Mutations in<i>Prokineticin 2</i>and<i>Prokineticin receptor 2</i>genes in Human Gonadotrophin-Releasing Hormone Deficiency: Molecular Genetics and Clinical Spectrum

Cole, Lindsay W.; Sidis, Yisrael; Zhang, Chengkang; Quinton, Richard; Plummer, Lacey; Pignatelli, Duarte; Hughes, Virginia; Dwyer, Andrew A.; Raivio, Taneli; Hayes, Frances J.; Seminara, Stephanie B.; Huot, Céline; Alos, Nathalie; Speiser, Phyllis; Takeshita, Akira; Vanvliet, G.; Pearce, Simon H. S.; Crowley, William F.; Zhou, Qun‐Yong; Pitteloud, Nelly

doi:10.1210/jc.2007-2654

Cited by 202 publications

(229 citation statements)

References 39 publications

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“…Genes encoding fibroblast growth factor 8 (FGF8) signalling pathway proteins, [17][18][19][20][21][22] chromodomain helicase DNA-binding protein 7 (CHD7) [23][24][25][26][27] and sex determining region Y-Box 10 (SOX10) 28,29 affect the neurogenic niche in the nasal area and craniofacial development. Conversely, Kallmann syndrome protein, which is now officially known as anosmin 1 (encoded by KAL1; following nomenclature change, the gene is now denoted as ANOS1), 2 prokineticin-2 and prokineticin receptor 2 (encoded by PROK2 and PROKR2, respectively), [30][31][32][33] WD repeat domain 11 (encoded by WDR11), 34,35 semaphorin 3A (encoded by SEMA3A) [36][37][38] and FEZ family zinc finger 1 (encoded by FEZF1) 39 influence migration of GnRH neurons.…”

Section: Biology Of the Gnrh Neuronal Systemmentioning

confidence: 99%

“…117,118 To date, >25 different genes have been implicated in Kallmann syndrome and/or CHH, which accounts for ~50% of cases. 21 Causative genes for Kallmann syndrome include: KAL1 (ANOS1) in the X-linked form; FGFR1 (encoding fibroblast growth factor receptor 1), 17,18 FGF8, 19,119 CHD7, [23][24][25][26][27] HS6ST1 (encoding heparan-sulphate 6-O-sulphotransferase 1), 20 SOX10, 28,29 SEMA3A (encoding semaphorin-3A), [36][37][38] WDR11 (encoding WD repeat-containing protein 11) 34,35 and IL17RD (encoding interleukin-17 receptor D) 21 in the autosomal dominant form; and PROKR2 and/or PROK2, [30][31][32][33] and FEZF1 39 in the autosomal recessive form, even though it should be noted that most patients carrying mutations in PROKR2 or PROK2 carry these mutations in the heterozygous state. 120,121 Genes involved in CHH that are associated with a normal sense of smell include GNRHR (encoding gonadotropinreleasing hormone receptor), 122,123 GNRH1 (encoding gonadotropin-releasing hormone 1), 124,125 KISS1R, 41,42 KISS1, 40,126 TACR3 and TAC3.…”

Section: Genetics Of Chhmentioning

confidence: 99%

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European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

et al. 2015

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| Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder caused by the deficient production, secretion or action of gonadotropin-releasing hormone (GnRH), which is the master hormone regulating the reproductive axis. CHH is clinically and genetically heterogeneous, with >25 different causal genes identified to date. Clinically, the disorder is characterized by an absence of puberty and infertility. The association of CHH with a defective sense of smell (anosmia or hyposmia), which is found in ~50% of patients with CHH is termed Kallmann syndrome and results from incomplete embryonic migration of GnRHsynthesizing neurons. CHH can be challenging to diagnose, particularly when attempting to differentiate it from constitutional delay of puberty. A timely diagnosis and treatment to induce puberty can be beneficial for sexual, bone and metabolic health, and might help minimize some of the psychological effects of CHH. In most cases, fertility can be induced using specialized treatment regimens and several predictors of outcome have been identified. Patients typically require lifelong treatment, yet ~10-20% of patients exhibit a spontaneous recovery of reproductive function. This Consensus Statement summarizes approaches for the diagnosis and treatment of CHH and discusses important unanswered questions in the field.

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Section: Biology Of the Gnrh Neuronal Systemmentioning

confidence: 99%

Section: Genetics Of Chhmentioning

confidence: 99%

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

et al. 2015

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“…Deleterious effects on prokineticin signalling, however, have subsequently been shown in vitro for nearly all the missense mutations. 67,68 The finding, for given PROKR2 and PROK2 mutations, of both heterozygous and homozygous (or compound heterozygous) unrelated patients 10,69 is quite remarkable, and argues in favour of a digenic or oligogenic mode of inheritance in heterozygous patients. To date, digenic inheritance of KS has been shown in three such patients, who had monoallelic missense mutations both in PROKR2 and PROK2, 67 FGFR1 (C Dodé, unpublished), or KAL1.…”

Section: The Complex Genetics Of Ksmentioning

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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“…2). However, there have been several reports over the years of families in which some members have Kallmann's syndrome, while others have normal or apparently normal olfaction (not always assessed by semi-quantitative olfactometry) (2, 3, 18,24,30,[128][129][130]. Since the discovery of five genetic specific causes of Kallmann's syndrome, it has been established that this dissociation between the two cardinal signs of Kallmann's syndrome is mainly seen in patients with autosomal forms, while in X-linked forms with documented KAL1 mutations, the two cardinal signs are almost always present together (17,18,25).…”

Section: Gnrh1 Mutations As a Cause Of Chh In Humansmentioning

confidence: 99%

“…Indeed, they described a patient who was heterozygous for the p.L173R loss-of-function mutation in PROKR2 that also carried a missense mutation, p.S396L, in KAL1 exon 8. Since then, digenic inheritance has been shown in other Kallmann's syndrome or normosmic CHH patients who beared mutations in both PROKR2 and PROK2 or in FGFR1 and NELF or GNRHR (132) as well as in PROKR2 and GNRH1, GNRHR, or KISS1R (30,127,129). Defects in different genes could act synergistically to induce the CHH or the Kallmann's syndrome phenotype, or to modify the severity of the GNRH deficiency, partially explaining the phenotypic variability observed within and across families with CHH and Kallmann's syndrome.…”

Section: Digenic Inheritancementioning

confidence: 99%

Non-syndromic congenital hypogonadotropic hypogonadism: clinical presentation and genotype–phenotype relationships

Brioude

Bouligand

Trabado

et al. 2010

European Journal of Endocrinology

102

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Congenital hypogonadotropic hypogonadism (CHH) results from abnormal gonadotropin secretion, and it is characterized by impaired pubertal development. CHH is caused by defective GNRH release, or by a gonadotrope cell dysfunction in the pituitary. Identification of genetic abnormalities related to CHH has provided major insights into the pathways critical for the development, maturation, and function of the reproductive axis. Mutations in five genes have been found specifically in Kallmann's syndrome, a disorder in which CHH is related to abnormal GNRH neuron ontogenesis and is associated with anosmia or hyposmia.In combined pituitary hormone deficiency or in complex syndromic CHH in which gonadotropin deficiency is either incidental or only one aspect of a more complex endocrine disorder or a nonendocrine disorder, other mutations affecting GNRH and/or gonadotropin secretion have been reported.Often, the CHH phenotype is tightly linked to an isolated deficiency of gonadotropin secretion. These patients, who have no associated signs or hormone deficiencies independent of the deficiency in gonadotropin and sex steroids, have isolated CHH. In some familial cases, they are due to genetic alterations affecting GNRH secretion (mutations in GNRH1, GPR54/KISS1R and TAC3 and TACR3) or the GNRH sensitivity of the gonadotropic cells (GNRHR). A minority of patients with Kallmann's syndrome or a syndromic form of CHH may also appear to have isolated CHH, but close clinical, familial, and genetic studies can reorient the diagnosis, which is important for genetic counseling in the context of assisted reproductive medicine.This review focuses on published cases of isolated CHH, its clinical and endocrine features, genetic causes, and genotype-phenotype relationships.

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Mutations inProkineticin 2andProkineticin receptor 2genes in Human Gonadotrophin-Releasing Hormone Deficiency: Molecular Genetics and Clinical Spectrum

Abstract: Loss-of-function mutations in PROK2 and PROKR2 underlie both KS and nIHH.

Cited by 202 publications

References 39 publications

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

Kallmann syndrome

Non-syndromic congenital hypogonadotropic hypogonadism: clinical presentation and genotype–phenotype relationships

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