Galactose-1-phosphate uridyl transferase gene mutations in women with premature ovarian failure
2005; Elsevier BV; Volume: 84; Issue: 1 Linguagem: Inglês
10.1016/j.fertnstert.2004.09.041
ISSN1556-5653
AutoresBarbara Mlinar, Ksenija Geršak, Nataša Karas Kuželički, Irena Prodan Žitnik, Tadej Battelino, Jana Lukač‐Bajalo,
Tópico(s)Growth Hormone and Insulin-like Growth Factors
ResumoWe determined the frequency of galactose-1-phosphate uridyl transferase gene mutations: Q188R, K285N, and the Duarte allelle in 86 patients with idiopathic premature ovarian failure (POF) and 95 controls. No association of the mutations with POF was found. We determined the frequency of galactose-1-phosphate uridyl transferase gene mutations: Q188R, K285N, and the Duarte allelle in 86 patients with idiopathic premature ovarian failure (POF) and 95 controls. No association of the mutations with POF was found. Premature ovarian failure (POF) is defined as the complete cessation of menses before the age of 40 years and occurs in 1% of women. Hypergonadotropic hypogonadal state is characteristic of POF, and patients may present with either primary or secondary amenorrhea. In the absence of pelvic surgery, chemotherapy, or autoimmune diseases, the cause of most cases with POF and normal female karyotype (46,XX) remains unknown. Various genetic bases for POF have been proposed: FSH receptor gene mutations (1Aittomaki K. Lucena J.L. Pakarinen P. Sistonen P. Tapanainen J. Gromoll J. et al.Mutation in the follicle-stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure.Cell. 1995; 82: 959-968Abstract Full Text PDF PubMed Scopus (816) Google Scholar), LH receptor gene mutations (2Takahashi K. Ozaki T. Kanasaki H. Miyazaki K. Successful pregnancy in a woman with ovarian failure associated with mutation in the beta-subunit of luteinizing hormone.Horm Res. 2001; 55: 258-263Crossref PubMed Scopus (13) Google Scholar), FOXL2 (3Harris S.E. Chand A.L. Winship I.M. Gersak K. Aittomaki K. Shelling A.N. Identification of novel mutations in FOXL2 associated with premature ovarian failure.Mol Hum Reprod. 2002; 8: 729-733Crossref PubMed Scopus (153) Google Scholar), INHalpha (4Shelling A.N. Burton K.A. Chand A.L. van Ee C.C. France J.T. Farquhar C.M. et al.Inhibin a candidate gene for premature ovarian failure.Hum Reprod. 2000; 15: 2644-2649Crossref PubMed Scopus (147) Google Scholar) gene mutations, and miscellaneous endocrine disorders. Classical galactosemia, an inborn deficiency of galactose-1-phosphate uridyl transferase (GALT) activity, presents largely with hypergonadotropic hypogonadism in female patients (5Holton J.B. Walter J.H. Tyfield L.A. Galactosemia.in: Scriver C.R. Beaudet A.L. Valle D. Sly W.S. 6th ed. The metabolic and molecular basis of inherited disease. Vol. 1. Mc Graw-Hill, New York2001: 1553-1587Google Scholar). The most common cause of classical galactosemia is the Q188R mutation (6Elsas 2nd, L.J. Langley S. Paulk E.M. Hjelm L.N. Dembure P.P. A molecular approach to galactosemia.Eur J Pediatr. 1995; 154: S21-S27Crossref PubMed Scopus (50) Google Scholar), which is followed by the K285N in central European populations (7Greber-Platzer S. Guldberg P. Scheibenreiter S. Item C. Schuller E. Patel N. et al.Molecular heterogeneity of classical and Duarte galactosemia mutation analysis by denaturing gradient gel electrophoresis.Hum Mutat. 1997; 10: 49-57Crossref PubMed Scopus (46) Google Scholar). A milder form of GALT deficiency is Duarte galactosemia, characterized by the N314D mutation and additional intron and promoter sequence variations, among which IVS5-24G>A is most easily detected (5Holton J.B. Walter J.H. Tyfield L.A. Galactosemia.in: Scriver C.R. Beaudet A.L. Valle D. Sly W.S. 6th ed. The metabolic and molecular basis of inherited disease. Vol. 1. Mc Graw-Hill, New York2001: 1553-1587Google Scholar). For partial GALT deficiency, characteristic of classical galactosemia heterozygotes and Duarte galactosemia cases, some evidence of later reproductive complications exists; however, the reports are contradictory: from significant (8Cramer D.W. Harlow B.L. Barbieri R.L. Ng W.G. Galactose-1-phosphate uridyl transferase activity associated with age at menopause and reproductive history.Fertil Steril. 1989; 51: 609-615Abstract Full Text PDF PubMed Google Scholar, 9Cramer D.W. Barbieri R.L. Xu H. Reichardt J.K. Determinants of basal follicle-stimulating hormone levels in premenopausal women.J Clin Endocrinol Metab. 1994; 79: 1105-1109Crossref PubMed Scopus (77) Google Scholar) to no association between GALT gene mutations and POF (10Kaufman F.R. Devgan S. Donnell G.N. Results of a survey of carrier women for the galactosemia gene.Fertil Steril. 1993; 60: 727-728PubMed Scopus (17) Google Scholar, 11Sayle A.E. Cooper G.S. Savitz D.A. Menstrual and reproductive history of mothers of galactosemic children.Fertil Steril. 1996; 65: 534-538PubMed Google Scholar). Because of these discrepancies and lack of GALT gene analyses in women with ovarian insufficiency, our aim was to test the frequency of the Q188R and K285N mutations and the Duarte allele (the N314D mutation and the IVS5-24G>A intron variation) in women with idiopathic POF. Eighty-six consecutive women with sporadic idiopathic POF were included in the study. Thirty-one patients were diagnosed with primary hypergonadotropic amenorrhea, and 55, with secondary hypergonadotropic amenorrhea. Their age at the onset of amenorrhea was 15–39 years. They were phenotypically normal, had normal female karyotype (46,XX), and no history of pelvic surgery, chemotherapy or autoimmune diseases, or family history of mental retardation. Ninety-five healthy women, aged 19–27 years, were recruited as controls. The study was approved by the Ethics Committee of the Ministry of Health of Slovenia. Genomic DNA was isolated from peripheral blood by the salt extraction method. Polymerase chain reactions for three DNA fragments were performed as described (12Lukac-Bajalo J. Marc J. Mlinar B. Karas N. Krzisnik C. Battelino T. The frequencies of Q188R and N314D mutations and IVS5-24G→A intron variation in the galactose-1-phosphate uridyl transferase (GALT) gene in the Slovenian population.Clin Chem Lab Med. 2002; 40: 1109-1113Crossref PubMed Google Scholar, 13Karas N. Gobec L. Pfeifer V. Mlinar B. Battelino T. Lukac-Bajalo J. Mutations in galactose-1-phosphate uridyltransferase gene in patients with idiopathic presenile cataract.Inherit Metab Dis. 2003; 26: 699-704Crossref PubMed Scopus (27) Google Scholar). Restriction fragment length polymorphism analyses with HpaII, Tsp509I, AvaII, and SacI restriction enzymes were used to detect the Q188R, K285N, and N314D mutations and the IVS5-24G>A intron variation, respectively (12Lukac-Bajalo J. Marc J. Mlinar B. Karas N. Krzisnik C. Battelino T. The frequencies of Q188R and N314D mutations and IVS5-24G→A intron variation in the galactose-1-phosphate uridyl transferase (GALT) gene in the Slovenian population.Clin Chem Lab Med. 2002; 40: 1109-1113Crossref PubMed Google Scholar, 13Karas N. Gobec L. Pfeifer V. Mlinar B. Battelino T. Lukac-Bajalo J. Mutations in galactose-1-phosphate uridyltransferase gene in patients with idiopathic presenile cataract.Inherit Metab Dis. 2003; 26: 699-704Crossref PubMed Scopus (27) Google Scholar). Duarte allelic genotype was attributed to alleles containing the N314D mutation and the IVS5-24G>A intron variation. For alleles with the N314D mutation, but lacking the IVS5-24G>A variation, the Los Angeles (LA) GALT genotype, associated with slightly increased GALT activity (5Holton J.B. Walter J.H. Tyfield L.A. Galactosemia.in: Scriver C.R. Beaudet A.L. Valle D. Sly W.S. 6th ed. The metabolic and molecular basis of inherited disease. Vol. 1. Mc Graw-Hill, New York2001: 1553-1587Google Scholar), was predicted. Statistical analysis was performed by using the χ2 test for two independent samples and the Fisher's exact test. Significance was defined as P<.05. There was no significant difference, with respect to the Q188R, K285N, and Duarte allele frequencies, between the primary and secondary amenorrhea patients and the controls (Table 1). On the basis of these results, there is no association between hypergonadotropic POF and the mutations analyzed in the heterozygous state.TABLE 1Allele frequencies of the Q188R and K285N mutations and the Duarte alleles in the primary and secondary amenorrhea and control groups.GroupAFQ188RPaTest for homogeneity applied to number of alleles: Fisher's exact tests (for frequencies <5) unless otherwise marked.AFK285NPaTest for homogeneity applied to number of alleles: Fisher's exact tests (for frequencies A.PaTest for homogeneity applied to number of alleles: Fisher's exact tests (for frequencies <5) unless otherwise marked.Control (n = 95)0.53—0.53—5.3—Primary amenorrhea (n = 31)01.001.04.81.0Secondary amenorrhea (n = 55)01.00.911.08.20.45 (χ2)All amenorrhea (n = 86)01.00.581.07.00.64 (χ2)Note: All the mutated alleles occurred in the heterozygous state. AF = allele frequency.Mlinar. GALT gene mutations in POF. Fertil Steril 2005.a Test for homogeneity applied to number of alleles: Fisher's exact tests (for frequencies A. Open table in a new tab Note: All the mutated alleles occurred in the heterozygous state. AF = allele frequency. Mlinar. GALT gene mutations in POF. Fertil Steril 2005. Two previous studies have confirmed an association between GALT polymorphisms and infertility or early menopause (8Cramer D.W. Harlow B.L. Barbieri R.L. Ng W.G. Galactose-1-phosphate uridyl transferase activity associated with age at menopause and reproductive history.Fertil Steril. 1989; 51: 609-615Abstract Full Text PDF PubMed Google Scholar) and higher basal FSH serum concentrations (9Cramer D.W. Barbieri R.L. Xu H. Reichardt J.K. Determinants of basal follicle-stimulating hormone levels in premenopausal women.J Clin Endocrinol Metab. 1994; 79: 1105-1109Crossref PubMed Scopus (77) Google Scholar). The GALT polymorphic cases consisted of Duarte heterozygotes and homozygotes and classical galactosemia heterozygotes. However, the genotype was here predicted from results of GALT activity and electrophoresis (8Cramer D.W. Harlow B.L. Barbieri R.L. Ng W.G. Galactose-1-phosphate uridyl transferase activity associated with age at menopause and reproductive history.Fertil Steril. 1989; 51: 609-615Abstract Full Text PDF PubMed Google Scholar) or from the existence of the Q188R and N314D mutation, together with electrophoresis results (9Cramer D.W. Barbieri R.L. Xu H. Reichardt J.K. Determinants of basal follicle-stimulating hormone levels in premenopausal women.J Clin Endocrinol Metab. 1994; 79: 1105-1109Crossref PubMed Scopus (77) Google Scholar). Our determination of the Duarte genotype was based on the presence of the IVS5-24G>A intron polymorphism that occurs uniquely in combination with the N314D mutation, two additional intron variations, and a promoter deletion in the Duarte alleles (5Holton J.B. Walter J.H. Tyfield L.A. Galactosemia.in: Scriver C.R. Beaudet A.L. Valle D. Sly W.S. 6th ed. The metabolic and molecular basis of inherited disease. Vol. 1. Mc Graw-Hill, New York2001: 1553-1587Google Scholar, 7Greber-Platzer S. Guldberg P. Scheibenreiter S. Item C. Schuller E. Patel N. et al.Molecular heterogeneity of classical and Duarte galactosemia mutation analysis by denaturing gradient gel electrophoresis.Hum Mutat. 1997; 10: 49-57Crossref PubMed Scopus (46) Google Scholar). It is the Duarte allele, but not the LA allele, that predisposes to lower than normal GALT activity (5Holton J.B. Walter J.H. Tyfield L.A. Galactosemia.in: Scriver C.R. Beaudet A.L. Valle D. Sly W.S. 6th ed. The metabolic and molecular basis of inherited disease. Vol. 1. Mc Graw-Hill, New York2001: 1553-1587Google Scholar). Two other studies found no increased frequency of Duarte or galactosemia heterozygotes in POF patients using GALT activity measurements (14Hagenfeldt K. von Dobeln U. Hagenfeldt L. Gonadal failure in young women and galactose-1-phosphate uridyl transferase activity.Fertil Steril. 1989; 51: 177-178PubMed Scopus (5) Google Scholar, 15Fraser I.S. Shearman R.P. Wilcken B. Brown A. Davis K. Failure to identify heterozygotes for galactosaemia in women with premature ovarian failure.Lancet. 1987; 2: 566Abstract PubMed Scopus (4) Google Scholar). Our results confirmed these conclusions on molecular level and on a larger group of patients. Women with early menopause and with a family history of early menopause, as well, did not appear to have lower GALT activity or to carry Duarte or classic galactosemia genes, as determined from GALT activity and electrophoresis (16Cramer D.W. Xu H. Harlow B.L. Family history as a predictor of early menopause.Fertil Steril. 1995; 64: 740-745PubMed Scopus (197) Google Scholar). No association was found between lower GALT activity and ovarian senescence, as measured by FSH levels in women of late reproductive age (17Cooper G.S. Hulka B.S. Baird D.D. Savitz D.A. Hughes Jr, C.L. Weinberg C.R. et al.Galactose consumption, metabolism, and follicle-stimulating hormone concentrations in women of late reproductive age.Fertil Steril. 1994; 62: 1168-1175PubMed Google Scholar), nor was variant galactose metabolism confirmed as influencing infertility (18Herrinton L.J. Lemaitre R.N. Beresford S.A. Stanford J.L. Wolfla D.M. Feng Z. et al.Lactose metabolism and time to pregnancy.Fertil Steril. 1996; 66: 384-388PubMed Google Scholar). Furthermore, mothers of galactosemic children, obligate heterozygotes, were found not to present more frequently with POF or decreased fertility than the normal population (10Kaufman F.R. Devgan S. Donnell G.N. Results of a survey of carrier women for the galactosemia gene.Fertil Steril. 1993; 60: 727-728PubMed Scopus (17) Google Scholar, 11Sayle A.E. Cooper G.S. Savitz D.A. Menstrual and reproductive history of mothers of galactosemic children.Fertil Steril. 1996; 65: 534-538PubMed Google Scholar). All these findings are in agreement with the discovery of Kaufman et al. (19Kaufman F.R. Xu Y.K. Ng W.G. Donnell G.N. Correlation of ovarian function with galactose-1-phosphate uridyl transferase levels in galactosemia.J Pediatr. 1988; 112: 754-756Abstract Full Text PDF PubMed Scopus (66) Google Scholar) that variant galactosemia cases with higher than zero red blood cell GALT activity did not develop hypergonadotropic hypogonadism. Our assumption is that the 50% decrease in GALT activity in Q188R or K285N heterozygotes (5Holton J.B. Walter J.H. Tyfield L.A. Galactosemia.in: Scriver C.R. Beaudet A.L. Valle D. Sly W.S. 6th ed. The metabolic and molecular basis of inherited disease. Vol. 1. Mc Graw-Hill, New York2001: 1553-1587Google Scholar), or the 25% decrease in GALT activity reported for Duarte heterozygotes (6Elsas 2nd, L.J. Langley S. Paulk E.M. Hjelm L.N. Dembure P.P. A molecular approach to galactosemia.Eur J Pediatr. 1995; 154: S21-S27Crossref PubMed Scopus (50) Google Scholar), is not sufficient to affect ovarian function. The authors are grateful to Jelica Rajner and Mateja Tomazin for technical assistance. The authors also thank Roger Pain, Ph.D., for advice on English language.
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