Genotype and phenotype of patients with gonadotropin-releasing hormone receptor mutations.
Human mutations in the gonadotropin-releasing hormone receptor (GNRHR) gene cause autosomal recessive, normosmic idiopathic hypogonadotropic hypogonadism (IHH). At least 19 different mutations have been identified in this G-protein-coupled receptor, which consist mostly of missense mutations. The Gln106Arg and Arg262Gln mutations comprise nearly half of the identified alleles. Most mutations impair ligand binding and all compromise cell signaling events. Some of the mutations also adversely affect activation of gonadotropin subunit or Gnrhr gene promoters. Interestingly, a number of the mutant GnRHRs can be rescued in vitro from misfolding and degradation within the cell by the addition of a GnRHR antagonist IN3. Most affected patients have compound heterozygous GNRHR mutations that may cause either complete IHH (no evidence of puberty) or incomplete IHH (partial evidence of puberty), although some genotypes are associated with mild disease in some families and severe disease in others. GNRHR mutations also appear to cause constitutional delay of puberty, and one genotype (homozygosity for Gln106Arg) may be reversible in patients with IHH. Mutations in the human GNRHR gene have contributed greatly to the understanding of normosmic IHH, as well as the structure and function of the GnRHR.
Kim
Hyung-Goo
HG
Pedersen-White
Jennifer
J
Bhagavath
Balasubramanian
B
Layman
Lawrence C
LC
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D005260:Female; D005838:Genotype; D006801:Humans; D007006:Hypogonadism / Q000235:genetics*; D017436:Kallmann Syndrome / Q000235:genetics*; D008297:Male; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype; D015995:Prevalence; D011966:Receptors, LHRH / Q000235:genetics*
C484844:GNRHR protein, human; D011966:Receptors, LHRH
J Mol Biol. 1998 Oct 23;283(2):489-506
9769220
J Clin Endocrinol Metab. 2000 Feb;85(2):556-62
10690855
Science. 1986 Dec 12;234(4782):1372-8
3097822
J Clin Endocrinol Metab. 2001 Apr;86(4):1580-8
11297587
J Clin Endocrinol Metab. 2001 Jun;86(6):2680-6
11397871
J Clin Endocrinol Metab. 1999 Oct;84(10):3811-6
10523035
J Clin Endocrinol Metab. 2002 Jul;87(7):3255-62
12107234
Science. 1986 Dec 12;234(4782):1366-71
3024317
Am J Hum Genet. 2008 Oct;83(4):511-9
18834967
Neuroendocrinology. 2006;84(5):301-8
17179725
J Clin Endocrinol Metab. 2002 May;87(5):2144-9
11994356
J Endocrinol. 2005 Dec;187(3):361-8
16423815
Clin Endocrinol (Oxf). 2001 Apr;54(4):493-8
11318785
Mol Cell Endocrinol. 2003 Jul 31;205(1-2):51-64
12890567
Proc Natl Acad Sci U S A. 2006 Apr 18;103(16):6281-6
16606836
Nat Genet. 1998 Jan;18(1):14-5
9425890
N Engl J Med. 1997 Nov 27;337(22):1597-602
9371856
N Engl J Med. 2007 Aug 30;357(9):863-73
17761590
Eur J Endocrinol. 2006 Aug;155(2):201-5
16868131
J Clin Endocrinol Metab. 2000 Sep;85(9):3002-8
10999776
Gastroenterology. 2005 Aug;129(2):537-49
16083711
Nucleic Acids Res. 2003 Jul 1;31(13):3812-4
12824425
Fertil Steril. 2002 Dec;78(6):1317-20
12477532
Mol Endocrinol. 2004 Jul;18(7):1787-97
15105440
Fertil Steril. 2001 Jun;75(6):1148-55
11384641
J Clin Endocrinol Metab. 2002 Oct;87(10):4825-8
12364481
Mol Cell Endocrinol. 2006 Jul 25;254-255:60-9
16764984
J Clin Endocrinol Metab. 2006 Dec;91(12):5117-21
16968799
J Clin Endocrinol Metab. 1999 Mar;84(3):990-6
10084584
Bioinformatics. 2001 Sep;17(9):849-50
11590105
N Engl J Med. 2003 Oct 23;349(17):1589-92
14573729
Endocrinology. 1997 Mar;138(3):1224-31
9048630
Fertil Steril. 2005 Oct;84(4):951-7
16213849
Endocr Rev. 2004 Apr;25(2):235-75
15082521
J Clin Endocrinol Metab. 1999 Feb;84(2):567-72
10022417
J Clin Endocrinol Metab. 2004 Jul;89(7):3189-98
15240592
Fertil Steril. 2005 Dec;84(6):1762-5
16359986
J Med Genet. 2002 Mar;39(3):153-61
11897813
Endocrinology. 2003 May;144(5):1802-11
12697686
J Clin Invest. 2007 Feb;117(2):457-63
17235395
Eur J Endocrinol. 2005 Dec;153(6):845-52
16322390
Mol Hum Reprod. 2008 Jun;14(6):367-70
18463157
Fertil Steril. 2002 Jun;77(6):1288-91
12057744
Biochem Biophys Res Commun. 1992 Nov 30;189(1):289-95
1333190
Semin Reprod Med. 2007 Sep;25(5):368-78
17710733
J Clin Endocrinol Metab. 2002 Jun;87(6):2973-7
12050282
Mol Cell Endocrinol. 1995 Feb;107(2):R1-8
7768323
Fertil Steril. 2003 Feb;79(2):442-4
12568864
Endocrinology. 2005 Jun;146(6):2639-49
15761034
Mol Cell Endocrinol. 1994 Jul;103(1-2):R1-6
7958384
Eur J Endocrinol. 2006 Nov;155 Suppl 1:S3-S10
17074994
J Clin Endocrinol Metab. 2001 Jun;86(6):2470-5
11397842
J Clin Endocrinol Metab. 2003 Apr;88(4):1873-9
12679486
Mol Endocrinol. 2005 Apr;19(4):972-81
15625238
J Clin Endocrinol Metab. 2003 Feb;88(2):834-43
12574221
Genomics. 1994 Apr;20(3):506-8
8034328