LH Receptor Defects

ABSTRACT

In this article the role of LH receptor gene mutations in patients with aberrant sex differentiation is discussed. In a dominant autosomal familial form of precocious puberty in boys (familial male-limited precocious puberty) LH receptor gene mutations have been identified. These single amino acid changes, mostly found in the sixth transmembrane helix and the third intracellular loop of the transmembrane domain of the LH receptor, cause constitutive activation of LH receptor protein without the hormone present, resulting in precocious production of testosterone by the testicular Leydig cells. The large number of activating LH receptor mutations have allowed more precise molecular modeling of the LH receptor protein. In a rare hereditary form of 46,XY male pseudohermaphroditism known as Leydig cell hypoplasia, LH receptor gene mutations have been identified that completely or partially inactivate the LH receptor protein. Large gene deletions cause complete absence of the LH receptor protein, whereas other, more subtle missense mutations prevent the receptor from assuming an active conformation.

KEYWORDS

LH receptor - precocious puberty - pseudohermaphroditism - Leydig cell hypoplasia

REFERENCES

• 1 Huhtaniemi I. Fetal testis: a very special endocrine organ.  Eur J Endocrinol . 1994;  130 25-31
• 2 Pelliniemi L J, Kuopio T, Fröjdman K. The cell biology and function of the fetal Leydig cell. In: Payne AH, Hardy MP, Russel LD, eds. The Leydig Cell Vienna, IL: Cache River Press 1996: 143-158
• 3 Seminara S B, Hayes F J, Crowley Jr F W. Gonadotropin-releasing hormone deficiency in the human (idiopathic hypogonadotropic hypogonadism and Kallmann's syndrome): pathophysiological and genetic considerations.  Endocr Rev . 1998;  19 521-539
• 4 Hardelin J P. Kallmann syndrome: towards molecular pathogenesis.  Mol Cell Endocrinol . 2001;  179 75-81
• 5 de Roux N, Milgrom E. Inherited disorders of GnRH and gonadotropin receptors.  Mol Cell Endocrinol . 2001;  179 83-87
• 6 Weiss J, Axelrod L, Whitcomb R W. Hypogonadism caused by a single amino acid substitution in the beta subunit of luteinizing hormone.  N Engl J Med . 1992;  326 179-183
• 7 Bhowmick N, Huang J, Puett D, Isaacs N W, Lapthorn A J. Determination of residues important in hormone binding to the extracellular domain of the luteinizing hormone/chorionic gonadotropin receptor by site-directed mutagenesis and modeling.  Mol Endocrinol . 1996;  10 1147-1159
• 8 Braun T, Schofield P R, Sprengel R. Amino-terminal leucine-rich repeats in gonadotropin receptors determine hormone selectivity.  EMBO J . 1991;  10 1885-1890
• 9 Ji I, Ji T H. Exons 1-10 of the rat LH receptor encode a high affinity hormone binding site and exon 11 encodes G-protein modulation and a potential second hormone binding site.  Endocrinology . 1991;  128 2648-2650
• 10 Fanelli F. Theoretical study on mutation-induced activation of the luteinizing hormone receptor.  J Mol Biol . 2000;  296 1333-1351
• 11 Herrlich A, Kuhn B, Grosse R. Involvement of Gs and Gi proteins in dual coupling of the luteinizing hormone receptor to adenylyl cyclase and phospholipase C.  J Biol Chem . 1996;  271 16764-16772
• 12 Kuhn B, Gudermann T. The luteinizing hormone receptor activates phospholipase C via preferential coupling to Gi2.  Biochemistry . 1999;  38 12490-12498
• 13 Themmen A PN, Huhtaniemi I. Mutations of gonadotropins and gonadotropin receptors: elucidating the physiology and pathophysiology of pituitary-gonadal function.  Endocr Rev . 2000;  21 551-583
• 14 Kjelsberg M A, Cotecchia S, Ostrowski J, Caron M G, Lefkowitz R J. Constitutive activation of the alpha 1B-adrenergic receptor by all amino acid substitutions at a single site: evidence for a region which constrains receptor activation.  J Biol Chem . 1992;  267 1430-1433
• 15 Kremer H, Mariman E, Otten B J. Cosegregation of missense mutations of the luteinizing hormone receptor gene with familial male-limited precocious puberty.  Hum Mol Genet . 1993;  2 1779-1783
• 16 Shenker A, Laue L, Kosugi S. A constitutively activating mutation of the luteinizing hormone receptor in familial male precocious puberty.  Nature . 1993;  365 652-654
• 17 Themmen A P, Brunner H G. Luteinizing hormone receptor mutations and sex differentiation.  Eur J Endocrinol . 1996;  134 533-540
• 18 Palczewski K, Kumasaka T, Hori T. Crystal structure of rhodopsin: a G protein-coupled receptor.  Science . 2000;  289 739-745
• 19 Liu G, Duranteau L, Carel J C. Leydig-cell tumors caused by an activating mutation of the gene encoding the luteinizing hormone receptor.  N Engl J Med . 1999;  341 1731-1736
• 20 Richter-Unruh A, Wessels H T, Menken U. Male LH-independent sexual precocity in a 3.5 year-old boy caused by a somatic activating mutation of the luteinizing hormone receptor in a Leydig cell tumor.  J Clin Endocrinol Metab . 2002;  87 1052-1056
• 21 Kremer H, Kraaij R, Toledo S P. Male pseudohermaphroditism due to a homozygous missense mutation of the luteinizing hormone receptor gene.  Nat Genet . 1995;  9 160-164
• 22 Laue L L, Wu S M, Kudo M. Compound heterozygous mutations of the luteinizing hormone receptor gene in Leydig cell hypoplasia.  Mol Endocrinol . 1996;  10 987-997
• 23 Latronico A C, Chai Y, Arnhold I J. 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 . 1998;  12 442-450
• 24 Wu S M, Hallermeier K M, Laue L. Inactivation of the luteinizing hormone/chorionic gonadotropin receptor by an insertional mutation in Leydig cell hypoplasia.  Mol Endocrinol . 1998;  12 1651-1660
• 25 Richter-Unruh A, Martens J W, Verhoef-Post M. Leydig cell hypoplasia: cases with new mutations, new polymorphisms and cases without mutations in the luteinizing hormone receptor gene.  Clin Endocrinol . 2002;  56 103-112
• 26 Martens J W, Verhoef-Post M, Abelin N. A homozygous mutation in the luteinizing hormone receptor causes partial Leydig cell hypoplasia: correlation between receptor activity and phenotype.  Mol Endocrinol . 1998;  12 775-784
• 27 Martens J W, Lumbroso S, Verhoef-Post M. Mutant luteinizing hormone receptors in a compound heterozygous patient with complete Leydig cell hypoplasia: abnormal processing causes signaling deficiency.  J Clin Endocrinol Metab . 2002;  87 2506-2513
• 28 Gromoll J, Eiholzer U, Nieschlag E, Simoni M. Male hypogonadism caused by homozygous deletion of exon 10 of the luteinizing hormone receptor: differential action of the luteinizing hormone (LH) and human chorionic gonadotropin (hCG).  J Clin Endocrin Metab . 2000;  85 2281-2286