This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Stavrou, S. S. Articles by Imperato-McGinley, J. Search for Related Content PubMed PubMed Citation Articles by Stavrou, S. S. Articles by Imperato-McGinley, J.

A Novel Mutation of the Human Luteinizing Hormone Receptor in 46XY and 46XX Sisters¹

Division of Endocrinology (S.S.S., Y.-S.Z., L.-Q.C., M.D.K., J.I.-M.), Diabetes and Metabolism, Department of Medicine, Cornell University Medical College, New York, New York 10021; and University of National Pedro Henriquez Urena (C.H., M.D.-R.), Santo Domingo, Dominican Republic

Address all correspondence and requests for reprints to: Julianne Imperato-McGinley, M.D., Cornell University Medical College, 1300 York Avenue, Room F-260, New York, New York 10021.

We report a novel homozygous mutation of the LH receptor (LHR) gene in three siblings: two 46XY and one 46XX. The 46XY siblings presented with female external genitalia, primary amenorrhea, and lack of breast development. Hormonal evaluation revealed a markedly elevated LH level with a low testosterone level, which failed to increase after human CG stimulation. Enzymatic deficiencies of testosterone biosynthesis were eliminated as possible etiologies. Histologic analysis of the inguinal gonads in a 46XY sibling revealed no Leydig cells; Sertoli cells, spermatogonia, and primary spermatocytes were seen. The 46XX sibling had female external genitalia, normal breast development, and primary amenorrhea. Hormonal analyses showed markedly elevated LH levels and low plasma 17ß-estradiol levels.

Genetic analysis of the LHR revealed a homozygous missense mutation at exon 11 of the LHR gene. Guanine was replaced by adenine (GAAAAA), resulting in a substitution of lysine for glutamic acid (glu) at amino acid position 354 of the receptor. This mutation is located in the extracellular domain adjacent to the first transmembrane helix of the LHR. Glutamic acid at position 354 of the LHR has been highly conserved throughout evolution. Functional analysis of the LHR mutation, using an in vitro mutagenesis-transfection assay, demonstrated complete loss of function, indicated by the lack of cAMP production after human CG stimulation in transfected human embryonic kidney 293 cells. Screening of family members demonstrated heterozygosity for the mutation, indicating autosomal recessive inheritance. Delineation of the specific genetic defect in this family confirms recent reports that a single mutation in the LHR gene causes male pseudohermaphroditism in 46XY subjects and primary amenorrhea in 46XX subjects. More importantly, it also defines a new region of the LHR molecule that is critical for biologic activity.

This article has been cited by other articles:

				G. Kleinau and G. Krause Thyrotropin and Homologous Glycoprotein Hormone Receptors: Structural and Functional Aspects of Extracellular Signaling Mechanisms Endocr. Rev., April 1, 2009; 30(2): 133 - 151. [Abstract] [Full Text] [PDF]

				S. Mueller, G. Kleinau, H. Jaeschke, S. Neumann, G. Krause, and R. Paschke Significance of Ectodomain Cysteine Boxes 2 and 3 for the Activation Mechanism of the Thyroid-stimulating Hormone Receptor J. Biol. Chem., October 20, 2006; 281(42): 31638 - 31646. [Abstract] [Full Text] [PDF]

				M. Y.-K. Leung, P. J. Steinbach, D. Bear, V. Baxendale, P. Y. Fechner, O. M. Rennert, and W.-Y. Chan Biological Effect of a Novel Mutation in the Third Leucine-Rich Repeat of Human Luteinizing Hormone Receptor Mol. Endocrinol., October 1, 2006; 20(10): 2493 - 2503. [Abstract] [Full Text] [PDF]

				A Richter-Unruh, E Korsch, O Hiort, P M Holterhus, A P Themmen, and S A Wudy Novel insertion frameshift mutation of the LH receptor gene: problematic clinical distinction of Leydig cell hypoplasia from enzyme defects primarily affecting testosterone biosynthesis Eur. J. Endocrinol., February 1, 2005; 152(2): 255 - 259. [Abstract] [Full Text] [PDF]

				S. N. Kalantaridou and G. P. Chrousos Monogenic Disorders of Puberty J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2481 - 2494. [Full Text] [PDF]

				J. W. M. Martens, S. Lumbroso, M. Verhoef-Post, V. Georget, A. Richter-Unruh, M. Szarras-Czapnik, T. E. Romer, H. G. Brunner, A. P. N. Themmen, and Ch. Sultan Mutant Luteinizing Hormone Receptors in a Compound Heterozygous Patient with Complete Leydig Cell Hypoplasia: Abnormal Processing Causes Signaling Deficiency J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2506 - 2513. [Abstract] [Full Text] [PDF]

				M. Ascoli, F. Fanelli, and D. L. Segaloff The Lutropin/Choriogonadotropin Receptor, A 2002 Perspective Endocr. Rev., April 1, 2002; 23(2): 141 - 174. [Abstract] [Full Text] [PDF]

				T. M. Plant and G. R. Marshall The Functional Significance of FSH in Spermatogenesis and the Control of Its Secretion in Male Primates Endocr. Rev., December 1, 2001; 22(6): 764 - 786. [Abstract] [Full Text] [PDF]

				Z. M. Lei, S. Mishra, W. Zou, B. Xu, M. Foltz, X. Li, and Ch. V. Rao Targeted Disruption of Luteinizing Hormone/Human Chorionic Gonadotropin Receptor Gene Mol. Endocrinol., January 1, 2001; 15(1): 184 - 200. [Abstract] [Full Text]

				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]

				J. C. Zenteno, P. Canto, S. Kofman-Alfaro, and J. P. Mendez Evidence for Genetic Heterogeneity in Male Pseudohermaphroditism due to Leydig Cell Hypoplasia J. Clin. Endocrinol. Metab., October 1, 1999; 84(10): 3803 - 3806. [Abstract] [Full Text] [PDF]

				N. Bhowmick, P. Narayan, and D. Puett Identification of Ionizable Amino Acid Residues on the Extracellular Domain of the Lutropin Receptor Involved in Ligand Binding Endocrinology, October 1, 1999; 140(10): 4558 - 4563. [Abstract] [Full Text]

				Y.-S. Zhu, L.-Q. Cai, J. J. Cordero, W. J. Canovatchel, M. D. Katz, and J. Imperato-McGinley A Novel Mutation in the CAG Triplet Region of Exon 1 of Androgen Receptor Gene Causes Complete Androgen Insensitivity Syndrome in a Large Kindred J. Clin. Endocrinol. Metab., May 1, 1999; 84(5): 1590 - 1594. [Abstract] [Full Text]

				C. A. Alvarez, P. Narayan, J. Huang, and D. Puett Characterization of a Region of the Lutropin Receptor Extracellular Domain Near Transmembrane Helix 1 That Is Important in Ligand-Mediated Signaling Endocrinology, April 1, 1999; 140(4): 1775 - 1782. [Abstract] [Full Text]