Journal of Clinical Endocrinology & Metabolism, Vol 80, 1257-1263, Copyright © 1995 by Endocrine Society

ARTICLES

Occurrence and biological properties of a common genetic variant of luteinizing hormone

AM Haavisto, K Pettersson, M Bergendahl, A Virkamaki and I Huhtaniemi
Department of Physiology, University of Turku, Finland.

We have characterized the frequency and selected biological properties of a variant form of LH caused by two point mutations in the gene of the LH beta-subunit. Detection of the LH variant (or polymorphism) is based on aberrant immunoreactivity; it is not detected by a monoclonal antibody (Mab) recognizing a specific epitope in the LH alpha/beta- dimer (assay 1), but an assay using two LH beta-specific Mab recognizes this LH form normally (assay 2). Hence, the ratio of LH measured by assays 1 and 2 is 1.18-2.10 (range of mean +/- 2 SD) in wild-type subjects, 0.54-0.98 in heterozygotes, and below 0.15 in homozygotes with regard to the mutant LH beta allele. Analysis of sera from 249 healthy male and female subjects of Finnish origin revealed a frequency of 24.1% heterozygotes and 3.6% homozygotes for the mutation, with similar proportions in each sex. The ratio of in vitro bioactivity to immunoreactivity (assay 2) of the variant LH was significantly (P < 0.01) increased (2.9 +/- 0.1; n = 11) compared to that of wild-type LH (2.2 +/- 0.1; n = 13). No difference was observed in LH pulsatility, measured from blood samples collected at 5-min intervals for 5 h, between three male and three female subjects homozygous for the LH variant and three matched male and three female controls with wild-type LH. Likewise, the responses of LH immunoreactivity (assay 2) to GnRH stimulation were similar with both types of LH. The half-time of the variant LH in rat circulation from both sexes was significantly shorter than that of LH from control subjects (males, 25.5 +/- 3.8 vs. 48.3 +/- 2.7 min, respectively; P < 0.01; n = 3). Upon isoelectric focusing of peripheral serum samples, the isoform distribution of the variant LH was similar to that of wild-type LH. In conclusion, the LH variant discovered by us appears to occur with high frequency in the Finnish population (28% homo- or heterozygotes). It has increased in vitro bioactivity and a decreased half-time in vivo. These differences are compatible with a putative extra carbohydrate chain in the LH beta- chain, as one of the two mutations introduces an extra glycosylation signal. The subjects homozygous for the LH polymorphism are apparently healthy. However, the altered bioactivity and in vivo kinetics of the LH variant may induce subtle changes in LH action, either predisposing the affected individuals to or protecting them from disease conditions related to LH action.

This article has been cited by other articles:

				L. Wide, K. Eriksson, P. M. Sluss, and J. E. Hall Serum Half-Life of Pituitary Gonadotropins Is Decreased by Sulfonation and Increased by Sialylation in Women J. Clin. Endocrinol. Metab., March 1, 2009; 94(3): 958 - 964. [Abstract] [Full Text] [PDF]

				L. Wide, T. Naessen, I. Sundstrom-Poromaa, and K. Eriksson Sulfonation and Sialylation of Gonadotropins in Women during the Menstrual Cycle, after Menopause, and with Polycystic Ovarian Syndrome and in Men J. Clin. Endocrinol. Metab., November 1, 2007; 92(11): 4410 - 4417. [Abstract] [Full Text] [PDF]

				W.-K. So, H.-F. Kwok, and W. Ge Zebrafish Gonadotropins and Their Receptors: II. Cloning and Characterization of Zebrafish Follicle-Stimulating Hormone and Luteinizing Hormone Subunits--Their Spatial-Temporal Expression Patterns and Receptor Specificity Biol Reprod, June 1, 2005; 72(6): 1382 - 1396. [Abstract] [Full Text] [PDF]

				H. F. Escobar-Morreale, M. Luque-Ramirez, and J. L. San Millan The Molecular-Genetic Basis of Functional Hyperandrogenism and the Polycystic Ovary Syndrome Endocr. Rev., April 1, 2005; 26(2): 251 - 282. [Abstract] [Full Text] [PDF]

				B. L. Powell, D. Piersma, M. E. Kevenaar, I. L. van Staveren, A. P. N. Themmen, B. J. Iacopetta, and E. M. J. J. Berns Luteinizing Hormone Signaling and Breast Cancer: Polymorphisms and Age of Onset J. Clin. Endocrinol. Metab., April 1, 2003; 88(4): 1653 - 1657. [Abstract] [Full Text] [PDF]

				T. Lamminen, M. Jiang, P. R. Manna, P. Pakarinen, H. Simonsen, R. J. Herrera, and I. Huhtaniemi Functional study of a recombinant form of human LH{beta}-subunit variant carrying the Gly102Ser mutation found in Asian populations Mol. Hum. Reprod., October 1, 2002; 8(10): 887 - 892. [Abstract] [Full Text] [PDF]

				R. Gazvani, P. Pakarinen, P. Fowler, S. Logan, and I. Huhtaniemi Lack of association of the common immunologically anomalous LH with endometriosis Hum. Reprod., June 1, 2002; 17(6): 1532 - 1534. [Abstract] [Full Text] [PDF]

				M. Jiang, T. Lamminen, P. Pakarinen, J. Hellman, P. Manna, R. J. Herrera, and I. Huhtaniemi A novel Ala-3Thr mutation in the signal peptide of human luteinizing hormone {beta}-subunit: potentiation of the inositol phosphate signalling pathway and attenuation of the adenylate cyclase pathway by recombinant variant hormone Mol. Hum. Reprod., March 1, 2002; 8(3): 201 - 212. [Abstract] [Full Text] [PDF]

				P. R. Manna, L. Joshi, V. N. Reinhold, M. L. Aubert, N. Suganuma, K. Pettersson, and I. T. Huhtaniemi Synthesis, purification and structural and functional characterization of recombinant form of a common genetic variant of human luteinizing hormone Hum. Mol. Genet., February 1, 2002; 11(3): 301 - 315. [Abstract] [Full Text] [PDF]

				A. Akhmedkhanov, P. Toniolo, A. Zeleniuch-Jacquotte, K. S. Pettersson, and I. T. Huhtaniemi Luteinizing Hormone, Its {beta}-Subunit Variant, and Epithelial Ovarian Cancer: The Gonadotropin Hypothesis Revisited Am. J. Epidemiol., July 1, 2001; 154(1): 43 - 49. [Abstract] [Full Text] [PDF]

				C.H. Nilsson, M. Kaleva, H. Virtanen, A.M. Haavisto, K. Pettersson, and I.T. Huhtaniemi Disparate response of wild-type and variant forms of LH to GnRH stimulation in individuals heterozygous for the LH{beta} variant allele Hum. Reprod., February 1, 2001; 16(2): 230 - 235. [Abstract] [Full Text] [PDF]

				A. P. N. Themmen and I. T. Huhtaniemi Mutations of Gonadotropins and Gonadotropin Receptors: Elucidating the Physiology and Pathophysiology of Pituitary-Gonadal Function Endocr. Rev., October 1, 2000; 21(5): 551 - 583. [Abstract] [Full Text]

				D.W. Cramer, K.S.I. Petterson, R.L. Barbieri, and I.T. Huhtaniemi Reproductive hormones, cancers, and conditions in relation to a common genetic variant of luteinizing hormone Hum. Reprod., October 1, 2000; 15(10): 2103 - 2107. [Abstract] [Full Text] [PDF]

				A. Akhmedkhanov, P. Toniolo, A. Zeleniuch-Jacquotte, K. Pettersson, and I. Huhtaniemi Genetic Variant of Luteinizing Hormone and Risk of Breast Cancer in Older Women Cancer Epidemiol. Biomarkers Prev., August 1, 2000; 9(8): 839 - 842. [Abstract] [Full Text]

				S. Y. Hsu and A. J. W. Hsueh Discovering New Hormones, Receptors, and Signaling Mediators in the Genomic Era Mol. Endocrinol., May 1, 2000; 14(5): 594 - 604. [Full Text]

				L.N. Ramanujam, W.-X. Liao, A.C. Roy, and S.C. Ng Association of molecular variants of luteinizing hormone with male infertility Hum. Reprod., April 1, 2000; 15(4): 925 - 928. [Abstract] [Full Text] [PDF]

				Y. Shuto, T. Nakano, N. Sanno, H. Domoto, H. Sugihara, and I. Wakabayashi Reduced Growth Hormone Receptor Messenger Ribonucleic Acid in an Aged Man with Chronic Malnutrition and Growth Hormone Resistance J. Clin. Endocrinol. Metab., July 1, 1999; 84(7): 2320 - 2323. [Abstract] [Full Text]

				J. S. Tapanainen, R. Koivunen, B. C. J. M. Fauser, A. E. Taylor, R. N. Clayton, M. Rajkowa, D. White, S. Franks, L. Anttila, K. S. I. Pettersson, et al. A New Contributing Factor to Polycystic Ovary Syndrome: The Genetic Variant of Luteinizing Hormone J. Clin. Endocrinol. Metab., May 1, 1999; 84(5): 1711 - 1715. [Abstract] [Full Text]

				A. W. van den Beld, I. T. Huhtaniemi, K. S. L. Pettersson, H. A. P. Pols, D. E. Grobbee, F. H. de Jong, and S. W. J. Lamberts Luteinizing Hormone and Different Genetic Variants, as Indicators of Frailty in Healthy Elderly Men J. Clin. Endocrinol. Metab., April 1, 1999; 84(4): 1334 - 1339. [Abstract] [Full Text]

				I. Galeraud-Denis, P. Bouchard, M. Herlicoviez, E. Marie, and S. Carreau Inhibitory effect of plasma obtained from hypophysectomized and control women on the assay of bioactive luteinizing hormone Hum. Reprod., February 1, 1999; 14(2): 312 - 317. [Abstract] [Full Text] [PDF]

				K. Hakola, D. D. Pierroz, A. Aebi, B. A.M. Vuagnat, M. L. Aubert, and I. Huhtaniemi Dose and Time Relationships of Intravenously Injected Rat Recombinant Luteinizing Hormone and Testicular Testosterone Secretion in the Male Rat Biol Reprod, August 1, 1998; 59(2): 338 - 343. [Abstract] [Full Text]

				J. Pantel, P. Robert, F. Troalen, M. Kujas, D. Bellet, and J.-M. Bidart Characterization of Human Lutropin Carboxyl- Terminus Isoforms Endocrinology, February 1, 1998; 139(2): 527 - 533. [Abstract] [Full Text] [PDF]