The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism

In the paper

“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.”

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

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“This pattern suggests that changes may occur in more than one gene and/or that sex-associated modifying factors may contribute to the phenotype.”

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

“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.”

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

“Two mutations (Asn267Lys and Glu514Lys) are expected to enhance heparin binding, which compromises the flexibility of anosmin 1.”

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

“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.”

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

In the paper

“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.”

In the paper

“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.”

What the sources say

• 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

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

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
• Not checked yetcites [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

In the paper

“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.”

What the sources say

• 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

In the paper

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

What the sources say

• Not checked yetcites [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 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

In the paper

“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.”

What the sources say

• 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
• 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

In the paper

“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.”

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 [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 [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

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

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

In the paper

“Similar to patients with PROKR2 mutations, Prokr2−/− mice exhibit olfactory bulb hypoplasia, hypogonadotropic hypogonadism, and a lack of GnRH neurons in the hypothalamus.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

“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”

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

“These inactivating mutations account for less than 5% of normosmic IHH and have an autosomal recessive pattern of transmission (Table 1).”

What the sources say

• Not checked yetcites Table 1

In the paper

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

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

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

“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”

What the sources say

• Not checked yetcites [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

In the paper

“The second mutation causes a frameshift and the introduction of a premature stop codon in the catalytic domain of the enzyme.66”

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

“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”

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

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

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

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

“This mutation is also within the catalytic domain and severely impairs the catalytic activity of the enzyme.68”

What the sources say

• Not checked yetcites [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

In the paper

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

In the paper

“The first report of a patient with congenital NEC 1 deficiency associated with obesity and hypogonadotropic hypogonadism was published in 1995.65”

What the sources say

• Not checked yetcites [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

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

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

“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”

In the paper

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

In the paper

“The parents of the affected siblings were phenotypically normal, despite each being heterozygous for one of these substitutions.73”

What the sources say

• Not checked yetcites [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).

In the paper

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

In the paper

“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”