Loss-of-function mutation in the
            <i>prokineticin 2</i>
            gene causes Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism

Pitteloud, Nelly; Zhang, Chengkang; Pignatelli, Duarte; Li, Jia‐Da; Raivio, Taneli; Cole, Lindsay W.; Plummer, Lacey; Jacobson-Dickman, Elka; Mellon, Pamela L.; Zhou, Qun‐Yong; Crowley, William F.

doi:10.1073/pnas.0707173104

Cited by 250 publications

(234 citation statements)

References 28 publications

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“…This peptide was not able to activate the PROKR2 receptor produced by transfected CHO cells. 15 The presence of PROK2 biallelic mutations in only two out of 320 patients analysed (273 sporadic cases and 47 familial cases), indicates that this genetic status is rare in KS. In addition, the present findings argue in favour of a digenic inheritance of the disease in patients carrying PROK2 mutations in the heterozygous state.…”

Section: Resultsmentioning

confidence: 99%

“…While this article was under review, the same PROK2 mutation was reported in the homozygous state in two brothers affected by KS, and their sister with isolated hypogonadotropic hypogonadism. 15 The premature stop codon is expected to result in mRNA decay or a truncated peptide of 27 amino-acids in its mature form. This peptide was not able to activate the PROKR2 receptor produced by transfected CHO cells.…”

Section: Resultsmentioning

confidence: 99%

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Biallelic mutations in the prokineticin-2 gene in two sporadic cases of Kallmann syndrome

et al. 2008

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Kallmann syndrome is a developmental disease that combines hypogonadotropic hypogonadism and anosmia. Putative loss-of-function mutations in PROKR2 or PROK2, encoding prokineticin receptor-2 (a G protein-coupled receptor), and one of its ligands, prokineticin-2, respectively, have recently been reported in approximately 10% of Kallmann syndrome affected individuals. Notably, given PROKR2 mutations were found in the heterozygous, homozygous, or compound heterozygous state in patients, thus raising the question of a possible digenic inheritance of the disease in heterozygous patients. Indeed, one of these patients was also carrying a missense mutation in KAL1, the gene responsible for the X chromosome-linked form of Kallmann syndrome. Mutations in PROK2, however, have so far been found only in the heterozygous state. Here, we report on the identification of PROK2 biallelic mutations, that is, a missense mutation, p.R73C, and a frameshift mutation, c.163delA, in two out of 273 patients presenting as sporadic cases. We conclude that PROK2 mutations in the homozygous state account for a few cases of Kallmann syndrome. Moreover, since the same R73C mutation was previously reported in the heterozygous state, and because Prok2 knockout mice exhibit an abnormal phenotype only in the homozygous condition, we predict that patients carrying monoallelic mutations in PROK2 have another disease-causing mutation, presumably in still undiscovered Kallmann syndrome genes.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Biallelic mutations in the prokineticin-2 gene in two sporadic cases of Kallmann syndrome

et al. 2008

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“…Prokineticins (especially PK2) and their receptors are largely expressed in CNS (Cheng et al, 2006) and regulate multiple biological functions in the CNS including hyperalgesia (Mollay et al, 1999), neurogenesis in the olfactory bulb (Ng et al, 2005), neuronal survival (Melchiorri et al, 2001) and inflammation (Martucci et al, 2006). Recent studies have implicated PK2 in human diseases such as, for example, Kallmann syndrome, which can be determined by loss-offunction mutations in the gene encoding for PK2 (Pitteloud et al, 2007) or CNS autoimmune demyelination, in which PK2 has been identified as a critical immune regulator (Abou-Hamdan et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Prokineticins are neuroprotective in models of cerebral ischemia and ischemic tolerance in vitro

Landucci

Lattanzi²,

Gerace

et al. 2016

Neuropharmacology

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“…15,16 In some families, both typical KS phenotypes and dissociated phenotypes with either hypogonadism or anosmia have been described. 7,10,13,14,17 In addition, apparent reversal of the hypogonadism after discontinuation of hormonal treatment has been reported in a few KS patients. 9,18,19 Finally, a variety of non-reproductive non-olfactory additional anomalies are present in only a fraction of KS patients.…”

Section: Clinical Overviewmentioning

confidence: 99%

“…In Prokr2 or Prok2 homozygous knockout mice, and mice carrying Fgfr1 or Fgf8 hypomorphic mutations in the homozygous state, however, the migration of these cells is disrupted too. 14,65,79,80 The mechanism of the putative defect of GnRH cell migration in KS is still conjectural. It could be either a consequence of the early degeneration of olfactory nerve and terminal nerve axons, which act as guiding cues, or a process directly affecting the GnRH cells themselves.…”

Section: Pathophysiologymentioning

confidence: 99%

Kallmann syndrome

2008

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The Kallmann syndrome (KS) combines hypogonadotropic hypogonadism (HH) with anosmia. This is a clinically and genetically heterogeneous disease. KAL1, encoding the extracellular glycoprotein anosmin-1, is responsible for the X chromosome-linked recessive form of the disease. Mutations in FGFR1 or FGF8, encoding fibroblast growth factor receptor-1 and fibroblast growth factor-8, respectively, underlie an autosomal dominant form with incomplete penetrance. Finally, mutations in PROKR2 and PROK2, encoding prokineticin receptor-2 and prokineticin-2, have been found in heterozygous, homozygous, and compound heterozygous states. These two genes are likely to be involved both in monogenic recessive and digenic/oligogenic KS transmission modes. Notably, mutations in any of the above-mentioned KS genes have been found in less than 30% of the KS patients, which indicates that other genes involved in the disease remain to be discovered.

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Loss-of-function mutation in the prokineticin 2 gene causes Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism

Cited by 250 publications

References 28 publications

Biallelic mutations in the prokineticin-2 gene in two sporadic cases of Kallmann syndrome

Biallelic mutations in the prokineticin-2 gene in two sporadic cases of Kallmann syndrome

Prokineticins are neuroprotective in models of cerebral ischemia and ischemic tolerance in vitro

Kallmann syndrome

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