Publications by authors named "Nicolas de Roux"

48 Publications

Prevalence and course of thyroid dysfunction in neonates at high risk of Graves' disease or with non-autoimmune hyperthyroidism.

Eur J Endocrinol 2021 Mar;184(3):431-440

Assistance Publique-Hôpitaux de Paris, Robert Debré University Hospital, Endocrinology-Diabetology Department, Reference Center for Growth and Development Endocrine Diseases, Paris, France.

Objective: Neonatal hyperthyroidism may be caused by a permanent non-autoimmune genetic disorder or, more frequently, by maternally transmitted high serum TRAb levels. Variable thyroid dysfunction may be observed in this second context. We aimed to evaluate the prevalence of neonatal non-autoimmune hyperthyroidism and of the different types of thyroid function in neonates with a high risk of hyperthyroidism due to maternal Graves' disease (GD).

Design And Methods: This observational cohort study included all neonates identified in the database of a single academic pediatric care center, over a period of 13 years, as having non-autoimmune hyperthyroidism or an autoimmune disorder with high TRAb levels (above 6 IU/L) transmitted by their mothers. Patients were classified as having neonatal hyperthyroidism, hypothyroidism, or euthyroidism with a permanent or transient disorder.

Results: Two of the 34 consecutive neonates selected (6%) had permanent non-autoimmune hyperthyroidism due to germline (n = 1) or somatic (n = 1) mutations of the TSH receptor gene. The patients with high serum TRAb levels at birth had transient hyperthyroidism (n = 23), hypothyroidism (primary n = 2, central n = 3) or persistent euthyroidism (n = 4).

Conclusion: These original findings highlight the need for careful and appropriate monitoring of thyroid function in the long term, not only for the rare patients with non-autoimmune neonatal hyperthyroidism, but also for repeat monitoring during the first month of life in neonates with maternally transmitted high TRAb levels, to ensure the early identification of thyrotoxicosis in more than two thirds of cases and to detect primary or central hypothyroidism, thereby potentially decreasing associated morbidity.
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http://dx.doi.org/10.1530/EJE-20-1320DOI Listing
March 2021

Prevalence and clinical characteristics of isolated forms of central precocious puberty: a cohort study at a single academic center.

Eur J Endocrinol 2021 Feb;184(2):243-251

Assistance Publique-Hôpitaux de Paris, Robert Debré University Hospital, Endocrinology-Diabetology Department, Reference Center for Growth and Development Endocrine Diseases, Paris, France.

Objective: Isolated central precocious puberty (CPP) includes sporadic, familial and adoption-related forms, and the characterization of its etiology is challenging. This study investigated the prevalence and clinical characteristics of isolated CPP.

Design And Methods: This observational cohort study included all patients (n = 395) with CPP included in the database of a single academic pediatric care center over a period of 11.5 years.

Results: In total, 332 of the 395 patients (84%) had isolated forms of CPP; the proportion of male patients was lower in this group than for non-isolated CPP (4 vs 33%, P < 0.0001). These patients had sporadic (n = 228, 68.5%), familial (n = 82, 25%) or adoption-related (n = 22, 6.5%) forms. Clinical characteristics at diagnosis were similar between groups, but girls with sporadic CPP were older at referral than those with familial or adoption-related CPP (P < 0.02), and birth weight SDS was lower in adopted patients than in those from the sporadic and familial groups (P < 0.01). In the 72 families containing patients with familial forms, both recessive and dominant transmissions were observed between first-degree relatives. Potential maternal or paternal transmission was identified in two-thirds of the studied families, in similar proportions. An autosomal dominant mode of transmission with low penetrance was suggested by the high proportion of affected parents (33 of the 72 families, 46%). Clinical presentation was similar whatever the mode of inheritance.

Conclusion: These findings highlight the need for careful monitoring of the various forms of CPP. Future studies should explore pathophysiological mechanisms, particularly for familial forms.
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http://dx.doi.org/10.1530/EJE-20-0862DOI Listing
February 2021

High prevalence of syndromic disorders in patients with non-isolated central precocious puberty.

Eur J Endocrinol 2018 Dec;179(6):373-380

Assistance Publique-Hôpitaux de Paris, Robert Debré University Hospital, Endocrinology-Diabetology Department, Reference Center for Endocrine Growth and Developmental Diseases, Paris, France.

Objective Non-idiopathic CPP is caused by acquired or congenital hypothalamic lesions visible on MRI or is associated with various complex genetic and/or syndromic disorders. This study investigated the different types and prevalence of non-isolated CPP phenotypes. Design and Methods This observational cohort study included all patients identified as having non-idiopathic CPP in the database of a single academic pediatric care center over a period of 11.5 years. Patients were classified on the basis of MRI findings for the CNS as having either hypothalamic lesions or complex syndromic phenotypes without structural lesions of the hypothalamus. Results In total, 63 consecutive children (42 girls and 21 boys) with non-isolated CPP were identified. Diverse diseases were detected, and the hypothalamic lesions visible on MRI (n = 28, 45% of cases) included hamartomas (n = 17; either isolated or with an associated syndromic phenotype), optic gliomas (n = 8; with or without neurofibromatosis type 1), malformations (n = 3) with interhypothalamic adhesions (n = 2; isolated or associated with syndromic CNS midline abnormalities, such as optic nerve hypoplasia, ectopic posterior pituitary) or arachnoid cysts (n = 1). The patients with non-structural hypothalamic lesions (n = 35, 55% of cases) had narcolepsy (n = 9), RASopathies (n = 4), encephalopathy or autism spectrum disorders with or without chromosomal abnormalities (n = 15) and other complex syndromic disorders (n = 7). Conclusion Our findings suggest that a large proportion (55%) of patients with non-isolated probable non-idiopathic CPP may have complex disorders without structural hypothalamic lesions on MRI. Future studies should explore the pathophysiological relevance of the mechanisms underlying CPP in these disorders.
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http://dx.doi.org/10.1530/EJE-18-0613DOI Listing
December 2018

Complete Kisspeptin Receptor Inactivation Does Not Impede Exogenous GnRH-Induced LH Surge in Humans.

J Clin Endocrinol Metab 2018 12;103(12):4482-4490

Paris Diderot University, Sorbonne Paris Cité, U1141, Inserm, Paris, France.

Context: Mutations in the kisspeptin receptor (KISS1R) gene have been reported in a few patients with normosmic congenital hypogonadotropic hypogonadism (nCHH) (OMIM #146110).

Objectives: To describe a female patient with nCHH and a novel homozygous KISS1R mutation and to assess the role of kisspeptin pathway to induce an ovulation by GnRH pulse therapy.

Design, Setting, And Intervention: Observational study of a patient including genetic and kisspeptin receptor functions and treatment efficiency using a GnRH pump.

Main Outcome Measure: Response to pulsatile GnRH therapy.

Results: A partial isolated gonadotropic deficiency was diagnosed in a 28-year-old woman with primary amenorrhea and no breast development. A novel homozygous c.953T>C variant was identified in KISS1R. This mutation led to substitution of leucine 318 for proline (p.Leu318Pro) in the seventh transmembrane domain of KISS1R. Signaling via the mutated receptor was profoundly impaired in HEK293-transfected cells. The mutated receptor was not detected on the membrane of HEK293-transfected cells. After several pulsatile GnRH therapy cycles, an LH surge with ovulation and pregnancy was obtained.

Conclusion: GnRH pulsatile therapy can induce an LH surge in a woman with a mutated KISS1R, which was previously thought to be completely inactivated in vivo.
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http://dx.doi.org/10.1210/jc.2018-00410DOI Listing
December 2018

Cerebellar hypoplasia with endosteal sclerosis is a POLR3-related disorder.

Eur J Hum Genet 2017 08 7;25(8):1011-1014. Epub 2017 Jun 7.

Service de Génétique Clinique, Hôpital Jeanne de Flandre, CHU Lille, Lille, France.

CHES (cerebellar hypoplasia with endosteal sclerosis) syndrome (OMIM#213002) associates hypomyelination, cerebellar atrophy, hypogonadism and hypodontia. So far, only five patients have been described. The condition is of neonatal onset. Patients have severe psychomotor delay and moderate to severe intellectual disability. Inheritance is assumed to be autosomal recessive due to recurrence in sibs, consanguinity of parents and absence of vertical transmission. CHES syndrome is reminiscent of 4H-leukodystrophy, a recessive-inherited affection due to variations in genes encoding subunits of the RNA polymerase III (POLR3A-POLR3B-POLR1C). POLR3B variants have been identified in one CHES patient. Here we report on a novel CHES patient, carrying compound heterozygous variations in POLR3B. This report confirms affiliation of CHES to POLR3-related disorders and suggests that CHES syndrome represents a severe form of 4H-leukodystrophy.
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http://dx.doi.org/10.1038/ejhg.2017.73DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567146PMC
August 2017

Rabconnectin-3α is required for the morphological maturation of GnRH neurons and kisspeptin responsiveness.

Sci Rep 2017 02 17;7:42463. Epub 2017 Feb 17.

Univ Paris Diderot, Sorbonne Paris Cité, U1141, Inserm, F- 75019, Paris, France.

A few hundred hypothalamic neurons form a complex network that controls reproduction in mammals by secreting gonadotropin-releasing hormone (GnRH). Timely postnatal changes in GnRH secretion are essential for pubertal onset. During the juvenile period, GnRH neurons undergo morphological remodeling, concomitantly achieving an increased responsiveness to kisspeptin, the main secretagogue of GnRH. However, the link between GnRH neuron activity and their morphology remains unknown. Here, we show that brain expression levels of Dmxl2, which encodes the vesicular protein rabconnectin-3α, determine the capacity of GnRH neurons to be activated by kisspeptin and estradiol. We also demonstrate that Dmxl2 expression levels control the pruning of GnRH dendrites, highlighting an unexpected role for a vesicular protein in the maturation of GnRH neuronal network. This effect is mediated by rabconnectin-3α in neurons or glial cells afferent to GnRH neurons. The widespread expression of Dmxl2 in several brain areas raises the intriguing hypothesis that rabconnectin-3α could be involved in the maturation of other neuronal populations.
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http://dx.doi.org/10.1038/srep42463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5314327PMC
February 2017

Genotype-Phenotype Relationship in Patients and Relatives with SHOX Region Anomalies in the French Population.

Horm Res Paediatr 2016 28;86(5):309-318. Epub 2016 Sep 28.

Department of Pediatrics and Medical Genetics, Brabois Hospital, Vandoeuvre-lès-Nancy, France.

Background: The aim of our study was to describe a large population with anomalies involving the SHOX region, responsible for idiopathic short stature and Léri-Weill dyschondrosteosis (LWD), and to identify a possible genotype/phenotype correlation.

Methods: We performed a retrospective multicenter study on French subjects with a SHOX region anomaly diagnosed by multiplex ligation-dependent probe amplification or Sanger sequencing. Phenotypes were collected in each of the 7 genetic laboratories practicing this technique for SHOX analysis.

Results: Among 205 index cases and 100 related cases, 91.3% had LWD. For index cases, median age at evaluation was 11.7 (9.0; 15.9) years and mean height standard deviation score was -2.3 ± 1.1. A deletion of either SHOX or PAR1 or both was found in 74% of patients. Duplications and point mutations/indels affected 8 and 18% of the population, respectively. Genotype-phenotype correlation showed that deletions were more frequently associated with Madelung deformity and mesomelic shortening in girls, as well as with presence of radiologic anomalies, than duplications.

Conclusions: Our results highlight genotype-phenotype relationships in the French population with a SHOX defect and provide new information showing that clinical expression is milder in cases of duplication compared to deletions.
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http://dx.doi.org/10.1159/000448282DOI Listing
April 2017

IGSF10 mutations dysregulate gonadotropin-releasing hormone neuronal migration resulting in delayed puberty.

EMBO Mol Med 2016 06 1;8(6):626-42. Epub 2016 Jun 1.

Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK

Early or late pubertal onset affects up to 5% of adolescents and is associated with adverse health and psychosocial outcomes. Self-limited delayed puberty (DP) segregates predominantly in an autosomal dominant pattern, but the underlying genetic background is unknown. Using exome and candidate gene sequencing, we have identified rare mutations in IGSF10 in 6 unrelated families, which resulted in intracellular retention with failure in the secretion of mutant proteins. IGSF10 mRNA was strongly expressed in embryonic nasal mesenchyme, during gonadotropin-releasing hormone (GnRH) neuronal migration to the hypothalamus. IGSF10 knockdown caused a reduced migration of immature GnRH neurons in vitro, and perturbed migration and extension of GnRH neurons in a gnrh3:EGFP zebrafish model. Additionally, loss-of-function mutations in IGSF10 were identified in hypothalamic amenorrhea patients. Our evidence strongly suggests that mutations in IGSF10 cause DP in humans, and points to a common genetic basis for conditions of functional hypogonadotropic hypogonadism (HH). While dysregulation of GnRH neuronal migration is known to cause permanent HH, this is the first time that this has been demonstrated as a causal mechanism in DP‡.
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http://dx.doi.org/10.15252/emmm.201606250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4888853PMC
June 2016

Congenital Hypogonadotropic Hypogonadism: A Trait Shared by Several Complex Neurodevelopmental Disorders.

Endocr Dev 2016 17;29:72-86. Epub 2015 Dec 17.

Reproductive function depends on the activity of the gonadotropic axis, which is controlled by a hypothalamic neural network whose main function is to regulate the secretion of gonadotropin-releasing hormone (GnRH). This endocrine network is not mature at birth, and several phases of activation-inactivation of the gonadotropic axis are necessary for its normal development. The postnatal maturation of the GnRH network lies under the control of a neurodevelopmental program that starts in fetal life and ends at puberty. There are many clinical situations in which this program is interrupted, leading to congenital hypogonadotropic hypogonadism (CHH) and an absence of puberty. For many years, attention has mainly been focused on the genetics of isolated CHH. More recently, the emergence of new genomics techniques has led to the description of genetic defects in very rare syndromes in which CHH is associated with complex neurological dysfunctions. Here, we review the clinical phenotype and genetic defects linked to such syndromic CHH. This analysis highlights the close link between the ubiquitin pathway, synaptic proteins and CHH, as well as unexpected mutations in genes encoding nucleolar proteins.
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http://dx.doi.org/10.1159/000438875DOI Listing
July 2016

Mutations in the maternally imprinted gene MKRN3 are common in familial central precocious puberty.

Eur J Endocrinol 2016 Jan 1;174(1):1-8. Epub 2015 Oct 1.

AP-HPService d'Endocrinologie Diabétologie Pédiatrique, Centre de Référence des Maladies Endocriniennes Rares de la Croissance, Hôpital Robert Debré, Paris F-75019, FranceUniversité Paris DiderotSorbonne Paris Cité F-75019, FranceInstitut National de la Santé et de la Recherche Médicale (INSERM)Unité 1141, DHU Protect, Paris F-75019, FranceAP-HPINSERM U1141, Laboratoire de Biochimie, Hôpital Robert Debré, 48 Boulevard Sérurier, Paris F-75019, FranceAP-HPExplorations Fonctionnelles Endocriniennes, Hôpital Armand Trousseau, Paris F-75012, FranceCentre d'Endocrinologie Pédiatrique14 Rue du Rempart St-Etienne, Toulouse F-31000, FrancePediatric Endocrinology UnitGaetano Rummo Hospital, Benevento 82100, ItalyPediatric Endocrinology UnitFederico II University, Naples 80131, ItalyService de Pédiatrie MultidisciplinaireCentre de Référence des Maladies Rares d'Origine Hypophysaire, Assistance Publique-Hopitaux de Marseille (APHM), Hôpital de la Timone, Aix-Marseille Université, Marseille F-13385, France AP-HPService d'Endocrinologie Diabétologie Pédiatrique, Centre de Référence des Maladies Endocriniennes Rares de la Croissance, Hôpital Robert Debré, Paris F-75019, FranceUniversité Paris DiderotSorbonne Paris Cité F-75019, FranceInstitut National de la Santé et de la Recherche Médicale (INSERM)Unité 1141, DHU Protect, Paris F-75019, FranceAP-HPINSERM U1141, Laboratoire de Biochimie, Hôpital Robert Debré, 48 Boulevard Sérurier, Paris F-75019, FranceAP-HPExplorations Fonctionnelles Endocriniennes, Hôpital Armand Trousseau, Paris F-75012, FranceCentre d'Endocrinologie Pédiatrique14 Rue du Rempart St-Etienne, Toulouse F-31000, FrancePediatric Endocrinology UnitGaetano Rummo Hospital, Benevento 82100, ItalyPediatric Endocrinology UnitFederico II University, Naples 80131, ItalyService de Pédiatrie MultidisciplinaireCentre de Référence des Maladies Rares d'Origine Hypophysaire, Assistance Publique-Hopitaux de Marseille (APHM), Hôpital de la T

Context And Objective: Idiopathic central precocious puberty (iCPP) is defined as early activation of the hypothalamic-pituitary-gonadal axis in the absence of identifiable central lesions. Mutations of the makorin RING finger 3 (MKRN3) gene are associated with iCPP. We aimed to assess the frequency of MKRN3 mutations in iCPP and to compare the phenotypes of patients with and without MKRN3 mutations.

Design: An observational study was carried out on patients recruited at pediatric hospitals in France and Italy. Forty-six index CPP cases were screened for mutations in the MKRN3 coding sequence: 28 index cases of familial cases and 18 cases did not report any familial history of CPP. The endocrine phenotype was compared between MKRN3 mutated and non-mutated patients.

Results: MKRN3 mutations were identified in one sporadic and 13 familial cases. We identified five new heterozygous missense mutations predicted to be deleterious for protein function and two frameshift mutations, one new and the other recurrent, predicted to result in truncated proteins. Age at puberty onset varied very little among patients with MKRN3 mutations and puberty occurred earlier in these patients than in those without MKRN3 mutations (6.0 years (5.4-6.0) vs 7.0 years (6.0-7.0), P=0.01).

Conclusions: MKRN3 mutations are common in familial iCPP. MKRN3 is one of the gatekeepers of the postnatal activation of the gonadotropic axis.
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http://dx.doi.org/10.1530/EJE-15-0488DOI Listing
January 2016

Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism--pathogenesis, diagnosis and treatment.

Nat Rev Endocrinol 2015 Sep 21;11(9):547-64. Epub 2015 Jul 21.

Bicêtre Hospital, France.

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 GnRH-synthesizing 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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http://dx.doi.org/10.1038/nrendo.2015.112DOI Listing
September 2015

Rational design of triazololipopeptides analogs of kisspeptin inducing a long-lasting increase of gonadotropins.

J Med Chem 2015 Apr 13;58(8):3459-70. Epub 2015 Apr 13.

‡Centre de Biophysique Moléculaire (CNRS UPR4301), Rue Charles Sadron, F-45071 Orléans Cedex 2, France.

New potent and selective KISS1R agonists were designed using a combination of rational chemical modifications of the endogenous neuropeptide kisspeptin 10 (KP10). Improved resistance to degradation and presumably reduced renal clearance were obtained by introducing a 1,4-disubstituted 1,2,3-triazole as a proteolysis-resistant amide mimic and a serum albumin-binding motif, respectively. These triazololipopeptides are highly potent full agonists of KISS1R and are >100 selective over the closely related NPFF1R. When injected in ewes with a quiescent reproductive system, the best compound of our series induced a much prolonged increase of luteinizing hormone release compared to KP10 and increased follicle-stimulating hormone plasma concentration. Hence, this KISS1R agonist is a new valuable pharmacological tool to explore the potential of KP system in reproduction control. Furthermore, it represents the first step to develop drugs treating reproductive system disorders due to a reduced activity of the hypothalamo-pituitary-gonadal axis such as delayed puberty, hypothalamic amenorrhea, and hypogonadotropic hypogonadism.
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http://dx.doi.org/10.1021/jm5019675DOI Listing
April 2015

Congenital hypogonadotropic hypogonadism with split hand/foot malformation: a clinical entity with a high frequency of FGFR1 mutations.

Genet Med 2015 Aug 13;17(8):651-9. Epub 2014 Nov 13.

1] Harvard Reproductive Endocrine Sciences Center and the Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA [2] Department of Endocrinology, Diabetology and Metabolism, Lausanne University Hospital (CHUV), Lausanne, Switzerland [3] Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.

Purpose: Congenital hypogonadotropic hypogonadism (CHH) and split hand/foot malformation (SHFM) are two rare genetic conditions. Here we report a clinical entity comprising the two.

Methods: We identified patients with CHH and SHFM through international collaboration. Probands and available family members underwent phenotyping and screening for FGFR1 mutations. The impact of identified mutations was assessed by sequence- and structure-based predictions and/or functional assays.

Results: We identified eight probands with CHH with (n = 3; Kallmann syndrome) or without anosmia (n = 5) and SHFM, seven of whom (88%) harbor FGFR1 mutations. Of these seven, one individual is homozygous for p.V429E and six individuals are heterozygous for p.G348R, p.G485R, p.Q594*, p.E670A, p.V688L, or p.L712P. All mutations were predicted by in silico analysis to cause loss of function. Probands with FGFR1 mutations have severe gonadotropin-releasing hormone deficiency (absent puberty and/or cryptorchidism and/or micropenis). SHFM in both hands and feet was observed only in the patient with the homozygous p.V429E mutation; V429 maps to the fibroblast growth factor receptor substrate 2α binding domain of FGFR1, and functional studies of the p.V429E mutation demonstrated that it decreased recruitment and phosphorylation of fibroblast growth factor receptor substrate 2α to FGFR1, thereby resulting in reduced mitogen-activated protein kinase signaling.

Conclusion: FGFR1 should be prioritized for genetic testing in patients with CHH and SHFM because the likelihood of a mutation increases from 10% in the general CHH population to 88% in these patients.
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http://dx.doi.org/10.1038/gim.2014.166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4430466PMC
August 2015

Haploinsufficiency of Dmxl2, encoding a synaptic protein, causes infertility associated with a loss of GnRH neurons in mouse.

PLoS Biol 2014 Sep 23;12(9):e1001952. Epub 2014 Sep 23.

Inserm, U1141, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Hôpital Robert Debré, Paris, France; AP-HP, Laboratoire de Biochimie, Hôpital Robert Debré, Paris, France.

Characterization of the genetic defects causing gonadotropic deficiency has made a major contribution to elucidation of the fundamental role of Kisspeptins and Neurokinin B in puberty onset and reproduction. The absence of puberty may also reveal neurodevelopmental disorders caused by molecular defects in various cellular pathways. Investigations of these neurodevelopmental disorders may provide information about the neuronal processes controlling puberty onset and reproductive capacity. We describe here a new syndrome observed in three brothers, which involves gonadotropic axis deficiency, central hypothyroidism, peripheral demyelinating sensorimotor polyneuropathy, mental retardation, and profound hypoglycemia, progressing to nonautoimmune insulin-dependent diabetes mellitus. High-throughput sequencing revealed a homozygous in-frame deletion of 15 nucleotides in DMXL2 in all three affected patients. This homozygous deletion was associated with lower DMXL2 mRNA levels in the blood lymphocytes of the patients. DMXL2 encodes the synaptic protein rabconnectin-3α, which has been identified as a putative scaffold protein for Rab3-GAP and Rab3-GEP, two regulators of the GTPase Rab3a. We found that rabconnectin-3α was expressed in exocytosis vesicles in gonadotropin-releasing hormone (GnRH) axonal extremities in the median eminence of the hypothalamus. It was also specifically expressed in cells expressing luteinizing hormone (LH) and follicle-stimulating hormone (FSH) within the pituitary. The conditional heterozygous deletion of Dmxl2 from mouse neurons delayed puberty and resulted in very low fertility. This reproductive phenotype was associated with a lower number of GnRH neurons in the hypothalamus of adult mice. Finally, Dmxl2 knockdown in an insulin-secreting cell line showed that rabconnectin-3α controlled the constitutive and glucose-induced secretion of insulin. In conclusion, this study shows that low levels of DMXL2 expression cause a complex neurological phenotype, with abnormal glucose metabolism and gonadotropic axis deficiency due to a loss of GnRH neurons. Our findings identify rabconectin-3α as a key controller of neuronal and endocrine homeostatic processes.
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http://dx.doi.org/10.1371/journal.pbio.1001952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4172557PMC
September 2014

Functional characterization of the novel sequence variant p.S304R in the hinge region of TSHR in a congenital hypothyroidism patients and analogy with other formerly known mutations of this gene portion.

J Pediatr Endocrinol Metab 2015 Jul;28(7-8):777-84

Context: Thyroid dysgenesis may be associated with loss-of-function mutations in the thyrotropin receptor (TSHR) gene.

Objectives: The aim of this study was to characterize a novel TSHR gene variant found in one patient harboring congenital hypothyroidism (CH) from a cohort of patients with various types of thyroid defects.

Materials And Methods: This cross-sectional cohort study involved 118 patients with CH and their family members, including 45 with familial and 73 with sporadic diseases. The thyroid gland was normal in 23 patients, 25 patients had hypoplasia, 25 hemithyroid agenesis, 21 had athyreosis, and 21 had ectopy. Genomic DNA was extracted, and 10 exons of the TSHR gene were amplified and sequenced. Mutations in other candidate genes were investigated. Ortholog alignment was performed, and TSHR functional assays were evaluated.

Results: We identified one previously unknown missense variation in the hinge region (HinR) of the TSHR gene (p.S304R) in one patient with thyroid hypoplasia. This variant is conserved in our ortholog alignment. However, the p.S304R TSHR variant presented a normal glycosylation pattern and signal transduction activity in functional analysis.

Conclusion: We report the ocurrence of a novel nonsynonymous substitution in the HinR of the large N-terminal extracellular domain of the TSHR gene in a patient with thyroid hypoplasia. In contrast with four others in whom TSHR mutations of the hinge portion were previously identified, the p.S304R TSHR variation neither affected TSH binding nor cAMP pathway activation. This TSHR gene variant was documented in a CH patient, but the current data do not support its role in the clinical phenotype.
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http://dx.doi.org/10.1515/jpem-2014-0194DOI Listing
July 2015

Absence of GPR54 and TACR3 mutations in sporadic cases of idiopathic central precocious puberty.

Horm Res Paediatr 2014 10;81(3):177-81. Epub 2014 Jan 10.

Division of Endocrinology, Metabolism and Diabetes, 1st Department of Pediatrics, University of Athens, Aghia Sophia Children's Hospital, Athens, Greece.

Background/aims: Kisspeptin (KISS1)/GPR54 (KISSR) signaling complex and neurokinin B (NKB)/NKB receptor (TACR3) signaling have been proposed as an integral part of the network coordinating GnRH release. GPR54 (KISS1R) and TACR3 gene mutations have been described in cases of idiopathic hypogonadotrophic hypogonadism, while limited data exist on gain-of-function mutation in GPR54 (KISS1R) gene causing idiopathic central precocious puberty (ICPP). No data on TACR3 mutations in ICPP have been described so far. The aim of this study was to elucidate the possible impact of GPR54 (KISS1R) and TACR3 mutations in ICPP.

Methods: PCR-amplified genomic DNA of 38 girls with ICPP was analyzed for GPR54 and TACR3 gene mutations.

Results: No GPR54 or TACR3 mutations were found. The A/G coding sequence single nucleotide polymorphism (SNP) on the GPR54 gene (dbSNP ID: rs10407968) was found in 2 patients with ICPP.

Conclusion: Our data indicate that GPR54 and TACR3 gene mutations are not a frequent cause of ICPP. The identified A/G synonymous SNP (dbSNP ID: rs10407968) located in exon 1 of the gene is not likely to have a pathogenic role in exon splicing and therefore in the premature initiation of puberty.
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http://dx.doi.org/10.1159/000356913DOI Listing
December 2014

Somatostatin receptors type 2 and 5 expression and localization during human pituitary development.

Endocrinology 2014 Jan 20;155(1):33-9. Epub 2013 Dec 20.

Medical Research Council Centre for Synaptic Plasticity (S.P.), University of Bristol, School of Physiology and Pharmacology, Bristol BS8 1TD, United Kingdom; Inserm (S.P., F.G., Z.C., S.J., A.F., L.S., N.d.R., P.G., S.A., P.D.), U676, 75019 Paris, France; University Paris Diderot (S.P., F.G., Z.C., S.J., A.F., L.S., N.d.R., P.G., S.A., P.D.), Sorbonne Paris Cité, UMR676, 75019 Paris, France; and Institute of Pharmacology and Toxicology (S.S.), Jena University Hospital, Friedrich Schiller University Jena, Germany.

Somatostatin (SRIF), by acting mainly through sst2 and sst5 receptors, is a potent inhibitor of hormonal secretion by the human anterior pituitary gland. However, the pattern of protein expression of these SRIF receptors remains unknown during pituitary development. To get further insights into the physiological role of SRIF receptors in human development and pituitary function, the present study examined the developmental expression of the sst2 and sst5 receptors in the individual cell types of the anterior human pituitary. Thirteen fetal human pituitaries were investigated between 13 to 38 weeks of gestation (WG) by double-labeling immunofluorescence with antibodies raised against sst2 or sst5 receptors and GH, LH, FSH, TSH, or pro-opiomelanocortin proteins. SRIF immunoreactivity in the hypothalamus and median eminence was investigated at the same developmental ages. Immunoreactivity for the sst2 receptor was evident as early as 13 to 15 WG and onward mainly in TSH-, LH-, and FSH-expressing cells, whereas sst5 immunoreactivity was apparent at the late development stages (35-38 WG). GH-expressing cells mainly expressed sst5 immunoreactivity. SRIF-positive fibers and cells were detected as soon as 13 to 16 WG in the hypothalamus and median eminence and their densities increased with gestational age. The early appearance of hypothalamic SRIF cells and fibers suggests a physiological link between SRIF and its receptors during pituitary development. Whereas sst2 receptors might play a primary role in the differentiation and regulation of TSH, LH, and FSH cells, sst5 receptors appear to be mainly involved in GH regulation from birth onward.
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http://dx.doi.org/10.1210/en.2013-1683DOI Listing
January 2014

PRR repeats in the intracellular domain of KISS1R are important for its export to cell membrane.

Mol Endocrinol 2013 Jun 22;27(6):1004-14. Epub 2013 Apr 22.

Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 676, Hôpital Robert Debré, 48 Boulevard Sérurier, 75019 Paris, France.

Inactivating mutations of KISS-1 receptor (KISS1R) have been recently described as a rare cause of isolated hypogonadotropic hypogonadism transmitted as a recessive trait. Few mutations have been described, and the structure-function relationship of KISS1R remains poorly understood. Here, we have taken advantage of the discovery of a novel mutation of KISS1R to characterize the structure and function of an uncommon protein motif composed of 3 proline-arginine-arginine (PRR) repeats located within the intracellular domain. A heterozygous insertion of 1 PRR repeat in-frame with 3 PRR repeats leading to synthesis of a receptor bearing 4 PRR repeats (PRR-KISS1R) was found in the index case. Functional analysis of PRR-KISS1R showed a decrease of the maximal response to kisspeptin stimulation, associated to a lower cell surface expression without modification of total expression. PRR-KISS1R exerts a dominant negative effect on the synthesis of the wild-type (WT)-KISS1R. This effect was due to the nature of inserted residues but also to the difference of the length of the intracellular domain between PRR-KISS1R and WT-KISS1R. A molecular dynamic analysis showed that the additional PRR constrained this arginine-rich region into a polyproline type II helix. Altogether, this study shows that a heterozygous insertion in KISS1R may lead to hypogonadotropic hypogonadism by a dominant negative effect on the WT receptor. An additional PRR repeat into a proline-arginine-rich motif can dramatically changed the conformation of the intracellular domain of KISS1R and its probable interaction with partner proteins.
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http://dx.doi.org/10.1210/me.2012-1386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5415274PMC
June 2013

[The genetic control of puberty onset].

Bull Acad Natl Med 2012 Feb;196(2):327-40; discussion 340-3

Endocrinologie, Inserm U 676, Hôpital Robert Debré, 48 bld Serurier-75935 Paris.

Puberty is triggered by a complex neuroendocrine mechanism that leads to an increase in GnRH release at the end of the childhood and, hence, to reactivation of the gonadotropic axis. Recent human genetic studies have led to major breakthroughs in our understanding of puberty onset. A network of hypothalamic neurons controlling GnRH release has just been characterized. It appears that the timing of puberty onset is under the control of the heterochronic gene Lin28, which encodes a protein regulating microRNA maturation. Characterization of additional gene defects associated with abnormal puberty onset is needed to further characterize this neuroendocrine network and to identify new therapeutic targets for reproductive disorders.
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February 2012

PROKR2 and PROK2 mutations cause isolated congenital anosmia without gonadotropic deficiency.

Eur J Endocrinol 2013 Jan 10;168(1):31-7. Epub 2012 Dec 10.

Service d'ORL et de Chirurgie Cervico-Faciale and CESEM, UMR, Paris-Descartes School of Medicine, Paris V University, Paris, France.

Objective: Isolated congenital anosmia (ICA) is a rare phenotype defined as absent recall of any olfactory sensations since birth and the absence of any disease known to cause anosmia. Although most cases of ICA are sporadic, reports of familial cases suggest a genetic cause. ICA due to olfactory bulb agenesis and associated to hypogonadotropic hypogonadism defines Kallmann syndrome (KS), in which several gene defects have been described. In KS families, the phenotype may be restricted to ICA. We therefore hypothesized that mutations in KS genes cause ICA in patients, even in the absence of family history of reproduction disorders.

Design And Methods: In 25 patients with ICA and olfactory bulb agenesis, a detailed phenotype analysis was conducted and the coding sequences of KAL1, FGFR1, FGF8, PROKR2, and PROK2 were sequenced.

Results: Three PROKR2 mutations previously described in KS and one new PROK2 mutation were found. Investigation of the families showed incomplete penetrance of these mutations.

Conclusions: This study is the first to report genetic causes of ICA and indicates that KS genes must be screened in patients with ICA. It also confirms the considerable complexity of GNRH neuron development in humans.
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http://dx.doi.org/10.1530/EJE-12-0578DOI Listing
January 2013

Negative fetal FSH/LH regulation in late pregnancy is associated with declined kisspeptin/KISS1R expression in the tuberal hypothalamus.

J Clin Endocrinol Metab 2012 Dec 26;97(12):E2221-9. Epub 2012 Sep 26.

Institut National de la Santé et de la Recherche Médicale, Unité 676, F-75739 Paris, France.

Objective: Kisspeptins were recently identified as hypothalamic neuropeptides that control GnRH release at pubertal onset and in adults via the activation of KISS-1 receptor (KISS1R). Here, we have tested whether the fetal activation of the gonadotropic axis is related to the hypothalamic expression of kisspeptins and KISS1R.

Design And Methods: LH and FSH levels were measured in fetal blood from the 15th week of gestation (WG) to birth. Immunohistochemistry was performed on the hypothalamus and pituitary at different developmental stages.

Results: Immunostaining for kisspeptins and KISS1R appeared for both proteins in the hypothalamus as early as 15 WG and subsequently increased until 30-31 WG. In the meantime, serum LH and FSH levels decreased from postmenopausal levels in females or adult levels in males to very low levels. At full term, kisspeptin and KISS1R staining was still observed in the paraventricular, supraoptic, and ventromedial hypothalamic nuclei but not in the arcuate nucleus or median eminence. Hypothalamic GnRH staining was observed at 15 WG and did not vary after the first trimester. In an arhinencephalic fetus of 23 WG, very few GnRH neurons were observed in the hypothalamus, but serum FSH and LH levels were postmenopausal.

Conclusion: Serum LH and FSH levels are independent from GnRH and kisspeptins at midgestation, and then GnRH progressively controls LH and FSH release. A shift from kisspeptin-independent to kisspeptin-dependent GnRH-induced LH and FSH release seems to occur after 30-31 WG. In addition to their function in adults, kisspeptins are also the master regulators of the gonadotropic axis activation in the fetus.
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http://dx.doi.org/10.1210/jc.2012-2078DOI Listing
December 2012

DLK1 is a somato-dendritic protein expressed in hypothalamic arginine-vasopressin and oxytocin neurons.

PLoS One 2012 26;7(4):e36134. Epub 2012 Apr 26.

INSERM, U676, Paris, France.

Delta-Like 1 Homolog, Dlk1, is a paternally imprinted gene encoding a transmembrane protein involved in the differentiation of several cell types. After birth, Dlk1 expression decreases substantially in all tissues except endocrine glands. Dlk1 deletion in mice results in pre-natal and post-natal growth deficiency, mild obesity, facial abnormalities, and abnormal skeletal development, suggesting involvement of Dlk1 in perinatal survival, normal growth and homeostasis of fat deposition. A neuroendocrine function has also been suggested for DLK1 but never characterised. To evaluate the neuroendocrine function of DLK1, we first characterised Dlk1 expression in mouse hypothalamus and then studied post-natal variations of the hypothalamic expression. Western Blot analysis of adult mouse hypothalamus protein extracts showed that Dlk1 was expressed almost exclusively as a soluble protein produced by cleavage of the extracellular domain. Immunohistochemistry showed neuronal DLK1 expression in the suprachiasmatic (SCN), supraoptic (SON), paraventricular (PVN), arcuate (ARC), dorsomedial (DMN) and lateral hypothalamic (LH) nuclei. DLK1 was expressed in the dendrites and perikarya of arginine-vasopressin neurons in PVN, SCN and SON and in oxytocin neurons in PVN and SON. These findings suggest a role for DLK1 in the post-natal development of hypothalamic functions, most notably those regulated by the arginine-vasopressin and oxytocin systems.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0036134PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3338567PMC
September 2012

DNA polymorphisms of the KiSS1 3' untranslated region interfere with the folding of a G-rich sequence into G-quadruplex.

Mol Cell Endocrinol 2012 Apr 30;351(2):239-48. Epub 2011 Dec 30.

INSERM, U676, Hôpital Robert-Debré, 75935 Paris Cedex 19, France; Paris Diderot University, 75018 Paris, France.

KISS1R and its ligand, the kisspeptins, are key hypothalamic factors that regulate GnRH hypothalamic secretion and therefore the pubertal timing. During studies analysing KiSS1 as a candidate gene in pubertal onset disorders, two SNP and one nucleotide insertion were observed in a 23 nucleotides G-rich sequence located 65 nucleotides downstream of the stop codon. The polymorphisms formed four haplotypes. Biophysical experiments revealed the ability of this G-rich sequence to fold into G-quadruplex structures and demonstrated that the three DNA polymorphisms did not perturb the folding into G-quadruplex but affected G-quadruplex conformation. A functional luciferase reporter-based assay revealed functional differences between 3'UTR haplotypes. These data show that polymorphisms in a G-rich sequence of the 3'UTR of KISS1, able to fold into G-quadruplex structures, can modulate gene expression. They highlight the potential role of this G-quadruplex in the regulation of KISS1 expression and in the timing of pubertal onset.
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http://dx.doi.org/10.1016/j.mce.2011.12.014DOI Listing
April 2012

Genetics of isolated hypogonadotropic hypogonadism: role of GnRH receptor and other genes.

Int J Endocrinol 2012 21;2012:147893. Epub 2011 Dec 21.

Division of Endocrinology and Diabetes, University Hospital Aachen, RWTH Aachen University, 52074 Aachen, Germany.

Hypothalamic gonadotropin releasing hormone (GnRH) is a key player in normal puberty and sexual development and function. Genetic causes of isolated hypogonadotropic hypogonadism (IHH) have been identified during the recent years affecting the synthesis, secretion, or action of GnRH. Developmental defects of GnRH neurons and the olfactory bulb are associated with hyposmia, rarely associated with the clinical phenotypes of synkinesia, cleft palate, ear anomalies, or choanal atresia, and may be due to mutations of KAL1, FGFR1/FGF8, PROKR2/PROK2, or CHD7. Impaired GnRH secretion in normosmic patients with IHH may be caused by deficient hypothalamic GPR54/KISS1, TACR3/TAC3, and leptinR/leptin signalling or mutations within the GNRH1 gene itself. Normosmic IHH is predominantly caused by inactivating mutations in the pituitary GnRH receptor inducing GnRH resistance, while mutations of the β-subunits of LH or FSH are very rare. Inheritance of GnRH deficiency may be oligogenic, explaining variable phenotypes. Future research should identify additional genes involved in the complex network of normal and disturbed puberty and reproduction.
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http://dx.doi.org/10.1155/2012/147893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3249753PMC
August 2012

A novel loss-of-function mutation in GPR54/KISS1R leads to hypogonadotropic hypogonadism in a highly consanguineous family.

J Clin Endocrinol Metab 2011 Mar 30;96(3):E536-45. Epub 2010 Dec 30.

The Jesse Z. and Sara Lea Shafer Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children's Medical Center of Israel, 14 Kaplan Street, Petah Tikva 49202, Israel.

Context: The G protein-coupled receptor 54 (GPR54), the kisspeptin receptor, is essential for stimulation of GnRH secretion and induction of puberty. Recently loss-of-function mutations of the GPR54 have been implicated as a cause of isolated idiopathic hypogonadotropic hypogonadism (IHH).

Objective: The objective of the study was to identify the genetic cause of IHH in a consanguineous pedigree and to characterize the phenotypic features from infancy through early adulthood.

Design: In six patients with normosmic IHH belonging to two families of Israeli Muslim-Arab origin highly related to one another, DNA was analyzed for mutations in the GnRHR and GPR54 genes, with functional analysis of the mutation found. The five males underwent comprehensive endocrine evaluation and were under longitudinal follow-up; the one female presented in early adulthood.

Results: A new homozygous mutation (c.T815C) in GPR54 leading to a phenylalanine substitution by serine (p.F272S) was detected in all patients. Functional analysis showed an almost complete inhibition of kisspeptin-induced GPR54 signaling and a dramatic decrease of the mutated receptor expression at the cell surface. The males exhibited the same clinical features from infancy to adulthood, characterized by cryptorchidism, a relatively short penis, and no spontaneous pubertal development. The female patient presented at 18 yr with impuberism and primary amenorrhea. Repeated stimulation tests demonstrated complete gonadotropin deficiency throughout follow-up.

Conclusion: A novel loss-of-function mutation (p.F272S) in the GPR54 gene is associated with familial normosmic IHH. Underdeveloped external genitalia and impuberism point to the major role of GPR54 in the activation of the gonadotropic axis from intrauterine life to adulthood.
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http://dx.doi.org/10.1210/jc.2010-1676DOI Listing
March 2011

Dental agenesis in Kallmann syndrome individuals with FGFR1 mutations.

Int J Paediatr Dent 2010 Jul;20(4):305-12

Paediatric Dentistry, Garancière Hotel-Dieu Hospital, Assistance Publique-Hôpitaux de Paris, Paris Diderot University, France.

Background: Kallmann syndrome (KS) is a rare genetic disorder characterised by central hypogonadism with a lack of sense of smell and in some cases renal aplasia, deafness, syndactyly, cleft lip/palate, and dental agenesis. To date, five genes for KS have been identified: KAL1, located on the X chromosome, and FGFR1, PROKR2, PROK2 and FGF8, which are involved in autosomally transmitted forms of KS.

Aim: The study characterised the dental ageneses of individuals with KS associated with mutations in the FGFR1 gene.

Design: Six individuals displaying dental agenesis were included. Clinical and radiological dental evaluations as well as medical anamneses were carried out.

Results: Microdontia, screwdriver-shaped mandibular incisors, thin molar roots, and patterns of dental agenesis in both dentitions were observed. One to nine teeth were missing, most frequently, in descending order, lateral mandibular incisors, second premolars of upper and lower jaws, and lateral maxillary incisors. The pattern of dental agenesis is associated with four new mutations in the FGFR1 gene.

Conclusion: Dental agenesis may be a clinical feature of Kallmann syndrome caused by a mutation in the FGFR1 gene. These findings highlight the role that odontologists can play in the early diagnosis and treatment of gonadotropic deficiency.
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http://dx.doi.org/10.1111/j.1365-263X.2010.01056.xDOI Listing
July 2010

KISS1 is down-regulated by 17beta-estradiol in MDA-MB-231 cells through a nonclassical mechanism and loss of ribonucleic acid polymerase II binding at the proximal promoter.

Endocrinology 2010 Aug 9;151(8):3764-72. Epub 2010 Jun 9.

Avenir Team Genetic and Physiology of the Onset of Puberty, Institut National de la Santé et de laRecherche Médicale Unité 676, Hopital Robert Debré, and Université Paris Diderot, 75019 Paris, France.

Kisspeptins are hypothalamic neuropeptides encoded by KISS1 and recently described as major regulators of GnRH release from hypothalamic neurons. Although 17beta-estradiol (E2)-induced up-regulation of KISS1 expression has been documented in anteroventral periventricular nucleus neurons, E2 down-regulates KISS1 expression in arcuate nucleus neurons via the estrogen receptor alpha by unknown molecular mechanisms. Because KISS1 was initially described as a metastasis inhibitor, notably in breast tumors, we used the MDA-MB-231 breast cancer cell line, which expresses high levels of KISS1, to characterize the molecular mechanism underlying KISS1 regulation by E2. E2 rapidly down-regulated endogenous KISS1 in a stable ERalpha-expressing MDA-MB-231 cell line. Promoter analysis revealed that E2 down-regulation was determined by a short 93-bp sequence devoid of estrogen response element and Sp1 sites. E2 down-regulation persisted with an ERalpha that was unable to bind DNA and in the presence of histone deacetylase inhibitor. In the absence of E2, unliganded ERalpha and RNA polymerase II (RNAPII) were present on the proximal promoter. E2 stimulation induced recruitment of ERalpha and loss of RNAPII at the proximal promoter. Along the gene body, total RNAPII amounts were similar in E2-treated and untreated cells, whereas the active form was significantly less abundant in E2-treated cells. Thus, E2-induced down-regulation of KISS1 is mediated by a pathway combining RNAPII loss at the proximal promoter and modulation of active RNAPII along the gene body, which is a novel mechanism in the complex process of E2-induced repression of gene expression.
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http://dx.doi.org/10.1210/en.2010-0260DOI Listing
August 2010

Pituitary-thyroid feedback in a patient with a sporadic activating thyrotropin (TSH) receptor mutation: implication that thyroid-secreted factors other than thyroid hormones contribute to serum TSH levels.

J Clin Endocrinol Metab 2009 Aug 19;94(8):2787-91. Epub 2009 May 19.

Pediatric Endocrinology Unit, Centre de Référence Maladies Endocriniennes de la Croissance, and INSERM Unité 690, Robert Debré Hospital, Université Paris-Diderot Paris 7, 48 Boulevard Sérurier, Paris, France.

Context: Constitutive mutations of the TSH receptor gene are a rare cause of severe congenital hyperthyroidism. Persistent TSH suppression has been described in euthyroid Graves' disease patients treated with antithyroid drugs. An ultrashort negative feedback loop affecting TSH secretion by activating the pituitary TSH receptor with TSH receptor autoantibodies has been suggested as a possible mechanism of TSH suppression in these patients.

Objective And Design: The aim of the study was to determine whether TSH suppression also occurs in euthyroid treated patients with non-autoimmune hyperthyroidism. We investigated the outcome of pituitary-thyroid feedback in a patient carrying an activating mutation of the TSH-R gene in an observational prospective study. Repeated clinical investigations from birth until the age of 14 yr are presented for the patient on drug treatment and after radical treatment.

Results: TSH was consistently undetectable or present at very low concentrations in the serum for several years, although FT(4) and FT(3) concentrations remained mostly in the normal range. Moreover, serum TSH concentrations increased only slightly when serum FT(4) concentrations fell below normal levels. During drug treatment, serum TSH concentrations expressed as a function of serum FT(4) and FT(3) concentrations were significantly lower than those for control or congenital hypothyroid populations. By contrast, after radical treatment, serum TSH levels increased, reaching the normal range, and low serum FT(4) and FT(3) concentrations were associated with appropriate increases in serum TSH concentrations.

Conclusion: These data provide insight into the regulation of serum TSH concentrations and suggest an alternative mechanism, in addition to serum thyroid hormone levels, for adjusting TSH secretion.
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http://dx.doi.org/10.1210/jc.2008-2524DOI Listing
August 2009

An inactivating mutation within the first extracellular loop of the thyrotropin receptor impedes normal posttranslational maturation of the extracellular domain.

Endocrinology 2009 Feb 16;150(2):1043-50. Epub 2008 Oct 16.

Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 690, Hôpital Robert-Debré, Paris, France.

The TSH receptor (TSHR), a member of the large family of G protein-coupled receptors, controls both function and growth of thyroid cells; hence, mutations of this receptor result in thyroid dysfunction. Here, we took advantage of the description of a new inactivating TSHR mutation (Q489H) in two brothers with hypothyroidism, to precise maturation, intracellular trafficking, exporting pathways, and activation mechanisms of this receptor. Functional characterization of the Q489H-TSHR in transiently transfected HEK293 cells showed cell surface expression, normal TSH binding affinity, and its inability to generate intracellular cAMP in response to TSH stimulation. Western blot analysis of the whole membrane proteins or proteins expressed at the cell surface showed that Q489H-TSHR expressed in HEK293 transfected cells are restricted to mannose-rich uncleaved receptor. Analysis of the export pathway toward cell surface indicated that both Q489H and wild-type receptors followed the same intracellular route to cell surface throughout endoplasmic reticulum and Golgi apparatus. This study shows that Q489H substitution impedes complete glycosylation of TSHR extracellular domain within the Golgi apparatus and that Q489H-TSHR expressed at the cell surface is unable to undergo intramolecular cleavage as well as to switch toward an active conformation under TSH stimulation. Altogether, our results show that 1) Q489H substitution within the first extracellular loop induces a misfolding of TSHR, blocking it into an inactive conformation and impeding complete glycosylation and intramolecular cleavage, and 2) a misfolded G protein-coupled receptor can bypass endoplasmic reticulum or Golgi apparatus quality control and reach the cell surface as an immature receptor.
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http://dx.doi.org/10.1210/en.2008-1145DOI Listing
February 2009

[Biological mechanisms and genes involved in puberty].

Rev Prat 2008 Jun;58(12):1305-9

Equipe Avenir Génétique et physiologie de l'initiation de la puberté Inserm U690, hôpital Robert-Debré, Université Paris-Diderot Paris-7, 75935 Paris Cedex 19, France.

Puberty is an important step in human development. Onset of puberty, including neurobiological mechanisms important for the increase of hypothalamic GnRH pulses remains a mystery. After birth, GnRH secretion remains elevated and then decreases during childhood regardless of any steroid gonadal feedback. This period of quiescence of the gonadotropic axis during childhood is linked to a central inhibition of GnRH secretion which is replaced by an activator tone at puberty. The study of the pathology of the pubertal timing, including delayed puberty led to the discovery of new genes involved in the migration of GnRH neurons and genes involved in the neuroendocrine regulation of the gonadotropic axis. Recently, the emphasis on the importance of the kiss/GPR54 system in modulating control of the gonadotropic axis at puberty has recently emerged from Human genetics studies.
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June 2008