Kallmann Syndrome: Mutations in the Genes Encoding Prokineticin-2 and Prokineticin Receptor-2

Dodé, Catherine; Teixeira, Luis; Levilliers, Jacqueline; Fouveaut, Corinne; Bouchard, Philippe; Kottler, Marie Laure; Lespinasse, James; Lienhardt-Roussie, Anne; Mathieu, M; Moerman, Alexandre; Morgan, Graeme; Murat, A.; Toublanc, J E; Wołczyński, S; Delpech, Marc; Petit, Christine; Young, Jacques; Hardelin, Jean Pierre

doi:10.1371/journal.pgen.0020175

Cited by 403 publications

(263 citation statements)

References 31 publications

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“…Of these putative SCN output pathways, therefore, deficiency of Prokr2 signaling shows the most distinctive and pronounced phenotype, and appropriate synthesis of Prok2 is probably necessary for competent circadian behavior. In R6/2 mice (a model for Huntington's disease) the progressive deterioration of the activity/rest cycle, which mimics that of patients, is accompanied by marked reduction in expression Prok2 mRNA in the SCN (23), and mutation of the human gene encoding Prok2 in Kallmann's syndrome is associated with sleep disturbance (24).…”

Section: Discussionmentioning

confidence: 99%

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Prokineticin receptor 2 (Prokr2) is essential for the regulation of circadian behavior by the suprachiasmatic nuclei

Prosser

Bradley

Chesham

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

130

138

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The suprachiasmatic nucleus (SCN), the brain's principal circadian pacemaker, coordinates adaptive daily cycles of behavior and physiology, including the rhythm of sleep and wakefulness. The cellular mechanism sustaining SCN circadian timing is well characterized, but the neurochemical pathways by which SCN neurons coordinate circadian behaviors remain unknown. SCN transplant studies suggest a role for (unidentified) secreted factors, and one potential candidate is the SCN neuropeptide prokineticin 2 (Prok2). Prok2 and its cognate prokineticin receptor 2 (Prokr2/Gpcr73l1) are widely expressed in both the SCN and its neural targets, and Prok2 is light-regulated. Hence, they may contribute to cellular timing within the SCN, entrainment of the clock, and/or they may mediate circadian output. We show that a targeted null mutation of Prokr2 disrupts circadian coordination of the activity cycle and thermoregulation. Specifically, mice lacking Prokr2 lost precision in timing the onset of nocturnal locomotor activity; and under both a light/dark cycle and continuous darkness, there was a pronounced temporal redistribution of activity away from early to late circadian night. Moreover, the coherence of circadian behavior was significantly reduced, and nocturnal body temperature was depressed. Entrainment by light is not, however, dependent on Prokr2, and bioluminescence real-time imaging of organotypical SCN slices showed that the mutant SCN is fully competent as a circadian oscillator. We conclude that Prokr2 is not necessary for SCN cellular timekeeping or entrainment, but it is an essential link for coordination of circadian behavior and physiology by the SCN, especially in defining the onset and maintenance of circadian night.T he suprachiasmatic nucleus (SCN) of the hypothalamus constitutes an autonomous circadian pacemaker necessary for the maintenance of daily rhythms, including the cycle of sleep and wakefulness (1). The molecular basis of the cellular oscillator of the SCN is broadly characterized, but how the SCN signals circadian time to other sites in the brain and thence to peripheral tissues is unclear (2). Neuroanatomical projections from the SCN run predominantly to local hypothalamic and thalamic structures (3), including the dorsomedial nucleus (DMN), a principal site for the regulation of sleep and wakefulness and circadian arousal by behavioral cues (4, 5). How such ''hard-wired'' connections influence SCN targets remains open to question. Although electrical signaling by means of synaptic contacts is likely important (6), encapsulated SCN grafts unable to form synaptic contacts with host tissues are nevertheless able to establish circadian activity/rest cycles in previously arrhythmic, SCN-lesioned recipients (7). This finding indicates that paracrine factors from the SCN mediate circadian coordination within the brain. A small number of candidate factors have been explored, including TGF-␣ (8) and cardiotrophin-like cytokine (9). These factors are expressed by the SCN on a circadian basis, and local ...

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Section: Discussionmentioning

confidence: 99%

“…Loss of Prok2/Prokr2 disrupts olfactory bulb development and leads to infertility (15,24,26). Disturbed circadian behavior may, therefore, be related indirectly to altered olfactory cues and/or infertility.…”

Section: Discussionmentioning

confidence: 99%

Prokineticin receptor 2 (Prokr2) is essential for the regulation of circadian behavior by the suprachiasmatic nuclei

Prosser

Bradley

Chesham

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

130

138

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“…Prokineticin 2 and its receptor may somehow converge with this pathway to orchestrate the migration and development of GnRH neurons (12). Of note, the prokineticin 2 receptor is not colocalized with the GnRH (6), suggesting that the prokineticin pathway acts on these neurons indirectly, perhaps by establishing a migratory pathway.…”

Section: Genetic Defects Have Been Found In (I) Gnrh Neuron Migratimentioning

confidence: 99%

“…Heterozygous carriers of this PROK2 mutation had normal smell and fertility. In another recent study, Dode et al (12) identified four potential heterozygous PROK2 mutations from a cohort of 192 patients. Of note, neither KAL1 nor PROKR2 mutations were found in the subjects with heterozygous PROK2 mutations.…”

Section: Genetic Defects Have Been Found In (I) Gnrh Neuron Migratimentioning

confidence: 99%

“…Patients with IHH are now being identified with combinatorial mutations in genes that act in the same pathway or at different steps in the reproductive axis. For example, recent studies have documented digenic inheritance of mutations of IHH genes (FGFR1 in combination with GNRHR; FGFR1 in combination with NELF; or FGFR1 in combination with PROKR2) (12,16). These observations suggest the possibility of dose effects of various genes in the pathway of GnRH production, release, or action.…”

Section: Genetic Defects Have Been Found In (I) Gnrh Neuron Migratimentioning

confidence: 99%

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Rites of passage through puberty: A complex genetic ensemble

Jameson

2007

Proc. Natl. Acad. Sci. U.S.A.

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Gonadotropin Hormones: Disorders

Martínez‐Aguayo

Dattani

Achermann

2011

Encyclopedia of Life Sciences

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Abnormalities in gonadotropin hormone release and function can arise from changes in a variety of genes expressed throughout the hypothalamic–pituitary (gonadotrope)–gonadal (HPG) axis. Alterations in these genes can disrupt proteins that are involved in many different biological processes such as neuronal migration, gonadotropin‐releasing hormone (GnRH) release and action, and pituitary development, as well as affecting synthesis and function of the gonadotropin hormones (follicle‐stimulating hormone and luteinising hormone) themselves. The identification and characterisation of these factors is providing important insight into the reproductive axis in humans and may result in improved treatment and counselling for patients with infertility problems. However, the underlying cause of GnRH deficiency or altered gonadotropin action is not currently known in most cases, and it is emerging that digenic or oligogenic inheritance patterns are important in some situations. Therefore, the molecular basis of disorders of gonadotropin hormones may be more complex than originally thought. Key Concepts: The gonadotropins, FSH and LH, are heterodimeric glycoprotein hormones released in pulses from the pituitary gonadotrope cells. FSH and LH secretion is regulated by hypothalamic GnRH, which itself is pulsatile. GnRH‐secreting neurons originate in the olfactory placode and migrate to the hypothalamus during development; defects affecting neuronal migration can be associated with a lack of smell (anosmia). Gonadotropes develop within the anterior pituitary gland, which originates from the oral ectoderm; defects affecting gonadotrope function can be associated with other pituitary hormone deficiencies. FSH and LH act through peripheral G protein‐coupled receptors to stimulate gonad development and function. Some factors can influence the hypothalamic–pituitary–gonadal axis at multiple levels. More than 30 single gene disorders affecting gonadotropin function have now been described, often affecting receptor‐ligand pairs. Phenotypic penetrance can be variable, even within families and may reflect the influence of modifier genes, epigenetic factors or environmental stimuli. In some situations, changes in two genes can result in a clinical phenotype (digenic inheritance). In many cases the underlying molecular basis of hypogonadism is still unknown.

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Kallmann Syndrome: Mutations in the Genes Encoding Prokineticin-2 and Prokineticin Receptor-2

Cited by 403 publications

References 31 publications

Prokineticin receptor 2 (Prokr2) is essential for the regulation of circadian behavior by the suprachiasmatic nuclei

Prokineticin receptor 2 (Prokr2) is essential for the regulation of circadian behavior by the suprachiasmatic nuclei

Rites of passage through puberty: A complex genetic ensemble

Gonadotropin Hormones: Disorders

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