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Cited by 336Hypothalamic control of reproductive hormonesPituitary Gland Disorders and TreatmentsSexual Differentiation and Disorders

The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism

Open access
Bianco, Suzy D. C., Kaiser, Ursula B.·2009·Nature Reviews Endocrinology
DOI 10.1038/nrendo.2009.177PMC PMC2864719
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Abstract

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.

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Written from the paper’s full text.

TL;DR

This review summarizes the genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (IHH), including Kallmann syndrome and normosmic IHH, organized by effects on GnRH neuron migration, secretion, and action. Despite identifying multiple causal genes, it concludes that the genetic basis of the vast majority of IHH cases remains unknown.

Key findings

  • IHH has an incidence of 1–10 cases per 100,000 births; about 60% of patients have anosmia (Kallmann syndrome). KAL1 and FGFR1 mutations together account for only about 15% of Kallmann syndrome cases, while PROK2/PROKR2 mutations may account for an additional 5–10%.
  • In normosmic IHH, GNRHR mutations account for 3.5–16% of sporadic cases and up to 40% of familial cases; KISS1R mutations represent about 5%, LEP/LEPR mutations less than 5%, and CHD7 mutations are predicted to account for 6% of all IHH cases. TAC3 or TACR3 mutations segregated with IHH in four of nine unrelated consanguineous families.
  • Some genes, including PROK2 and FGFR1, are associated with both anosmic and normosmic IHH. Many cases are predicted to be polygenic, and sex-associated factors contribute to the phenotype, reinforced by a 5:1 male predominance.
  • Reversal of hypogonadism after hormone treatment has been reported with KAL1, FGFR1, and GNRHR mutations, suggesting that partial loss of function may be compensated in some cases.

Methods

  • Narrative review based on literature searches of Google Scholar and MEDLINE from 1990 to 2009 using keywords including “IHH,” “hypogonadism,” “Kallmann syndrome,” “anosmia,” “FGFR1,” “KAL1,” “GnRH,” “GPR54,” “kisspeptin,” “PROK2,” “PROKR2,” “leptin,” and “prohormone convertase.”
  • No primary sample or new experimental data; the paper synthesizes human genetic findings with animal and in vitro functional studies, categorizing genes by roles in GnRH neuronal development/migration, GnRH secretion, or GnRH action.

Limitations

  • The paper states that the genetic causes of the vast majority of IHH cases remain unknown and that the individual and/or combined roles of many recently identified genes are not yet completely understood.
  • Evident from the text: this is a narrative review without a systematic quantitative synthesis; prevalence estimates are drawn from cited studies and vary widely (for example, GNRHR mutations in 3.5–16% of sporadic versus up to 40% of familial normosmic IHH), and several mechanisms are inferred from animal or in vitro models.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/nrendo.2009.177

Cites

75 of 75 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 109 cited sources checked · 0 supported · 0 flagged

  • Interpretationreasoning

    Gene mutations associated with Kallmann syndrome encode proteins that regulate GnRH and olfactory neuronal migration.

    “Accordingly, gene mutations associated with Kallmann syndrome encode proteins that regulate GnRH and olfactory neuronal migration.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Impaired migration of GnRH and olfactory neurons is the underlying cause of Kallmann syndrome.
  • Interpretationreasoning

    The genetic causes of the majority of IHH cases remain unknown.

    “Despite recent advances in the field, the genetic causes of the majority of cases of IHH remain unknown.”
    Quote in the paperSubstantial claim
  • Premisenone given

    Mutations in PROK2 and PROKR2 may account for an additional 5-10% 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.”
    Quote in the paperNot a substantial claim
  • Interpretationcitation

    Other associated neurological and somatic abnormalities may segregate with the Kallmann syndrome phenotype, suggesting a common genetic origin of these abnormalities.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Cariboni, A. & Maggi, R. Kallmann's syndrome, a neuronal migration defect. Cell. Mol. Life Sci. 63, 2512–2526 (2006). source

      Not checked in the free run.

  • Interpretationreasoning

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

    “Evidence for the contribution of sex-associated factors in IHH is reinforced by the 5:1 male predominance of the disorder.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 38
  • Classified as probably not a substantial claim. 1

  • May combine two claims.

    Premisecitation

    KAL1 is located on the X chromosome and encodes anosmin 1, an extracellular cell adhesion protein essential for axonal guidance and migration of olfactory and GnRH neurons from the nasal placode to the brain.

    “KAL1 is located on the X chromosome and encodes an extracellular cell adhesion protein, anosmin 1, essential for axonal guidance and migration of olfactory and GnRH neurons from the nasal placode to their final location in the brain.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Interpretationnone given

    The genetic mechanisms underlying IHH in patients with a normal sense of smell are diverse and may involve genes that regulate development and/or GnRH secretion or action.

    “The genetic mechanisms that underlie IHH in patients with a normal sense of smell are diverse and may involve genes that regulate development and/or GnRH secretion or action.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Anosmin 1 co-localizes with FGFR-1 in the olfactory bulb during development, suggesting that anosmin 1 is a component of FGFR-1 signaling.

    “Anosmin 1 co-localizes with basic fibroblast growth factor receptor 1 (FGFR-1, discussed further below), in the olfactory bulb during development, which suggests that this protein is a component of FGFR-1 signaling.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Ayari, B. & Soussi-Yanicostas, N. FGFR1 and anosmin-1 underlying genetically distinct forms of Kallmann syndrome are co-expressed and interact in olfactory bulbs. Dev. Genes Evol. 217, 169–175 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The dimorphic distribution with incomplete penetrance suggests that changes may occur in more than one gene and/or that sex-associated modifying factors may contribute to the phenotype.

    “This pattern suggests that changes may occur in more than one gene and/or that sex-associated modifying factors may contribute to the phenotype.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [6] Pitteloud, N. et al. Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism. J. Clin. Invest. 117, 457–463 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    KAL1 mutations are present in approximately 5-10% of patients with Kallmann syndrome, with the highest prevalence in families with X-linked inheritance.

    “Mutations in KAL1 disrupt the migration of olfactory and GnRH neurons and are reported to be present in approximately 5–10% of patients with Kallmann syndrome (Table 1),7,9–11 with the highest prevalence seen in families with X-linked inheritance patterns.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [11] Albuisson, J. et al. Kallmann syndrome: 14 novel mutations in KAL1 and FGFR1 (KAL2). Hum. Mutat. 25, 98–99 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The Asn267Lys and Glu514Lys mutations are expected to enhance heparin binding, compromising the flexibility of anosmin 1.

    “Two mutations (Asn267Lys and Glu514Lys) are expected to enhance heparin binding, which compromises the flexibility of anosmin 1.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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 in the free run.

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    Premisecitation

    In vitro studies indicate that a serine substitution at the Gly237 position destabilizes FGFR-1, causing misfolding and retention of the protein in the endoplasmic reticulum.

    “In vitro studies indicate that a serine substitution at this position destabilizes the receptor, which results in misfolding and retention of the protein in the endoplasmic reticulum.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Interpretationreasoning

    The Cys163Tyr and Cys172Arg mutations are expected to prevent disulfide bond formation, disrupting the tertiary structure of anosmin 1 and possibly causing misfolding and/or destabilization.

    “The Cys163Tyr and Cys172Arg mutations are expected to prevent disulfide bond formation, which disrupts the tertiary structure of anosmin 1 and might result in misfolding and/or destabilization of the protein.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    In vitro studies show that substitution of Leu173, Trp178, and Pro290 in PROKR2 impairs cell surface targeting, probably because the receptor protein is incorrectly folded.

    “In vitro studies have shown that substitution of Leu173, Trp178, and Pro290 in PROKR2 impairs the cell surface targeting of the receptor, probably because the receptor protein is incorrectly folded.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [32] Monnier, C. et al. PROKR2 missense mutations associated with Kallmann syndrome impair receptor signalling activity. Hum. Mol. Genet. 18, 75–81 (2009). source

      Not checked in the free run.

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    Premisecitation

    Kiss1r−/− mice have underdeveloped gonads, low gonadotropins and steroid hormone levels, and incomplete gametogenesis.

    “Kiss1r−/− mice have underdeveloped gonads, low gonadotropins and steroid hormone levels, and incomplete gametogenesis.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [35] Seminara, S. B. et al. The GPR54 gene as a regulator of puberty. N. Engl. J. Med. 349, 1614–1627 (2003). source

      Not checked in the free run.

    • cites [47] Funes, S. et al. The KiSS-1 receptor GPR54 is essential for the development of the murine reproductive system. Biochem. Biophys. Res. Commun. 312, 1357–1363 (2003). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The Arg73Cys substitution in PK2 greatly reduces activation of PK-R2-mediated calcium signaling and is predicted to disrupt a disulfide bond.

    “A single amino acid substitution in PK2 (Arg73Cys) that greatly reduces activation of PK-R2-mediated stimulation of calcium signaling is predicted to disrupt a disulfide bond.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    Prok2−/− mice fail to enter puberty, have low gonadotropin levels, and have a significant decrease in hypothalamic GnRH neurons.

    “Likewise, Prok2−/− mice fail to enter puberty, have low gonadotropin levels, and have a significant decrease in hypothalamic GnRH neurons.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [25] Matsumoto, S. et al. Abnormal development of the olfactory bulb and reproductive system in mice lacking prokineticin receptor PKR2. Proc. Natl Acad. Sci. USA 103, 4140–4145 (2006). source

      Not checked in the free run.

    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    GnRH neurons in Prok2−/− mice cross the cribriform plate to enter the central nervous system during embryonic development but do not migrate into and populate the hypothalamus.

    “Interestingly, GnRH neurons in Prok2−/− mice were able to cross the cribriform plate (a horizontal plate of the ethmoid bone) to enter the central nervous system during embryonic development, but the neurons did not migrate into and populate the hypothalamus.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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

      Not checked in the free run.

    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    Frameshift mutations that inactivate PK2 have been reported in sporadic Kallmann syndrome and in families with Kallmann syndrome or normosmic IHH.

    “Frameshift mutations that inactivate PK2 have been reported in sporadic cases of Kallmann syndrome28 and in families with a history of Kallmann syndrome or normosmic IHH.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The Leu102Pro substitution in the first extracellular loop of the KiSS-1 receptor decreases receptor expression and impairs its signaling ability.

    “Another single amino acid substitution of the KiSS-1 receptor (Leu102Pro) identified in patients with IHH is located in the first extracellular loop of the receptor. The mutation decreases the expression of the receptor and impairs its signaling ability.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Tenenbaum-Rakover, Y. et al. Neuroendocrine phenotype analysis in five patients with isolated hypogonadotropic hypogonadism due to a L102P inactivating mutation of GPR54 . J. Clin. Endocrinol. Metab. 92, 1137–1144 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a study of 192 patients with Kallmann syndrome, 10 PROKR2 mutations were identified, five of which resulted in single amino acid substitutions in transmembrane domains.

    “In a study of 192 patients with Kallmann syndrome, 10 mutations in PROKR2 were identified,27 five (50%) of which resulted in single amino acid substitutions in the transmembrane domains (Leu173Arg, Trp178Ser, Pro290Ser, Met323Ile, and Val331Met).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    Prokr2−/− mice exhibit olfactory bulb hypoplasia, hypogonadotropic hypogonadism, and a lack of GnRH neurons in the hypothalamus.

    “Similar to patients with PROKR2 mutations, Prokr2−/− mice exhibit olfactory bulb hypoplasia, hypogonadotropic hypogonadism, and a lack of GnRH neurons in the hypothalamus.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] Matsumoto, S. et al. Abnormal development of the olfactory bulb and reproductive system in mice lacking prokineticin receptor PKR2. Proc. Natl Acad. Sci. USA 103, 4140–4145 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    In mice, the IHH phenotype has been reported only in those homozygous for the Prok2 deletion, suggesting that one normal allele may compensate for the inactivity of the other.

    “Interestingly, in mice, the IHH phenotype has been reported only in those homozygous for the Prok2 deletion, which suggests that one normal allele may compensate for the inactivity of the other.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The Gly93Asn mutation was found in all affected members of one family, whereas the Pro353Ser mutation was found in all affected members of two other families.

    “The Gly93Asn mutation was found in all affected members of one family, whereas the Pro353Ser mutation was found in all affected members of two other families.63”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inactivating mutations in LEP or LEPR account for less than 5% of normosmic IHH and have an autosomal recessive pattern of transmission.

    “These inactivating mutations account for less than 5% of normosmic IHH and have an autosomal recessive pattern of transmission (Table 1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Table 1

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Leptin, encoded by LEP, is a fat-derived hormone that regulates food intake, energy expenditure and reproduction at the hypothalamic level.

    “Leptin, encoded by LEP, is a fat-derived hormone that regulates food intake, energy expenditure and reproduction at the hypothalamic level.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Ala213del eliminates a highly conserved alanine near His208, a residue known to be critical for catalytic activity.

    “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”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [67] Farooqi, S. & O'Rahilly, S. Genetics of obesity in humans. Endocr. Rev. 27, 710–718 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inheritance of GNRHR mutations is autosomal recessive and most patients have compound heterozygous GNRHR mutations.

    “Inheritance is autosomal recessive and most patients have compound heterozygous GNRHR mutations.70”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [70] de Roux, N. GnRH receptor and GPR54 inactivation in isolated gonadotropic deficiency. Best Pract. Res. Clin. Endocrinol. Metab. 20, 515–528 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice homozygous for an Asn222Asp NEC 1 substitution, which is also within the catalytic domain of the enzyme, are obese and have decreased fertility.

    “Accordingly, mice homozygous for an Asn222Asp NEC 1 substitution, which is also within the catalytic domain of the enzyme, are obese and have decreased fertility.69”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [69] Lloyd, D. J., Bohan, S. & Gekakis, N. Obesity, hyperphagia and increased metabolic efficiency in Pc1 mutant mice. Hum. Mol. Genet. 15, 1884–1893 (2006). source

      Not checked in the free run.

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    Premisecitation

    The second PCSK1 mutation causes a frameshift and the introduction of a premature stop codon in the catalytic domain of the enzyme.

    “The second mutation causes a frameshift and the introduction of a premature stop codon in the catalytic domain of the enzyme.66”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Large-scale screening indicates that GNRHR mutations account for 3.5-16% of sporadic cases of normosmic IHH and up to 40% of familial cases of normosmic IHH.

    “Large-scale screening indicates that GNRHR mutations account for 3.5–16% of sporadic cases of normosmic IHH and up to 40% of familial cases of normosmic IHH (Table 1).72”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Activation of the GnRH receptor increases calcium mobilization and stimulates influx of extracellular calcium.

    “Activation of the GnRH receptor increases calcium mobilization and stimulates influx of extracellular calcium.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [70] de Roux, N. GnRH receptor and GPR54 inactivation in isolated gonadotropic deficiency. Best Pract. Res. Clin. Endocrinol. Metab. 20, 515–528 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Although the Arg297Leu mutation only slightly decreased KiSS-1 receptor activity, the combination of Arg297Leu and Cys223Arg was enough to cause hypogonadism.

    “Although the mutation in the other allele—Arg297Leu—only slightly decreased the activity of the KiSS-1 receptor, the combination of the two mutated alleles was enough to cause hypogonadism.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] Semple, R. K. et al. Two novel missense mutations in G protein-coupled receptor 54 in a patient with hypogonadotropic hypogonadism. J. Clin. Endocrinol. Metab. 90, 1849–1855 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Although no reports have been published on the molecular mechanisms by which PCSK1 mutations cause hypogonadism, impairment of GnRH prohormone precursor processing is probably involved in these cases.

    “Although no reports have been published on the molecular mechanisms by which mutations in PCSK1 cause hypogonadism, the impairment of GnRH prohormone precursor processing is probably involved in these cases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The Ser307Leu mutation is within the catalytic domain and severely impairs the catalytic activity of the enzyme.

    “This mutation is also within the catalytic domain and severely impairs the catalytic activity of the enzyme.68”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [68] Farooqi, I. S. et al. Hyperphagia and early-onset obesity due to a novel homozygous missense mutation in prohormone convertase 1/3. J. Clin. Endocrinol. Metab. 92, 3369–3373 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Only two of 11 mutations identified in transmembrane domains encode a partially functional receptor; the other nine encode completely inactive receptors.

    “Only two of 11 mutations identified in transmembrane domains encode a partially functional receptor; the other nine encode completely inactive receptors.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The first report of a patient with congenital NEC 1 deficiency associated with obesity and hypogonadotropic hypogonadism was published in 1995.

    “The first report of a patient with congenital NEC 1 deficiency associated with obesity and hypogonadotropic hypogonadism was published in 1995.65”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [65] O'Rahilly, S. et al. Brief report: impaired processing of prohormones associated with abnormalities of glucose homeostasis and adrenal function. N. Engl. J. Med. 333, 1386–1390 (1995). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NKB is expressed in the arcuate nucleus and its receptor is expressed in GnRH neurons of rodents.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Gln106Arg maps to the first extracellular loop of the GnRHR and decreases GnRH binding.

    “Gln106Arg maps to the first extracellular loop of the GnRHR and decreases GnRH binding.71”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Molecular mechanisms that underlie IHH in patients with a normal sense of smell are diverse and may involve genes that regulate development and/or GnRH secretion or action.

    “Molecular mechanisms that underlie IHH in patients with a normal sense of smell are diverse and may involve genes that regulate development and/or GnRH secretion or action”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    While some genetic mutations are sufficient to cause IHH, other cases are predicted to result from the combination of more than one genetic abnormality.

    “While some genetic mutations are sufficient to cause IHH, other cases are predicted to result from the combination of more than one genetic abnormality.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The parents of the affected siblings were phenotypically normal, despite each being heterozygous for one of the Gln106Arg and Arg262Gln substitutions.

    “The parents of the affected siblings were phenotypically normal, despite each being heterozygous for one of these substitutions.73”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [73] Beranova, M. et al. Prevalence, phenotypic spectrum, and modes of inheritance of gonadotropin-releasing hormone receptor mutations in idiopathic hypogonadotropic hypogonadism. J. Clin. Endocrinol. Metab. 86, 1580–1588 (2001).

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    The Arg262Gln substitution is located in the third intracellular loop, the main site of G-protein interaction.

    “The Arg262Gln substitution is located in the third intracellular loop, the main site of G-protein interaction.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    IHH with anosmia (Kallmann syndrome) is caused by the defective developmental migration of GnRH and olfactory neurons; associated genes encode proteins involved in this migration.

    “IHH with anosmia (Kallmann syndrome) is caused by the defective developmental migration of gonadotropin-releasing hormone (GnRH) and olfactory neurons; associated genes encode proteins involved in this migration”
    Quote in the paperNot a substantial claim
39 of 39

  • The paper relies on this without support.

    The major underlying cause of IHH is failure to activate pulsatile secretion of gonadotropin-releasing hormone (GnRH) during puberty.

    “The major underlying cause of IHH is failure to activate pulsatile secretion of gonadotropin-releasing hormone (GnRH) during puberty, a developmental stage characterized by a substantial increase in the frequency and amplitude of pulses of this hormone.”

  • The paper relies on this without support.

    Impaired migration of GnRH and olfactory neurons is the underlying cause of Kallmann syndrome.

    “Impaired migration of GnRH and olfactory neurons is the underlying cause of Kallmann syndrome (IHH associated with anosmia).”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Isolated hypogonadotropic hypogonadism is more typically associated with normal olfactory and GnRH neuronal development, but impaired regulation of GnRH secretion.

    “By contrast, isolated hypogonadotropic hypogonadism is more typically associated with normal olfactory and GnRH neuronal development, but impaired regulation of GnRH secretion.33,35”

    From Pubertal development and regulation (2016) · cites this paper as [33]

  • Impairment of the migration of GnRH and olfactory neurons is often associated with genetic defects.

    “Impairment of the migration of these neurons is often associated with genetic defects.33–35”

    From Pubertal development and regulation (2016) · cites this paper as [33]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • LEP and LEPR citations are reversed

    Minor

    The text cites reference 58 for LEP and 59 for LEPR, but the reference list identifies 58 as a leptin receptor study and 59 as a leptin mutation study.

  • Anosmin 1 is described as both 680 and 610 amino acids long

    Minor

    The KAL1 section states that anosmin 1 is 680 amino acids long, but later calculates the extent of a truncation using a 610-amino-acid protein. A stop at amino acid 85 would leave approximately 595, not 525, amino acids missing from a 680-amino-acid protein.

2 of 2

Cites

Flagged first, then by citations

2 of the 77 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
Bianco, S. D. C., & Kaiser, U. B.
Affiliations
  • University of Miami (US)
  • Brigham and Women's Hospital (US)
Corresponding author
Kaiser, Ursula B.
ORCID
Venue
Nature Reviews Endocrinology
Publisher
Springer Science and Business Media LLC
Published
2009-08-25
Volume
5
Issue
10
Pages
569-576
ISSN
  • 1759-5029 (ISSN-L)
  • 1759-5037
DOI
10.1038/nrendo.2009.177
PMC
PMC2864719
OpenAlex
W2051108558
Semantic Scholar
334b3bd07e60cf46bd38933af90a2261a348376b
Cited by
336
References
77
Citations by year
2026: 7 · 2025: 16 · 2024: 18 · 2023: 20 · 2022: 31 · 2021: 22 · 2020: 16 · 2019: 22 · 2018: 17 · 2017: 21 · 2016: 14 · 2015: 20 · 2014: 22 · 2013: 24 · 2012: 21
FWCI
3.11
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Reviews Endocrinology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD019938, K12HD051959, HD028138, R01 HD051959, R21HD059015, U54HD028138)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
Keywords
idiopathic hypogonadotropic hypogonadism, Kallmann syndrome, anosmia, KAL1, FGFR1, prokineticin 2, PROKR2, GnRH receptor, KISS1R, TAC3, TACR3, nasal placode, hypothalamus, genetic mutations, molecular mechanisms
MeSH terms
Olfaction Disorders, Gastrointestinal Hormones, Humans, Hypogonadism, Nerve Tissue Proteins, Neuropeptides, Extracellular Matrix Proteins, Receptors, Peptide, Receptors, G-Protein-Coupled, Receptor, Fibroblast Growth Factor, Type 1

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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