The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism.
Idiopathic hypogonadotropic hypogonadism (IHH) has an incidence of 1-10 cases per 100,000 births. About 60% of patients with IHH present with associated anosmia, also known as Kallmann syndrome, characterized by total or partial loss of olfaction. Many of the gene mutations associated with Kallmann syndrome have been mapped to KAL1 or FGFR1. However, together, these mutations account for only about 15% of Kallmann syndrome cases. More recently, mutations in PROK2 and PROKR2 have been linked to the syndrome and may account for an additional 5-10% of cases. The remaining 40% of patients with IHH have a normal sense of smell. Prior to 2003, the only gene linked to normosmic IHH was the gonadotropin-releasing hormone receptor gene. However, mutations in this receptor are believed to account for only 10% of cases. Subsequently, mutations in KISS1R, TAC3 and TACR3 were identified as causes of normosmic IHH. Certain genes, including PROK2 and FGFR1, are associated with both anosmic and normosmic IHH. Despite recent advances in the field, the genetic causes of the majority of cases of IHH remain unknown. This Review discusses genes associated with hypogonadotropic disorders and the molecular mechanisms by which mutations in these genes may result in IHH.
Bianco
Suzy D C
SD
Department of Molecular and Cellular Pharmacology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA.
Kaiser
Ursula B
UB
D016326:Extracellular Matrix Proteins / Q000235:genetics; D005768:Gastrointestinal Hormones / Q000235:genetics; D006801:Humans; D007006:Hypogonadism / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics; D009479:Neuropeptides / Q000235:genetics; D000857:Olfaction Disorders / Q000235:genetics; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D018000:Receptors, Peptide / Q000235:genetics
C076266:ANOS1 protein, human; D016326:Extracellular Matrix Proteins; D005768:Gastrointestinal Hormones; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; C423608:PROK2 protein, human; C470838:PROKR2 protein, human; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1
N Engl J Med. 2003 Oct 23;349(17):1614-27
14573733
Am J Physiol Endocrinol Metab. 2008 May;294(5):E827-32
18285524
Endocrinology. 2006 Dec;147(12):5817-25
16959837
Neuroendocrinology. 2004;80(4):264-72
15665556
Semin Reprod Med. 2007 Sep;25(5):368-78
17710733
Front Neuroendocrinol. 2008 Jan;29(1):48-69
17870152
Best Pract Res Clin Endocrinol Metab. 2006 Dec;20(4):515-28
17161329
J Cell Sci. 1996 Jul;109 ( Pt 7):1749-57
8832397
J Clin Endocrinol Metab. 2005 Mar;90(3):1849-55
15598687
J Clin Endocrinol Metab. 2008 Mar;93(3):758-63
18160472
Pharmacol Rev. 2007 Sep;59(3):225-50
17878512
N Engl J Med. 1997 Nov 27;337(22):1597-602
9371856
Hum Mol Genet. 2006 Jun 1;15(11):1884-93
16644867
Biochem Biophys Res Commun. 2003 Dec 26;312(4):1357-63
14652023
Mol Cell Endocrinol. 2006 Jul 25;254-255:60-9
16764984
Biochem Biophys Res Commun. 2004 Jul 23;320(2):383-8
15219839
J Biol Chem. 2001 Sep 14;276(37):34631-6
11457843
J Clin Endocrinol Metab. 2001 Apr;86(4):1580-8
11297587
J Biol Chem. 2008 Nov 7;283(45):31068-78
18772143
J Clin Endocrinol Metab. 2007 Mar;92(3):1137-44
17164310
Eur J Endocrinol. 2007 Mar;156(3):285-90
17322486
J Clin Endocrinol Metab. 2008 Oct;93(10):4113-8
18682503
J Physiol. 2004 Dec 1;561(Pt 2):379-86
15486019
Proc Natl Acad Sci U S A. 2005 Feb 8;102(6):2129-34
15684075
Hum Mol Genet. 2009 Jan 1;18(1):75-81
18826963
Neuroendocrinology. 2006;83(5-6):275-81
16940711
Proc Natl Acad Sci U S A. 2006 Mar 14;103(11):4140-5
16537498
Nature. 1991 Oct 10;353(6344):529-36
1922361
J Neuroendocrinol. 2008 Feb;20(2):141-63
18034870
Endocrinology. 2007 Apr;148(4):1774-83
17204549
Cell Mol Life Sci. 2006 Nov;63(21):2512-26
16952059
J Clin Invest. 2007 Feb;117(2):457-63
17235395
Eur J Hum Genet. 2008 Jul;16(7):865-8
18285834
Nat Genet. 1996 Mar;12(3):318-20
8589726
N Engl J Med. 2004 Sep 2;351(10):987-97
15342807
Nat Genet. 2009 Mar;41(3):354-358
19079066
Endocrinology. 2004 Sep;145(9):4073-7
15217982
Proc Natl Acad Sci U S A. 2007 Jun 19;104(25):10714-9
17563351
Nat Genet. 1998 Mar;18(3):213-5
9500540
N Engl J Med. 1995 Nov 23;333(21):1386-90
7477119
Mol Pharmacol. 2007 Apr;71(4):959-64
17192495
Am J Hum Genet. 2008 Oct;83(4):511-9
18834967
Eur J Neurosci. 2007 Dec;26(12):3339-44
18052978
Mol Pharmacol. 2004 Mar;65(3):582-8
14978236
N Engl J Med. 2008 Feb 14;358(7):709-15
18272894
PLoS Genet. 2006 Oct 20;2(10):e175
17054399
Dev Genes Evol. 2007 Feb;217(2):169-75
17186267
Microsc Res Tech. 1999 Jan 1;44(1):2-10
9915559
Mol Pharmacol. 2001 Apr;59(4):692-8
11259612
J Clin Endocrinol Metab. 2001 Jun;86(6):2470-5
11397842
J Clin Invest. 2008 Aug;118(8):2822-31
18596921
Proc Natl Acad Sci U S A. 2007 Oct 30;104(44):17447-52
17959774
Endocr Rev. 2006 Dec;27(7):710-18
17122358
Peptides. 2009 Jan;30(1):111-22
18614256
Cell. 1991 Oct 18;67(2):423-35
1913827
Hum Mutat. 2005 Jan;25(1):98-9
15605412
Trends Endocrinol Metab. 2001 Mar;12(2):65-72
11167124
Nature. 2001 May 31;411(6837):613-7
11385580
Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4531-6
15070752
Horm Res. 2007;67(5):231-42
17191030
Endocrinology. 2004 Aug;145(8):3830-9
15117872
Nat Genet. 1997 Jul;16(3):303-6
9207799
J Biol Chem. 2002 May 31;277(22):19276-80
11886876
Endocr Rev. 2005 Feb;26(1):63-77
15689573
J Clin Endocrinol Metab. 2007 Sep;92(9):3369-73
17595246
Biochem Biophys Res Commun. 2001 Jun 29;284(5):1189-93
11414709
Hum Mol Genet. 1993 Apr;2(4):373-7
8504298
Nature. 1998 Mar 26;392(6674):398-401
9537324
Clin Exp Pharmacol Physiol. 2001 Jul;28(7):493-503
11422214
Mol Psychiatry. 1997 Jul;2(4):267-9
9246658
Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):10972-6
12944565
J Clin Endocrinol Metab. 2005 Mar;90(3):1317-22
15613419
Proc Natl Acad Sci U S A. 2006 Apr 18;103(16):6281-6
16606836
Nature. 2002 May 23;417(6887):405-10
12024206
J Clin Endocrinol Metab. 2008 Sep;93(9):3551-9
18559922