help button home button Endocrine Society Molecular Endocrinology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Laue, L. L.
Right arrow Articles by Chan, W. Y.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Laue, L. L.
Right arrow Articles by Chan, W. Y.

Molecular Endocrinology, Vol 10, 987-997, Copyright © 1996 by Endocrine Society

ARTICLES

Compound heterozygous mutations of the luteinizing hormone receptor gene in Leydig cell hypoplasia

LL Laue, SM Wu, M Kudo, CJ Bourdony, GB Cutler Jr, AJ Hsueh and WY Chan
Department of Pediatrics, Georgetown University, Washington, DC 20007, USA.

The human LH receptor (hLHR) is a member of the G protein-coupled receptors characterized by the presence of seven-transmembrane (TM) helices. Inactivating mutations of the hLHR lead to Leydig cell hypoplasia (LCH), a form of male pseudohermaphroditism resulting from the failure of fetal testicular Leydig cell differentiation. We have identified three mutations of the hLHR in a patient with LCH: deletion of exon 8 (delta Exon 8), A872G transition resulting in Asn291Ser substitution in the extracellular domain, and C1847A transversion resulting in Ser616Tyr substitution in the seventh TM helix. Nucleotide sequencing, gene dosage, and allele-specific amplification analyses revealed that exon 8 deletion and the two missense mutations are present in different alleles of the hLHR. Constructs of mutated hLHR (hLHR-delta Exon8, hLHR-872/1847, hLHR-1847, and hLHR-872) were used to transfect 293 cells, and the properties of the hLHR expressed were examined. Ligand-binding assays failed to detect the expression of hLHR- delta Exon8. Transfectants expressing hLHR-872/1847 demonstrated greatly reduced ligand binding and ligand-induced cAMP accumulation in comparison to those expressing wild type hLHR. Similar reduction in cAMP accumulation was observed in transfectants expressing hLHR-1847, but not hLHR-872 alone. These findings suggest that, in addition to the 7-TM helices, the polypeptide encoded by exon 8 plays an important role in LHR expression and signal transduction. On the other hand, glycosylation of Asn291 may not be critical for these activities. These results also establish that LCH can result from impaired signal transduction due to compound heterozygous mutations. Implications of these mutations on structure-function relationship of the hLHR and the genotype-phenotype correlation in LCH are discussed.


This article has been cited by other articles:


Home page
 Hum ReprodHome page
M. Bruysters, S. Christin-Maitre, M. Verhoef-Post, C. Sultan, J. Auger, I. Faugeron, L. Larue, S. Lumbroso, A.P.N. Themmen, and P. Bouchard
A new LH receptor splice mutation responsible for male hypogonadism with subnormal sperm production in the propositus, and infertility with regular cycles in an affected sister
Hum. Reprod., August 1, 2008; 23(8): 1917 - 1923.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
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]

Home page
 J. Clin. Endocrinol. Metab.Home page
A. De Leener, L. Montanelli, J. Van Durme, H. Chae, G. Smits, G. Vassart, and S. Costagliola
Presence and Absence of Follicle-Stimulating Hormone Receptor Mutations Provide Some Insights into Spontaneous Ovarian Hyperstimulation Syndrome Physiopathology
J. Clin. Endocrinol. Metab., February 1, 2006; 91(2): 555 - 562.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
S. Yamashita, K. Nakamura, Y. Omori, K. Tsunekawa, M. Murakami, and T. Minegishi
Association of Human Follitropin (FSH) Receptor with Splicing Variant of Human Lutropin/Choriogonadotropin Receptor Negatively Controls the Expression of Human FSH Receptor
Mol. Endocrinol., August 1, 2005; 19(8): 2099 - 2111.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
A. Richter-Unruh, M. Verhoef-Post, S. Malak, J. Homoki, B. P. Hauffa, and A. P. N. Themmen
Leydig Cell Hypoplasia: Absent Luteinizing Hormone Receptor Cell Surface Expression Caused by a Novel Homozygous Mutation in the Extracellular Domain
J. Clin. Endocrinol. Metab., October 1, 2004; 89(10): 5161 - 5167.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
K. Nakamura, S. Yamashita, Y. Omori, and T. Minegishi
A Splice Variant of the Human Luteinizing Hormone (LH) Receptor Modulates the Expression of Wild-Type Human LH Receptor
Mol. Endocrinol., June 1, 2004; 18(6): 1461 - 1470.
[Abstract] [Full Text] [PDF]

Home page
 Hum ReprodHome page
L. A. Allen, J. C. Achermann, P. Pakarinen, T. J. Kotlar, I. T. Huhtaniemi, J. L. Jameson, T. D. Cheetham, and S. G. Ball
A novel loss of function mutation in exon 10 of the FSH receptor gene causing hypergonadotrophic hypogonadism: clinical and molecular characteristics
Hum. Reprod., February 1, 2003; 18(2): 251 - 256.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
K. Angelova, F. Fanelli, and D. Puett
A Model for Constitutive Lutropin Receptor Activation Based on Molecular Simulation and Engineered Mutations in Transmembrane Helices 6 and 7
J. Biol. Chem., August 23, 2002; 277(35): 32202 - 32213.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
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]

Home page
 Mol. Endocrinol.Home page
I. Ji, C. Lee, Y. Song, P. M. Conn, and T. H. Ji
Cis- and Trans-Activation of Hormone Receptors: the LH Receptor
Mol. Endocrinol., June 1, 2002; 16(6): 1299 - 1308.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
C. Lee, I. Ji, K. Ryu, Y. Song, P. M. Conn, and T. H. Ji
Two Defective Heterozygous Luteinizing Hormone Receptors Can Rescue Hormone Action
J. Biol. Chem., May 3, 2002; 277(18): 15795 - 15800.
[Abstract] [Full Text] [PDF]

Home page
 Endocr. Rev.Home page
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]

Home page
 Mol. Endocrinol.Home page
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]

Home page
 Endocr. Rev.Home page
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]

Home page
 J. Clin. Endocrinol. Metab.Home page
J. Gromoll, U. Eiholzer, E. Nieschlag, and M. Simoni
Male Hypogonadism Caused by Homozygous Deletion of Exon 10 of the Luteinizing Hormone (LH) Receptor: Differential Action of Human Chorionic Gonadotropin and LH
J. Clin. Endocrinol. Metab., June 1, 2000; 85(6): 2281 - 2286.
[Abstract] [Full Text]

Home page
 Mol. Endocrinol.Home page
K. Angelova, P. Narayan, J. P. Simon, and D. Puett
Functional Role of Transmembrane Helix 7 in the Activation of the Heptahelical Lutropin Receptor
Mol. Endocrinol., April 1, 2000; 14(4): 459 - 471.
[Abstract] [Full Text]

Home page
 Mol. Endocrinol.Home page
M. Kudo, T. Chen, K. Nakabayashi, S. Yu Hsu, and A. J. W. Hsueh
The Nematode Leucine-Rich Repeat-Containing, G Protein-Coupled Receptor (LGR) Protein Homologous to Vertebrate Gonadotropin and Thyrotropin Receptors is Constitutively Activated in Mammalian Cells
Mol. Endocrinol., February 1, 2000; 14(2): 272 - 284.
[Abstract] [Full Text]

Home page
 J. Clin. Endocrinol. Metab.Home page
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]

Home page
 Mol. Endocrinol.Home page
A. N. Abell, D. J. McCormick, and D. L. Segaloff
Certain Activating Mutations within Helix 6 of the Human Luteinizing Hormone Receptor May Be Explained by Alterations That Allow Transmembrane Regions to Activate Gs
Mol. Endocrinol., December 1, 1998; 12(12): 1857 - 1869.
[Abstract] [Full Text]

Home page
 Mol. Endocrinol.Home page
S.-M. Wu, K. M. Hallermeier, L. Laue, C. Brain, A. C. Berry, D. B. Grant, J. E. Griffin, J. D. Wilson, G. B. Cutler Jr., and W.-Y. Chan
Inactivation of the Luteinizing Hormone/Chorionic Gonadotropin Receptor by an Insertional Mutation in Leydig Cell Hypoplasia
Mol. Endocrinol., November 1, 1998; 12(11): 1651 - 1660.
[Abstract] [Full Text]

Home page
 Mol. Endocrinol.Home page
J. W. M. Martens, M. Verhoef-Post, N. Abelin, M. Ezabella, S. P. A. Toledo, H. G. Brunner, and A. P. N. Themmen
A Homozygous Mutation in the Luteinizing Hormone Receptor Causes Partial Leydig Cell Hypoplasia: Correlation between Receptor Activity and Phenotype
Mol. Endocrinol., June 1, 1998; 12(6): 775 - 784.
[Abstract] [Full Text]

Home page
 J. Clin. Endocrinol. Metab.Home page
S. S. Stavrou, Y.-S. Zhu, L.-Q. Cai, M. D. Katz, C. Herrera, M. DeFillo-Ricart, and J. Imperato-McGinley
A Novel Mutation of the Human Luteinizing Hormone Receptor in 46XY and 46XX Sisters
J. Clin. Endocrinol. Metab., June 1, 1998; 83(6): 2091 - 2098.
[Abstract] [Full Text]

Home page
 EndocrinologyHome page
T. G. Rozell, D. P. Davis, Y. Chai, and D. L. Segaloff
Association of Gonadotropin Receptor Precursors with the Protein Folding Chaperone Calnexin
Endocrinology, April 1, 1998; 139(4): 1588 - 1593.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
A. C. Latronico, Y. Chai, I. J.P. Arnhold, X. Liu, B. B. Mendonca, and D. L. Segaloff
A Homozygous Microdeletion in Helix 7 of the Luteinizing Hormone Receptor Associated with Familial Testicular and Ovarian Resistance Is Due to Both Decreased Cell Surface Expression and Impaired Effector Activation by the Cell Surface Receptor
Mol. Endocrinol., March 1, 1998; 12(3): 442 - 450.
[Abstract] [Full Text]

Home page
 NEJMHome page
N. de Roux, J. Young, M. Misrahi, R. Genet, P. Chanson, G. Schaison, and E. Milgrom
A Family with Hypogonadotropic Hypogonadism and Mutations in the Gonadotropin-Releasing Hormone Receptor
N. Engl. J. Med., November 27, 1997; 337(22): 1597 - 1603.
[Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
K. Yano, L. D. Kohn, M. Saji, A. Okuno, and G. B. Cutler Jr.
Phe576 Plays an Important Role in the Secondary Structure and Intracellular Signaling of the Human Luteinizing Hormone/Chorionic Gonadotropin Receptor
J. Clin. Endocrinol. Metab., August 1, 1997; 82(8): 2586 - 2591.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
M. Misrahi, G. Meduri, S. Pissard, C. Bouvattier, I. Beau, H. Loosfelt, A. Jolivet, R. Rappaport, E. Milgrom, and P. Bougneres
Comparison of Immunocytochemical and Molecular Features with the Phenotype in a Case of Incomplete Male Pseudohermaphroditism Associated with a Mutation of the Luteinizing Hormone Receptor
J. Clin. Endocrinol. Metab., July 1, 1997; 82(7): 2159 - 2165.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
F.-P. Zhang, A. S. Rannikko, P. R. Manna, H. M. Fraser, and I. T. Huhtaniemi
Cloning and Functional Expression of the Luteinizing Hormone Receptor Complementary Deoxyribonucleic Acid from the Marmoset Monkey Testis: Absence of Sequences Encoding Exon 10 in Other Species
Endocrinology, June 1, 1997; 138(6): 2481 - 2490.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals
Copyright © 1996 by The Endocrine Society