation in the gene encoding steroidogenic factor-1 causes XY sex reversal and adrenal failure in humans (1999) Nat Genet, 22 (SUPPL 2), pp. 125-126 Achermann, J.C., Ozisik, G., Ito, M., Orun, U.A., Harmanci, K., Gurakan, B., Jameson, J.L., Gonadal determination and adrenal development are regulated by the orphan nuclear receptor steroidogenic factor-1, in a dose-dependent manner (2002) J Clin Endocrinol Metab, 87 (SUPPL 4), pp. 1829-1833 Lourenco, D., Brauner, R., Lin, L., De Perdigo, A., Weryha, G., Muresan, M., Boudjenah, R., Bashamboo, A., Mutations in the NR5A1 associated with ovarian insufficiency (2009) New Eng J Med, 360, pp. 1200-1210. , 10.1056/NEJMoa0806228, 2778147, 19246354 Philibert, P., Paris, F., Lakhal, B., Audran, F., Gaspari, L., Saâd, A., Christin-Maître, S., Sultan, C., NR5A1 (SF-1) gene variants in a group of 26 young women with XX primary ovarian insufficiency (2013) Fertil Steril, 99 (SUPPL 2), pp. 484-489 Camats, N., Pandey, A.V., Fernandez-Cancio, M., Andaluz, P., Janner, M., Toran, N., Moreno, F., Flück, C.E., Ten novel mutations in the NR5A1 gene cause Disordered Sex Development in 46, XY and Ovarian Insufficiency in 46,XX individuals (2012) Clin Endocrinol Metab, 97 (SUPPL 7), pp. 1294-1306 Bashamboo, A., Ferraz-de-Souza, B., Lourenço, D., Lin, L., Sebire, N.J., Montjean, D., Bignon-Topalovic, J., McElreavey, K., Human male infertility associated with mutations in NR5A1 encoding steroidogenic factor 1 (2010) Am J Hum Genet, 87, pp. 505-512. , 10.1016/j.ajhg.2010.09.009, 2948805, 20887963 Röpke, A., Tewes, A.C., Gromoll, J., Kliesch, S., Wieacker, P., Tüttelmann, F., Comprehensive sequence analysis of the NR5A1 gene encoding steroidogenic factor 1 in a large group of infertile males (2013) Eur J Hum Genet, , in press Brauner, R., Neve, M., Allali, S., Trivin, C., Lottmann, H., Bashamboo, A., McElreavey, K., Clinical, biological and genetic analysis of anorchia in 26 boys (2011) PLoS One, 6, pp. e23292. , 10.1371/journal.pone.0023292, 3154292, 21853106 Ferraz-de-Souza, B., Lin, L., Achermann, J.C., Steroidogenic factor-1 (SF-1, NR5A1) and human disease (2011) Mol Cell Endocrinol, 336 (1-2 SUPPL), pp. 198-205. , 3057017, 21078366 De Mello, M.P., França, E.S.S., Fabbri, H.C., Maciel-Guerra, A.T., Guerra-Júnior, G., Multifunctional role of steroidogenic factor 1 and disorders of sex development (2011) Arq Bras Endocrinol Metabol, 55 (SUPPL 8), pp. 607-612 Coutant, R., Mallet, D., Lahlou, N., Bouhours-Nouet, N., Guichet, A., Coupris, L., Croué, A., Morel, Y., Heterozygous mutation of steroidogenic factor-1 in 46,XY subjects may mimic partial androgen insensitivity syndrome (2007) J Clin Endocrinol Metab, 92, pp. 2866-2873. , 10.1210/jc.2007-0336, 17682085 van Silfhout, A., Boot, A.M., Dijkhuizen, T., Hoek, A., Nijman, R., Sikkema-Raddatz, B., van Ravenswaaij-Arts, C.M., A unique 970 kb microdeletion in 9q33.3 including the NR5A1 gene in a 46,XY female (2009) Eur J Med Genet, 52, pp. 157-160. , 10.1016/j.ejmg.2009.02.009, 19269353 Wu, J.Y., McGown, I.N., Lin, L., Achermann, J.C., Harris, M., Coley, D.M., Aftimos, S., Cotterill, A.M., A novel NR5A1 variant in an infant with elevated testosterone from an Australian cohort of 46,XY patients with disorders of sex development (2013) Clin Endocrinol, 78, pp. 545-550 Veiga-Junior, N.N., Medaets, P.A., Petroli, R.J., Calais, F.L., de Mello, M.P., Castro, C.C., Guaragna-Filho, G., Guerra-Junior, G., Clinical and laboratorial features that may differentiate 46, XY DSD due to partial androgen insensitivity and 5α-reductase type 2 deficiency (2012) Int J Endocrinol, 2012, p. 964876. , 3238364, 22194745 Petroli, R.J., Maciel-Guerra, A.T., Soardi, F.C., de Calais, F.L., Guerra-Junior, G., de Mello, M.P., Severe forms of partial androgen insensitivity syndrome due to p.L830F novel mutation in androgen receptor gene in a Brazilian family (2011) BMC Res Notes, 4, p. 173. , 10.1186/1756-0500-4-173, 3121623, 21645389 Little, T.H., Zhang, Y., Matulis, C.K., Weck, J., Zhang, Z., Ramachandran, A., Mayo, K.E., Radhakrishnan, I., Sequence-specific deoxyribonucleic acid (DNA) recognition by steroidogenic factor 1: a helix at the carboxy terminus of the DNA binding domain is necessary for complex stability (2006) Mol Endocrinol, 20 (SUPPL 4), pp. 831-843 Ng, P.C., Henikoff, S., Predicting the effects of amino acid substitutions on protein function (2006) Annu Rev Genomics Hum Genet, 7, pp. 61-80. , 10.1146/annurev.genom.7.080505.115630, 16824020 Mathe, E., Olivier, M., Kato, S., Ishioka, C., Hainaut, P., Tavtigian, S.V., Computational approaches for predicting the biological effect of p53 missense mutations: a comparison of three sequence analysis based methods (2006) Nucleic Acids Res, 34 (SUPPL 5), pp. 1317-1325. , 1390679, 16522644 Tantawy, S., Lin, L., Akkurt, I., Borck, G., Klingmüller, D., Hauffa, B.P., Krude, H., Köhler, B., Testosterone production during puberty in two 46, XY patients with disorders of sex development and novel NR5A1 (SF-1) mutations (2012) Eur J Endocrinol, 167, pp. 125-130. , 10.1530/EJE-11-0944, 3381348, 22474171 Philibert, P., Leprieur, E., Zenaty, D., Thibaud, E., Polak, M., Frances, A.M., Lespinasse, J., Sultan, C., Steroidogenic factor-1 (SF-1) gene mutation as a frequent cause of primary amenorrhea in 46, XY female adolescents with low testosterone concentration (2010) Reprod Biol Endocrinol, 8, p. 28. , 10.1186/1477-7827-8-28, 2848664, 20302644 Barbaro, M., Cools, M., Looijenga, L.H.J., Drop, S.L.S., Wedell, A., Partial deletion of the NR5A1 (SF1) gene detected by synthetic probe MLPA in a patient with XY Gonadal disorder of sex development (2011) Sex Dev, 5, pp. 181-187. , 10.1159/000328821, 21654157 Betts, M.J., Russell, R.B., Amino acid properties and consequences of substitutions (2003) Bioinformatics for Geneticists, pp. 289-313. , West Sussex: John Wiley & Sons, Ltd, Barnes MR, Gray IC