Naturally Occurring Mutations of the Luteinizing Hormone Receptor Gene Affecting Reproduction

ABSTRACT

The luteinizing hormone receptor (LHR) plays a critical role in reproductive physiology in both males and females. Naturally occurring mutations in this receptor can cause genetically transmitted disorders by producing either gain or loss of receptor function. The clinical phenotype of the heterozygous activating mutations of the LHR gene has been exclusively described in males, who present familial or sporadic pseudoprecocious puberty. Affected boys were usually fertile at an adult age. In contrast, homozygous inactivating mutations of the LHR gene can cause a distinct spectrum of phenotypes. Severe inactivating mutations of the LHR have been recognized as the cause of Leydig cell hypoplasia, a rare form of male pseudohermaphroditism, in genetic males and as a novel cause of amenorrhea and infertility in genetic females. In addition, inactivating mutations that partially inactivate LH signaling can cause micropenis, sometimes accompanied by hypospadias and cryptorchidism. Both males and females with homozygous inactivating mutations of the LHR gene have suppression of fertility, which can represent the chief complaint of these patients.

KEYWORD

receptor - mutations - infertility

REFERENCES

• 1 Segaloff D L, Ascoli M. The lutropin/choriogonadotropin receptor: 4 years later.  Endocr Rev . 1993;  14 324-347
• 2 Latronico A C, Segaloff D L. Naturally occurring mutations of the luteinizing hormone receptor: lessons learned about reproductive physiology and G protein-coupled receptors.  Am J Hum Genet . 1999;  65 949-958
• 3 Shenker A, Laue L, Kosugi S, Merendino J JM, Minegishi T, Cutler G B. A constitutively activating mutation of the luteinizing hormone receptor in familial male precocious puberty.  Nature . 1993;  365 652-654
• 4 Laue L, Chan W Y, Hsueh A JW. Genetic heterogeneity of constitutively activating mutations of the human luteinizing hormone receptor in familial male-limited precocious puberty.  Proc Natl Acad Sci U S A . 1995;  92 1906-1910
• 5 Latronico A C, Anasti J, Arnhold I JP. A novel mutation of the luteinizing hormone receptor gene causing male gonadotropin-independent precocious puberty.  J Clin Endocrinol Metab . 1995;  80 2490-2494
• 6 Latronico A C, Abell A N, Arnhold I JP. A unique constitutively activating mutation in third transmembrane helix of luteinizing hormone receptor causes sporadic male gonadotropin-independent precocious puberty.  J Clin Endocrinol Metab . 1998;  83 2435-2440
• 7 Leschek E W, Jones J, Barnes K M, Hill S C, Cutler G B. Six-year results of spironolactone and testolactone treatment of familial male-limited precocious puberty with addition deslorelin after central puberty onset.  J Clin Endocrinol Metab . 1999;  84 175-178
• 8 Rosenthal I R, Refetoff S, Rich B. Response to challenge with gonadotropin-releasing hormone agonist in a mother and her two sons with a constitutively activating mutation of the luteinizing hormone receptor: a clinical research center study.  J Clin Endocrinol Metab . 1996;  81 3802-3806
• 9 Latronico A C, Lins T SS, Brito V N, Arnhold I JP, Mendonca B B. Effects of distinct activating mutations of the luteinizing hormone receptor on the pituitary gonadal axis in both sexes.  Clin Endocrinol (Oxf) (in press). 2000; 
• 10 Liu G, Duranteau L, Carel J C, Monroe J, Doyle D A, Shenker A. Leydig-cell tumors caused by an activating mutation of the gene enconding the luteinizing hormone receptor.  N Engl J Med . 1999;  341 1731-1736
• 11 Kremer H, Kraaij R, Toledo S PA. Male pseudohermaphroditism due to a homozygous missense mutation of the luteinizing hormone receptor gene.  Nat Genet . 1995;  9 160-164
• 12 Latronico A C, Anasti J, Arnhold I JP. Brief report: testicular and ovarian resistance to luteinizing hormone caused by inactivating mutations of the luteinizing hormone-receptor gene.  N Engl J Med . 1996;  334 507-512
• 13 Martens J WM, Post M V, 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
• 14 Stavros S S, Zhu Y S, Cai L Q. A novel mutation of the human luteinizing hormone receptor in 46,XX and 46,XX sisters.  J Clin Endocrinol Metab . 1998;  83 2091-2098
• 15 Toledo S PA, Brunner H G, Kraaij R. An inactivating mutation of the luteinizing hormone receptor causes amenorrhea in a 46,XX female.  J Clin Endocrinol Metab . 1996;  81 3850-3854
• 16 Arnhold I JP, Latronico A C, Batista M C, Izzo C R, Mendonca B B. Clinical features of women with resistance to luteinizing hormone.  Clin Endocrinol (Oxf) . 1999;  51 701-707
• 17 Latronico A C, Chai Y, Arnhold I JP, Liu X, Mendonca B B, Segaloff D L. 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
• 18 Zenteno J C, Canto P, Kofman-Alfaro S, Mendez J P. Evidence for genetic heterogeneity in male pseudohermaphroditism due to Leydig cell hypoplasia.  J Clin Endocrinol Metab . 1999;  84 3803-3806