The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism

In the paper

“Accordingly, gene mutations associated with Kallmann syndrome encode proteins that regulate GnRH and olfactory neuronal migration.”

In the paper

“Despite recent advances in the field, the genetic causes of the majority of cases of IHH remain unknown.”

In the paper

“More recently, mutations in PROK2 and PROKR2 have been linked to the syndrome and may account for an additional 5–10% of cases.”

In the paper

“Other associated neurological and somatic abnormalities, such as synkinesia, cerebellar ataxia, sensorineural deafness, mental retardation, unilateral renal agenesis and cleft palate, may segregate with the Kallmann syndrome phenotype, which suggests a common genetic origin of these abnormalities.”

What the sources say

• Not checked yetcites [3] Cariboni, A. & Maggi, R. Kallmann's syndrome, a neuronal migration defect. Cell. Mol. Life Sci. 63, 2512–2526 (2006). source

In the paper

“Evidence for the contribution of sex-associated factors in IHH is reinforced by the 5:1 male predominance of the disorder.”

In the paper

“In some cases, the severity of hypogonadism and the presence of associated phenotypes in a pedigree present in a dimorphic distribution with incomplete penetrance.”

What the sources say

• Not checked yetcites [4] Pitteloud, N. et al. Mutations in fibroblast growth factor receptor 1 cause both Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism. Proc. Natl Acad. Sci. USA 103, 6281–6286 (2006). source
• Not checked yetcites [5] Pitteloud, N. et al. Mutations in fibroblast growth factor receptor 1 cause Kallmann syndrome with a wide spectrum of reproductive phenotypes. Mol. Cell Endocrinol. 254–255, 60–69 (2006). source
• Not checked yetcites [6] Pitteloud, N. et al. Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism. J. Clin. Invest. 117, 457–463 (2007). source

In the paper

“In addition, male patients often present with a more severe phenotype than affected female individuals within a given family.”

In the paper

“However, together, these mutations account for only about 15% of Kallmann syndrome cases.”

In the paper

“Mutations in the tyrosine kinase domain of FGFR-1 are predicted to decrease or inhibit kinase activity by disrupting receptor conformation (Ile538Val, Asn724Lys, and Gly703Arg) and/or altering the normal pattern of phosphorylation of the kinase domain (Ala520Thr, Gly703Ser, Pro722Ser, Pro745Ser, and Pro772Ser).”

What the sources say

• Not checked yetcites [5] Pitteloud, N. et al. Mutations in fibroblast growth factor receptor 1 cause Kallmann syndrome with a wide spectrum of reproductive phenotypes. Mol. Cell Endocrinol. 254–255, 60–69 (2006). source
• Not checked yetcites [13] Kim, S. H., Hu, Y., Cadman, S. & Bouloux, P. Diversity in fibroblast growth factor receptor 1 regulation: learning from the investigation of Kallmann syndrome. J. Neuroendocrinol. 20, 141–163 (2008). source
• Not checked yetcites [17] Böttcher, R. T. & Niehrs, C. Fibroblast growth factor signaling during early vertebrate development. Endocr. Rev. 26, 63–77 (2005). source

In the paper

“Unlike the situation with KAL1 mutations, mutations in FGFR1 have been reported in patients with IHH without anosmia, termed normosmic IHH.”

In the paper

“Reversal of hypogonadism has been described in a patient with a frameshift mutation in KAL1 that introduced a premature stop codon at amino acid 85.”

What the sources say

• Not checked yetcites [14] Ribeiro, R. S., Vieira, T. C. & Abucham, J. Reversible Kallmann syndrome: report of the first case with a KAL1 mutation and literature review. Eur. J. Endocrinol. 156, 285–290 (2007). source

In the paper

“The majority of FGFR1 mutations associated with Kallmann syndrome are single amino acid substitutions located in the immunoglobulin-like domains or tyrosine kinase domain.”

In the paper

“An Asp224His substitution, also in the second immunoglobulin-like domain, is believed to prevent ligand-induced or heparin-sulfate-induced FGFR-1 dimerization and signaling.”

What the sources say

• Not checked yetcites [5] Pitteloud, N. et al. Mutations in fibroblast growth factor receptor 1 cause Kallmann syndrome with a wide spectrum of reproductive phenotypes. Mol. Cell Endocrinol. 254–255, 60–69 (2006). source

In the paper

“Mutations in PK2 or PK-R2 are estimated to account for 5–10% of all Kallmann syndrome cases (Table 1).”

What the sources say

• Not checked yetcites Table 1

In the paper

“Mutations in FGFR1 account for approximately 10% of Kallmann cases (Table 1).”

What the sources say

• Not checked yetcites Table 1

In the paper

“FGFR-1 signaling through this pathway regulates neuronal migration, differentiation, and survival, as well as cell proliferation during embryonic development.”

What the sources say

• Not checked yetcites [15] Ford-Perriss, M., Abud, H. & Murphy, M. Fibroblast growth factors in the developing central nervous system. Clin. Exp. Pharmacol. Physiol. 28, 493–503 (2001). source
• Not checked yetcites [16] Gill, J. C., Moenter, S. M. & Tsai, P. S. Developmental regulation of gonadotropin-releasing hormone neurons by fibroblast growth factor signaling. Endocrinology 145, 3830–3839 (2004). source
• Not checked yetcites [17] Böttcher, R. T. & Niehrs, C. Fibroblast growth factor signaling during early vertebrate development. Endocr. Rev. 26, 63–77 (2005). source

In the paper

“Reversal of IHH in this case suggests that FGFR-1 might regulate reproduction beyond the stage of embryonic GnRH neuronal migration.”

What the sources say

• Not checked yetcites [19] Pitteloud, N. et al. Reversible Kallmann syndrome, delayed puberty, and isolated anosmia occurring in a single family with a mutation in the fibroblast growth factor receptor 1 gene. J. Clin. Endocrinol. Metab. 90, 1317–1322 (2005). source

In the paper

“Reversal of IHH after testosterone treatment has been reported in a patient harboring a heterozygous mutation in the tyrosine kinase domain of FGFR-1 (Arg622X).”

What the sources say

• Not checked yetcites [19] Pitteloud, N. et al. Reversible Kallmann syndrome, delayed puberty, and isolated anosmia occurring in a single family with a mutation in the fibroblast growth factor receptor 1 gene. J. Clin. Endocrinol. Metab. 90, 1317–1322 (2005). source

In the paper

“Less than 20% of the different mutations associated with Kallmann syndrome result in amino acid substitutions.”

What the sources say

• Not checked yetcites [13] Kim, S. H., Hu, Y., Cadman, S. & Bouloux, P. Diversity in fibroblast growth factor receptor 1 regulation: learning from the investigation of Kallmann syndrome. J. Neuroendocrinol. 20, 141–163 (2008). source

In the paper

“Mutations in KAL1 disrupt the migration of olfactory and GnRH neurons”

What the sources say

• Not checked yetcites [7] Legouis, R. et al. The candidate gene for the X-linked Kallmann syndrome encodes a protein related to adhesion molecules. Cell 67, 423–435 (1991). source
• Not checked yetcites [9] Franco, B. et al. A gene deleted in Kallmann's syndrome shares homology with neural cell adhesion and axonal path-finding molecules. Nature 353, 529–536 (1991). source
• Not checked yetcites [10] Hardelin, J. P. et al. Heterogeneity in the mutations responsible for X chromosome-linked Kallmann syndrome. Hum. Mol. Genet. 2, 373–377 (1993). source
• Not checked yetcites [11] Albuisson, J. et al. Kallmann syndrome: 14 novel mutations in KAL1 and FGFR1 (KAL2). Hum. Mutat. 25, 98–99 (2005). source

In the paper

“The KAL1 mutations identified to date predominantly consist of nucleotide deletions or insertions that result in sequence frameshifts or the introduction of premature stop codons.”

In the paper

“Mutations in the gene FGF8, which encodes one of the many ligands of FGFR-1, have recently been linked to Kallmann syndrome.”

What the sources say

• Not checked yetcites [20] Falardeau, J. et al. Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice. J. Clin. Invest. 118, 2822–2831 (2008). source

In the paper

“This finding suggests that FGF-8 is the FGFR-1 ligand responsible for GnRH neuronal development and/or migration.”

What the sources say

• Not checked yetcites [20] Falardeau, J. et al. Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice. J. Clin. Invest. 118, 2822–2831 (2008). source

In the paper

“Amino acid substitutions that map to the third immunoglobulin-like domain of FGFR-1, such as Val273Met, Glu274Gly, Tyr339Cys, and Ser346Cys, are predicted to disrupt a characteristic Cys277–Cys341 disulfide bond in this domain.”

What the sources say

• Not checked yetcites [4] Pitteloud, N. et al. Mutations in fibroblast growth factor receptor 1 cause both Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism. Proc. Natl Acad. Sci. USA 103, 6281–6286 (2006). source
• Not checked yetcites [5] Pitteloud, N. et al. Mutations in fibroblast growth factor receptor 1 cause Kallmann syndrome with a wide spectrum of reproductive phenotypes. Mol. Cell Endocrinol. 254–255, 60–69 (2006). source

In the paper

“When PK2 binds to PK-R2, signaling cascades that are important for development of the olfactory system and GnRH neuronal progenitors are initiated.”

What the sources say

• Not checked yetcites [21] Li, M., Bullock, C. M., Knauer, D. J., Ehlert, F. J. & Zhou, Q. Y. Identification of two prokineticin cDNAs: recombinant proteins potently contract gastrointestinal smooth muscle. Mol. Pharmacol. 59, 692–698 (2001). source
• Not checked yetcites [22] Lin, D. C. et al. Identification and molecular characterization of two closely related G protein-coupled receptors activated by prokineticins/endocrine gland vascular endothelial growth factor. J. Biol. Chem. 277, 19276–19280 (2002). source
• Not checked yetcites [23] Cheng, M. Y. et al. Prokineticin 2 transmits the behavioural circadian rhythm of the suprachiasmatic nucleus. Nature 417, 405–410 (2002). source
• Not checked yetcites [24] Prosser, H. M., Bradley, A. & Caldwell, M. A. Olfactory bulb hypoplasia in Prokr2 null mice stems from defective neuronal progenitor migration and differentiation. Eur. J. Neurosci. 26, 3339–3344 (2007). source

In the paper

“The reproductive roles of the G-protein-coupled KiSS-1 receptor (also known as GPR54, encoded by KISS1R) and its endogenous ligand, kisspeptin 1 (encoded by KISS1) were revealed in 2003 when inactivating mutations in the KiSS-1 receptor were found in the homozygous state in members of two large, consanguineous families with a history of normosmic IHH.”

What the sources say

• Not checked yetcites [34] de Roux, N. et al. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc. Natl Acad. Sci. USA 100, 10972–10976 (2003). source
• Not checked yetcites [35] Seminara, S. B. et al. The GPR54 gene as a regulator of puberty. N. Engl. J. Med. 349, 1614–1627 (2003). source

In the paper

“Accordingly, in vitro studies showed impaired function of both the Arg331X and X399Arg mutant KiSS-1 receptors.”

What the sources say

• Not checked yetcites [35] Seminara, S. B. et al. The GPR54 gene as a regulator of puberty. N. Engl. J. Med. 349, 1614–1627 (2003). source

In the paper

“Mutations in KISS1R represent about 5% of cases of normosmic IHH (Table 1).”

What the sources say

• Not checked yetcites Table 1

In the paper

“These mutations are believed to result in a milder form of CHARGE syndrome that manifests as normosmic IHH or Kallmann syndrome.”

What the sources say

• Not checked yetcites [33] Kim, H. G. et al. Mutations in CHD7, encoding a chromatin-remodeling protein, cause idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. Am. J. Hum. Genet. 83, 511–519 (2008). source

In the paper

“Mutations in CHD7 are predicted to account for 6% of all IHH cases (Table 1).”

What the sources say

• Not checked yetcites [33] Kim, H. G. et al. Mutations in CHD7, encoding a chromatin-remodeling protein, cause idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. Am. J. Hum. Genet. 83, 511–519 (2008). source

In the paper

“Many of the mutations identified in PROKR2 map to the highly conserved transmembrane domains of the receptor encoded by this gene.”

In the paper

“Other mutants with amino acid substitutions in the first, second and third intracellular loops, or in the carboxyl tail of PK-R2 have similarly impaired calcium signaling but normal expression levels and cell surface targeting.”

What the sources say

• Not checked yetcites [27] Dodé, C. et al. Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2. PLoS Genet. 2, e175 (2006). source
• Not checked yetcites [29] Cole, L. W. et al. Mutations in prokineticin 2 and prokineticin receptor 2 genes in human gonadotrophin-releasing hormone deficiency: molecular genetics and clinical spectrum. J. Clin. Endocrinol. Metab. 93, 3551–3559 (2008). source
• Not checked yetcites [32] Monnier, C. et al. PROKR2 missense mutations associated with Kallmann syndrome impair receptor signalling activity. Hum. Mol. Genet. 18, 75–81 (2009). source

In the paper

“Furthermore, seven mutations in CHD7 were recently identified in patients with sporadic, normosmic IHH or Kallmann syndrome who were not diagnosed as having CHARGE syndrome.”

What the sources say

• Not checked yetcites [33] Kim, H. G. et al. Mutations in CHD7, encoding a chromatin-remodeling protein, cause idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. Am. J. Hum. Genet. 83, 511–519 (2008). source

In the paper

“In fact, kisspeptin 1 is recognized as the most potent regulator of GnRH secretion in humans and animal models.”

In the paper

“These mutants probably have impaired G-protein coupling.”

What the sources say

• Not checked yetcites [27] Dodé, C. et al. Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2. PLoS Genet. 2, e175 (2006). source
• Not checked yetcites [29] Cole, L. W. et al. Mutations in prokineticin 2 and prokineticin receptor 2 genes in human gonadotrophin-releasing hormone deficiency: molecular genetics and clinical spectrum. J. Clin. Endocrinol. Metab. 93, 3551–3559 (2008). source
• Not checked yetcites [32] Monnier, C. et al. PROKR2 missense mutations associated with Kallmann syndrome impair receptor signalling activity. Hum. Mol. Genet. 18, 75–81 (2009). source

In the paper

“Human mutations in PROK2 and PROKR2 have been found in the heterozygous, homozygous, or compound heterozygous state.”

What the sources say

• Not checked yetcites [26] Pitteloud, N. et al. Loss-of-function mutation in the prokineticin 2 gene causes Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism. Proc. Natl Acad. Sci. USA 104, 17447–17452 (2007). source
• Not checked yetcites [27] Dodé, C. et al. Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2. PLoS Genet. 2, e175 (2006). source
• Not checked yetcites [28] Leroy, C. et al. Biallelic mutations in the prokineticin-2 gene in two sporadic cases of Kallmann syndrome. Eur. J. Hum. Genet. 16, 865–868 (2008). source
• Not checked yetcites [29] Cole, L. W. et al. Mutations in prokineticin 2 and prokineticin receptor 2 genes in human gonadotrophin-releasing hormone deficiency: molecular genetics and clinical spectrum. J. Clin. Endocrinol. Metab. 93, 3551–3559 (2008). source
• Not checked yetcites [30] Abreu, A. P. et al. Loss-of-function mutations in the genes encoding prokineticin-2 or prokineticin receptor-2 cause autosomal recessive Kallmann syndrome. J. Clin. Endocrinol. Metab. 93, 4113–4118 (2008). source

In the paper

“This substitution is located near the DRW(Y) motif, a motif that has an important role in regulating the activation and inactivation of many G-protein-coupled receptors.”

What the sources say

• Not checked yetcites [49] Rovati, G. E., Capra, V. & Neubig, R. R. The highly conserved DRY motif of class A G protein-coupled receptors: beyond the ground state. Mol. Pharmacol. 71, 959–964 (2007). source
• Not checked yetcites [50] Wacker, J. L. et al. Disease-causing mutation in GPR54 reveals the importance of the second intracellular loop for class A G-protein-coupled receptor function. J. Biol. Chem. 283, 31068–31078 (2008). source

In the paper

“A compound heterozygous mutation (Glu250X and Ala213del) was identified in a female infant.”

In the paper

“Evidence from studies of animal models points to a role for kisspeptin 1 in the reproductive effects of leptin.”

What the sources say

• Not checked yetcites [62] Tena-Sempere, M. KiSS-1 and reproduction: focus on its role in the metabolic regulation of fertility. Neuroendocrinology 83, 275–281 (2006). source

In the paper

“The second case involved a 6-year-old boy with a homozygous Ser307Leu substitution.”

In the paper

“NKB is expressed in the arcuate nucleus and its receptor is expressed in GnRH neurons of rodents, which suggests it has a possible role in the regulation of GnRH secretion.63”

What the sources say

• Not checked yetcites [63] Topaloglu, A. K. et al. TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for neurokinin B in the central control of reproduction. Nat. Genet. 41, 354–358 (2009). source

In the paper

“Germ-line mutations in GNRHR were among the first genetic mutations identified in patients with IHH.71”

What the sources say

• Not checked yetcites [71] de Roux, N. et al. A family with hypogonadotropic hypogonadism and mutations in the gonadotropin-releasing hormone receptor. N. Engl. J. Med. 337, 1597–1602 (1997). source

In the paper

“The gain-of-function in this case was not achieved by constitutive activation of the KiSS-1 receptor. Instead, the apparent ‘activation’ of the receptor was the result of a reduced rate of receptor desensitization.”

What the sources say

• Not checked yetcites [53] Teles, M. G. et al. A GPR54-activating mutation in a patient with central precocious puberty. N. Engl. J. Med. 358, 709–715 (2008). source

In the paper

“Taken together, these results strongly suggest that NKB and NKR have important roles as central regulators of reproductive capability.”

In the paper

“The key role of the KiSS-1 receptor in the regulation of the onset of puberty was recently reinforced when the first identifiable genetic cause of central precocious puberty was recognized as a gain-of-function mutation in the receptor.”

What the sources say

• Not checked yetcites [53] Teles, M. G. et al. A GPR54-activating mutation in a patient with central precocious puberty. N. Engl. J. Med. 358, 709–715 (2008). source

In the paper

“In vitro studies showed that the stimulation of NKR by NKB is markedly impaired by the Met90Thr substitution.63”

What the sources say

• Not checked yetcites [63] Topaloglu, A. K. et al. TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for neurokinin B in the central control of reproduction. Nat. Genet. 41, 354–358 (2009). source

In the paper

“In vitro studies showed that these two mutations impair the ability of NKR to activate signal transduction.63”

What the sources say

• Not checked yetcites [63] Topaloglu, A. K. et al. TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for neurokinin B in the central control of reproduction. Nat. Genet. 41, 354–358 (2009). source

In the paper

“Only two other cases with a similar phenotype associated with PCSK1 mutations have been identified in humans.”

In the paper

“The tachykinin motif is predicted to undergo post-translational amidation for full activation of NKB.63”

What the sources say

• Not checked yetcites [63] Topaloglu, A. K. et al. TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for neurokinin B in the central control of reproduction. Nat. Genet. 41, 354–358 (2009). source

In the paper

“Two mutations found in TACR3 replace highly conserved amino acids located in the first (Gly93Asn) or sixth (Pro353Ser) transmembrane domain of NKR.”

What the sources say

• Not checked yetcites [63] Topaloglu, A. K. et al. TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for neurokinin B in the central control of reproduction. Nat. Genet. 41, 354–358 (2009). source

In the paper

“A recent genome-wide single nucleotide polymorphism analysis identified homozygous mutations in TAC3 or TACR3 that segregated with the IHH phenotype in four (of nine) unrelated consanguineous families.”

What the sources say

• Not checked yetcites [63] Topaloglu, A. K. et al. TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for neurokinin B in the central control of reproduction. Nat. Genet. 41, 354–358 (2009). source

In the paper

“Glu250X is predicted to truncate the protein within its catalytic domain, whereas the mutation in the other allele (Ala213del) eliminates a highly conserved alanine near His208, a residue known to be critical for catalytic activity.67”

What the sources say

• Not checked yetcites [67] Farooqi, S. & O'Rahilly, S. Genetics of obesity in humans. Endocr. Rev. 27, 710–718 (2006). source

In the paper

“given the co-expression of NKB with kisspeptin in neurons in the arcuate nucleus of the hypothalamus.64”

What the sources say

• Not checked yetcites [64] Rance, N. E. Menopause and the human hypothalamus: evidence for the role of kisspeptin/neurokinin B neurons in the regulation of estrogen negative feedback. Peptides 30, 111–122 (2009). source

In the paper

“During the past 10 years, at least 19 additional loss-of-function mutations in the GnRH receptor have been identified in patients with IHH.72”

What the sources say

• Not checked yetcites [72] Bédécarrats, G. Y. & Kaiser, U. B. Mutations in the human gonadotropin-releasing hormone receptor: insights into receptor biology and function. Semin. Reprod. Med. 25, 368–378 (2007). source

In the paper

“On the basis of phenotypic similarities, infertility is expected in these two patients once they reach pubertal age.”

In the paper

“All but two known GNRHR mutations are missense, leading to single amino acid substitutions.”

In the paper

“In one family, a Met90Thr amino acid substitution of NKB affected individuals homozygous for the mutation but not those who were heterozygous.”

What the sources say

• Not checked yetcites [63] Topaloglu, A. K. et al. TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for neurokinin B in the central control of reproduction. Nat. Genet. 41, 354–358 (2009). source

In the paper

“About 82% of all transmembrane domain mutations cause complete impairment of ligand binding and signaling.”

In the paper

“While the underlying mechanism has not been established, it probably involves the regulation of GnRH secretion, perhaps via interactions with the kisspeptin 1–KiSS-1 receptor system given the co-expression of NKB with kisspeptin in neurons in the arcuate nucleus of the hypothalamus.64”

What the sources say

• Not checked yetcites [64] Rance, N. E. Menopause and the human hypothalamus: evidence for the role of kisspeptin/neurokinin B neurons in the regulation of estrogen negative feedback. Peptides 30, 111–122 (2009). source

In the paper

“This increase in intracellular calcium induces pituitary luteinizing hormone and follicle-stimulating hormone secretion.70”

What the sources say

• Not checked yetcites [70] de Roux, N. GnRH receptor and GPR54 inactivation in isolated gonadotropic deficiency. Best Pract. Res. Clin. Endocrinol. Metab. 20, 515–528 (2006). source

In the paper

“A compound heterozygous mutation in PCSK1 was later identified in this patient in which a Gly483Arg substitution impairs the maturation of the inactive NEC 1 propeptide so that the propeptide is trapped in the endoplasmic reticulum.”

What the sources say

• Not checked yetcites [66] Jackson, R. S. et al. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat. Genet. 16, 303–306 (1997). source

In the paper

“These mutations impair GnRH signaling through loss of receptor expression, ligand binding, G-protein coupling, and/or abnormal intracellular trafficking of the receptor.”

In the paper

“This mutation is located within the canonical tachykinin motif in the carboxyl terminus of the mature ligand.”

What the sources say

• Not checked yetcites [63] Topaloglu, A. K. et al. TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for neurokinin B in the central control of reproduction. Nat. Genet. 41, 354–358 (2009). source

In the paper

“In humans, leptin has a permissive role in the control of reproduction, being necessary but not sufficient for the onset of puberty and maintenance of fertility.”

In the paper

“A compound heterozygous mutation in PCSK1 was later identified in this patient in which a Gly483Arg substitution impairs the maturation of the inactive NEC 1 propeptide so that the propeptide is trapped in the endoplasmic reticulum.”

What the sources say

• Not checked yetcites [66] Jackson, R. S. et al. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat. Genet. 16, 303–306 (1997). source

In the paper

“This mutation impairs signal transduction, suggesting that activation of G proteins is affected.”

In the paper

“Some GNRHR mutations with partial effects on signaling were found in patients with compound heterozygous mutations, such as Gln106Arg–Arg262Gln.”

In the paper

“A considerable number of IHH cases probably involve mutations in more than one gene; that is, these cases are polygenic”

In the paper

“Despite these recent advances, the genetic basis of the vast majority of cases of IHH remains unknown, and much room remains for further discovery.”

• Also stated in: § Key points · plain

  “The genetic basis of the vast majority of cases of idiopathic hypogonadotropic hypogonadism (IHH) remains unknown”

In the paper

“This mutation impairs signal transduction, suggesting that activation of G proteins is affected.”

In the paper

“The reversal of the phenotype after treatment suggests that hormonal replacement may compensate for an underlying genetic abnormality in cases where the mutations result in only partial loss of function.”

In the paper

“Mutations in a number of genes have been identified in patients as the primary genetic cause of IHH.”

In the paper

“These genes encode proteins that regulate GnRH neuronal development, migration from the nasal placode to the hypothalamus, GnRH secretion, or GnRH action.”

In the paper

“In such cases, the partial loss of function caused by one genetic mutation may not manifest with a reproductive phenotype, whereas the presence of a second mutation overwhelms the ability to compensate for the effects of the first mutation, resulting in IHH.”

In the paper

“The reversal of IHH in a patient carrying a homozygous mutation in GNRHR has been reported by Pitteloud and colleagues.75”

What the sources say

• Not checked yetcites [75] Pitteloud, N. et al. The fertile eunuch variant of idiopathic hypogonadotropic hypogonadism: spontaneous reversal associated with a homozygous mutation in the gonadotropin-releasing hormone receptor. J. Clin. Endocrinol. Metab. 86, 2470–2475 (2001).

In the paper

“On the other hand, only one of the mutations reported in other domains encodes a completely inactive receptor.”