Complex genetics in idiopathic hypogonadotropic hypogonadism.
Idiopathic hypogonadotropic hypogonadism (IHH) is an important human disease model. Investigations of the genetics of IHH have facilitated insights into critical pathways regulating sexual maturation and fertility. IHH has been traditionally considered a monogenic disorder. This model holds that a single gene defect is responsible for the disease in each patient. In the case of IHH, 30% of cases are explained by mutations in one of eleven genes. In recent years, several lines of evidence have challenged the monogenic paradigm in IHH. First, disease-associated mutations display striking incomplete penetrance and variable expressivity within and across IHH families. Second, each locus is responsible for only a small percentage of cases. Third, more than one disease-associated mutation seems to be segregating in some families with IHH, and their combined or separate presence in individuals accounts for the variability in disease severity. Finally, IHH is not strictly a congenital and life-long disorder; occasionally it manifests itself during adulthood (adult-onset IHH); in other cases, the disease is not permanent, as evidenced by normal activity of the hypothalamic-pituitary-gonadal axis after discontinuation of treatment in adulthood (IHH reversal). Together, these observations suggest that IHH is not strictly a monogenic mendelian disease, as previously thought. Rather, it is emerging as a digenic, and potentially oligogenic disease, in which hormonal and/or environmental factors may critically influence genetic predisposition and clinical course. Future investigations of IHH should characterize the extent of the involvement of multiple genes in disease pathogenesis, and elucidate the contributions of epigenetic factors.
Pitteloud
Nelly
N
Durrani
Sadia
S
Raivio
Taneli
T
Sykiotis
Gerasimos P
GP
D000328:Adult; D004265:DNA Helicases / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000235:genetics; D051524:Fibroblast Growth Factor 8 / Q000235:genetics; D005768:Gastrointestinal Hormones / Q000235:genetics; D050172:Genes, X-Linked; D056726:Genetic Association Studies; D007987:Gonadotropin-Releasing Hormone / Q000235:genetics / Q000627:therapeutic use; D006801:Humans; D007006:Hypogonadism / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D017436:Kallmann Syndrome / Q000235:genetics*; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics; D009479:Neuropeptides / Q000235:genetics; D019683:Penetrance; D011498:Protein Precursors / Q000235:genetics; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D000074502:Receptors, Kisspeptin-1; D011966:Receptors, LHRH / Q000235:genetics; D018000:Receptors, Peptide / Q000235:genetics; D018039:Receptors, Tachykinin / Q000235:genetics; D012741:Sexual Maturation / Q000235:genetics; D015320:Tachykinins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
C076266:ANOS1 protein, human; D004268:DNA-Binding Proteins; D016326:Extracellular Matrix Proteins; C496456:FGF8 protein, human; C484844:GNRHR protein, human; D005768:Gastrointestinal Hormones; C118688:KISS1R protein, human; C411985:NSMF protein, human; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; C423608:PROK2 protein, human; C470838:PROKR2 protein, human; D011498:Protein Precursors; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D011966:Receptors, LHRH; D018000:Receptors, Peptide; D018039:Receptors, Tachykinin; D015320:Tachykinins; D014157:Transcription Factors; C050866:progonadoliberin I; D051524:Fibroblast Growth Factor 8; D007987:Gonadotropin-Releasing Hormone; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D004265:DNA Helicases; C491434:CHD7 protein, human