Publications by authors named "Anne Lienhardt-Roussie"

13 Publications

  • Page 1 of 1

Presenting features and molecular genetics of primary hyperparathyroidism in the paediatric population.

Eur J Endocrinol 2021 Feb;184(2):347-355

Paediatric Unit, Limoges University Hospital, Limoges, France.

Aim: To describe the presenting features and molecular genetics of primary hyperparathyroidism (PHPT) in the paediatric population.

Methods: Retrospective study of 63 children diagnosed with primary PHPT from 1998 to 2018.

Results: Compared to older children, infants were often asymptomatic (54% vs 15%, P = 0.002) with a milder form of PHPT. When symptomatic, children and adolescents mostly presented with non-specific complaints such as asthenia, depression, weight loss, vomiting or abdominal pain. A genetic cause of PHPT was identified in about half of this cohort (52%). The infancy period was almost exclusively associated with mutation in genes involved in the calcium-sensing receptor (CaSR) signalling pathway (i.e. CaSR and AP2S1 genes, 'CaSR group'; 94% of infants with mutations) whereas childhood and adolescence were associated with mutation in genes involved in parathyroid cell proliferation (i.e. MEN1, CDC73, CDKN1B and RET genes, 'cell proliferation group'; 69% of children and adolescents with mutations). Although serum calcium levels did not differ between the two groups (P = 0.785), serum PTH levels and the urinary calcium/creatinine ratio were significantly higher in 'cell proliferation group' patients compared to those in the 'CaSR group' (P = 0.001 and 0.028, respectively).

Conclusion: Although far less common than in adults, PHPT can develop in children and is associated with significant morbidity. Consequently, this diagnosis should be considered in children with non-specific complaints and lead to monitoring of mineral homeostasis parameters. A genetic cause of PHPT can be identified in about half of these patients.
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http://dx.doi.org/10.1530/EJE-20-1119DOI Listing
February 2021

Demographic Characteristics, Risk Factors, and Presenting Features of Children with Symptomatic Nutritional Rickets: A French Series.

Horm Res Paediatr 2020 29;93(5):304-312. Epub 2020 Oct 29.

Reference and Competence Centers for Rare Diseases of the Calcium and Phosphate Metabolism, OSCAR Network for Rare Diseases, Paris, France,

Aim: To describe the demographic characteristics, risk factors, and presenting features of children with symptomatic nutritional rickets in France.

Methods: This is a retrospective study of 38 children diagnosed with nutritional rickets from 1998 to 2019.

Results: We observed a higher frequency of rickets in males (74 vs. 26%), in young children (median age at diagnosis: 23 months; 82% were younger than 5 years), and in children with a non-Caucasian ethnic background (89%). Most children were exclusively breastfed (78%) without adequate vitamin D supplementation (89%). The most common presentations were bowed legs (63%), hypocalcemic seizures (21%), and growth retardation (11%). Approximately half (62%) of the children were hypocalcemic. The children presenting with hypocalcemic seizures were significantly younger (0.8 vs. 2.2 years; p = 0.041) and had lower total serum calcium levels (1.44 vs. 2.17 mmol/L; p < 0.0001), higher phosphatemia (1.43 vs. 1.23 mmol/L; p = 0.020), and lower 25-hydroxy vitamin D levels (3 vs. 7 ng/mL; p = 0.020) but similar parathyroid hormone levels (357 vs. 289 ng/mL; p = 0.940) compared to rickets cases who did not experience hypocalcemic seizures. A dilated cardiomyopathy was detected in 14% of the children who had undergone echocardiography.

Conclusion: Nutritional rickets remains endemic in the pediatric population and its most severe forms can have life-threatening sequelae. Health practitioners need to be cognizant of these facts to raise awareness and screen high-risk populations.
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http://dx.doi.org/10.1159/000511419DOI Listing
October 2020

Aberrant Splicing Is the Pathogenicity Mechanism of the p.Glu314Lys Variant in Gene.

Front Endocrinol (Lausanne) 2018 5;9:491. Epub 2018 Sep 5.

Laboratoire de Biochimie et Biologie Moléculaire Grand Est, UM Pathologies Endocriniennes Rénales Musculaires et Mucoviscidose, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France.

The cholesterol side chain cleavage enzyme (CYP11A1) catalyzes the conversion of cholesterol to pregnenolone, the first rate-limiting step of steroidogenesis. mutations are associated with primary adrenal insufficiency (PAI) as well as disorders of sex development (DSD) in 46,XY patients. To define the pathogenicity mechanism for the p.Glu314Lys variant, previously reported, and found in four additional patients with CYP11A1 deficiency. DNA of four patients presenting with delayed PAI and/or 46,XY DSD were studied by Sanger or Massively Parallel sequencing. Three mutations were characterized and , and one by mRNA analysis on testicular tissue. All patients were compound heterozygous for the previously described p.Glu314Lys variant. studies predicted this mutation as benign with no effect on splicing but mRNA analysis found that it led to incomplete exon 5 skipping. This mechanism was confirmed by minigene experiment. The protein carrying this mutation without exon skipping should conserve almost normal activity, according to studies. Two other mutations found in , the p.Arg120Gln and p.Arg465Trp, had similar activity compared to negative control, consistent with the studies. We provide biological proof that the p. Glu314Lys variant is pathogenic due to its impact on splicing and seems responsible for the moderate phenotype of the four patients reported herein. The present study highlights the importance of considering the potential effect of a missense variant on splicing when it is not predicted to be disease causing.
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http://dx.doi.org/10.3389/fendo.2018.00491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6134065PMC
September 2018

Genetic disruption of the oncogenic HMGA2-PLAG1-IGF2 pathway causes fetal growth restriction.

Genet Med 2018 02 10;20(2):250-258. Epub 2017 Aug 10.

Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, Paris, France.

PurposeFetal growth is a complex process involving maternal, placental and fetal factors. The etiology of fetal growth retardation remains unknown in many cases. The aim of this study is to identify novel human mutations and genes related to Silver-Russell syndrome (SRS), a syndromic form of fetal growth retardation, usually caused by epigenetic downregulation of the potent fetal growth factor IGF2.MethodsWhole-exome sequencing was carried out on members of an SRS familial case. The candidate gene from the familial case and two other genes were screened by targeted high-throughput sequencing in a large cohort of suspected SRS patients. Functional experiments were then used to link these genes into a regulatory pathway.ResultsWe report the first mutations of the PLAG1 gene in humans, as well as new mutations in HMGA2 and IGF2 in six sporadic and/or familial cases of SRS. We demonstrate that HMGA2 regulates IGF2 expression through PLAG1 and in a PLAG1-independent manner.ConclusionGenetic defects of the HMGA2-PLAG1-IGF2 pathway can lead to fetal and postnatal growth restriction, highlighting the role of this oncogenic pathway in the fine regulation of physiological fetal/postnatal growth. This work defines new genetic causes of SRS, important for genetic counseling.
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http://dx.doi.org/10.1038/gim.2017.105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846811PMC
February 2018

Association of environmental markers with childhood type 1 diabetes mellitus revealed by a long questionnaire on early life exposures and lifestyle in a case-control study.

Authors:
F Balazard S Le Fur S Valtat A J Valleron P Bougnères Dominique Thevenieau Corinne Fourmy Chatel Rachel Desailloud Hélène Bony-Trifunovic Pierre-Henri Ducluzeau Régis Coutant Sophie Caudrelier Armelle Pambou Emmanuelle Dubosclard Florence Joubert Philippe Jan Estelle Marcoux Anne-Marie Bertrand Brigitte Mignot Alfred Penformis Chantal Stuckens Régis Piquemal Pascal Barat Vincent Rigalleau Chantal Stheneur Sylviane Fournier Véronique Kerlan Chantal Metz Anne Fargeot-Espaliat Yves Reznic Frédérique Olivier Iva Gueorguieva Arnaud Monier Catherine Radet Vincent Gajdos Daniel Terral Christine Vervel Djamel Bendifallah Candace Ben Signor Daniel Dervaux Abdelkader Benmahammed Guy-André Loeuille Françoise Popelard Agnès Guillou Pierre-Yves Benhamou Jamil Khoury Jean-Pierre Brossier Joachim Bassil Sylvaine Clavel Bernard Le Luyer Pierre Bougnères Françoise Labay Isabelle Guemas Jacques Weill Jean-Pierre Cappoen Sylvie Nadalon Anne Lienhardt-Roussie Anne Paoli Claudie Kerouedan Edwige Yollin Marc Nicolino Gilbert Simonin Jacques Cohen Catherine Atlan Agnès Tamboura Hervé Dubourg Marie-Laure Pignol Philippe Talon Stéphanie Jellimann Lucy Chaillous Sabine Baron Marie-Noëlle Bortoluzzi Elisabeth Baechler Randa Salet Ariane Zelinsky-Gurung Fabienne Dallavale Etienne Larger Marie Laloi-Michelin Jean-François Gautier Bénédicte Guérin Laure Oilleau Laetitia Pantalone Céline Lukas Isabelle Guilhem Marc De Kerdanet Marie-Claire Wielickzo Mélanie Priou-Guesdon Odile Richard François Kurtz Norbert Laisney Déborah Ancelle Guilhem Parlier Catherine Boniface Dominique Paris Bockel Denis Dufillot Berthe Razafimahefa Pierre Gourdy Pierre Lecomte Myriam Pepin-Donat Marie-Emmanuelle Combes-Moukhovsky Brigitte Zymmermann Marina Raoulx Anne Gourdin Et Catherine Dumont

BMC Public Health 2016 Sep 29;16(1):1021. Epub 2016 Sep 29.

INSERM U1169, Hôpital Bicêtre, Université Paris-Sud, Kremlin-Bicêtre, France.

Background: The incidence of childhood type 1 diabetes (T1D) incidence is rising in many countries, supposedly because of changing environmental factors, which are yet largely unknown. The purpose of the study was to unravel environmental markers associated with T1D.

Methods: Cases were children with T1D from the French Isis-Diab cohort. Controls were schoolmates or friends of the patients. Parents were asked to fill a 845-item questionnaire investigating the child's environment before diagnosis. The analysis took into account the matching between cases and controls. A second analysis used propensity score methods.

Results: We found a negative association of several lifestyle variables, gastroenteritis episodes, dental hygiene, hazelnut cocoa spread consumption, wasp and bee stings with T1D, consumption of vegetables from a farm and death of a pet by old age.

Conclusions: The found statistical association of new environmental markers with T1D calls for replication in other cohorts and investigation of new environmental areas.

Trial Registration: Clinical-Trial.gov NCT02212522 . Registered August 6, 2014.
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http://dx.doi.org/10.1186/s12889-016-3690-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5041527PMC
September 2016

P450 Oxidoreductase Deficiency: Loss of Activity Caused by Protein Instability From a Novel L374H Mutation.

J Clin Endocrinol Metab 2016 12 7;101(12):4789-4798. Epub 2016 Sep 7.

Pediatric Endocrinology, Diabetology, and Metabolism (S.P., C.E.F., A.V.P.), University Children's Hospital, and Department of Clinical Research, University of Bern, CH-3010 Bern, Switzerland; Service d'Endocrinologie Moléculaire et Maladies Rares (F.R.-B., D.M., Y.M.), Centre de Biologie et Pathologie Est, Hospices Civils de Lyon, Université Lyon 1, 69002 Bron-Lyon, France; and Endocrinologie Pédiatrique Département de Pédiatrie Médicale (A.L.-R.), Hôpital de la Mère et de l'Enfant, 87042 Limoges, France.

Context: P450 oxidoreductase (POR) is required for the activities of steroid-metabolizing cytochrome P450 enzymes in the endoplasmic reticulum. POR deficiency (PORD) is a form of congenital adrenal hyperplasia. Objective and Aim: Enzymatic and structural analysis of a novel L374H POR mutation from a patient with 46,XX disorder of sexual development. Design, Setting, Patient, and Intervention: The patient was a 46,XX girl with nonconsanguineous Turkish parents. She had virilized external genitalia at birth, a uterus and ovaries, and no sign of Antley-Bixler syndrome. The initial diagnosis was CYP21A2 deficiency with no mutations in CYP21A2, but POR mutations were found. Functional testing was done after producing recombinant POR proteins for analyzing enzymatic and structural properties.

Main Outcome: Novel mutations were causing severe loss of POR activities for metabolism of steroids and small molecules.

Results: The L374H mutation reduced activities by 80% in cytochrome c, 97% in thiazolyl blue tetrazolium bromide, and 86% in ferricyanide reduction assays. The catalytic efficiency of the 17 α-hydroxylation of progesterone and the 17,20-lyase reaction of 17-OH pregnenolone was decreased by 87 and 90%, respectively; 21-hydroxylation of progesterone was decreased by 96%, and androstenedione aromatization was decreased by 90%. Analysis of the mutant structure by molecular dynamics simulations revealed structural instability. Flavin release and fast proteolysis assays showed that the L374H mutant is less stable than wild-type POR, confirming the bioinformatics prediction.

Conclusions: This is the first report of a mutation causing PORD by affecting protein stability that causes severe reduction in POR activities. Detailed characterization of individual mutations in POR is required for understanding novel molecular mechanisms causing PORD.
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http://dx.doi.org/10.1210/jc.2016-1928DOI Listing
December 2016

Treatment experience and long-term follow-up data in two severe neonatal hyperparathyroidism cases.

J Pediatr Endocrinol Metab 2016 Sep;29(9):1103-10

The calcium sensing receptor (CASR) is expressed most abundantly in the parathyroid glands and the kidney. CASR regulates calcium homeostasis through its ability to modulate parathormone secretion and renal calcium reabsorption. Inactivating mutations in the CASR gene may result in disorders of calcium homeostasis manifesting as familial benign hypocalciuric hypercalcemia (FBHH) and neonatal severe hyperparathyroidsm (NSHPT). Two cases were referred with severe hypercalcemia in the neonatal period. Laboratory evaluation revealed severe hypercalcemia and elevated PTH. The parents also had mild hypercalcemia. The serum calcium level did not normalize with conventional hypercalcemia treatment and there was also no response to cinacalcet in case 1. Total parathyroidectomy was performed when the patient was 70 days old. Genetic analysis revealed a novel homozygous p.Arg544* mutation in the CASR gene. Case 2 underwent total parathyroidectomy and autoimplantation when she was 97 days old, but the parathyroid gland implanted into the forearm was removed 27 days later because the hypercalcemia continued. Genetic evaluation revealed a novel homozygous p.Pro682Leu mutation with normal anthropometric measurements. The neurological development is consistent with age in both cases while case 2 has mild mental retardation. No bone deformity or fracture is present in either case and normocalcemia is ensured with calcitriol in both cases.
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http://dx.doi.org/10.1515/jpem-2015-0261DOI Listing
September 2016

Late prenatal dexamethasone and phenotype variations in 46,XX CAH: concerns about current protocols and benefits for surgical procedures.

J Pediatr Urol 2014 Oct 15;10(5):941-7. Epub 2014 Mar 15.

Service d'Urologie Pédiatrique, Hôpital Mère-Enfant, Centre Hospitalo-Universitaire de Lyon, GHE, 59, boulevard Pinel, 69677 Bron Cedex, France. Electronic address:

Objective: To describe the action of prenatal dexamethasone (PreDex) on the anatomy of female congenital adrenal hyperplasia (CAH) genitalia when started at later stages of gestation.

Materials And Methods: Our group follows a large cohort of French CAH patients who underwent PreDex therapy, of whom 258 were recently reported. Four 46,XX patients with a delayed PreDex treatment presented with a virilized genitalia and required surgical reconstruction. This is a retrospective report on genital phenotyping at the time of surgery of these four patients who began PreDex therapy at 8, 12, 20, and 28 weeks of gestation.

Results: Although this series is limited in number, the anatomical description of the length of the genital tubercle, the height of the urethra-vaginal confluence, and the degree of fusion of the genital folds seems to be dependent upon the starting date of PreDex. Most PreDex treatments prescribed up to now have covered the full duration of gestation.

Conclusions: Our findings suggest that PreDex therapy could be limited to the period of the partitioning window. It is hoped that further prospective multicentric clinical studies will obtain ethical approval in order to elucidate the place and protocols of PreDex therapy in the management of CAH.
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http://dx.doi.org/10.1016/j.jpurol.2014.02.003DOI Listing
October 2014

Two novel mutations of the calcium-sensing receptor gene affecting the same amino acid position lead to opposite phenotypes and reveal the importance of p.N802 on receptor activity.

Eur J Endocrinol 2013 Feb 17;168(2):K27-34. Epub 2013 Jan 17.

EA 6309 - Maintenance Myélinique et Neuropathies Périphériques, Faculté de Médecine - Biochimie, Université de Limoges, 6ème étage, 2 rue du Dr Marcland, 87025 Limoges, France.

Objective: Gain-of-function mutations of the calcium-sensing receptor (CASR) gene have been identified in patients with sporadic or familial autosomal dominant hypocalcemia (ADH). Inactivating mutations of the CASR gene cause familial hypocalciuric hypercalcemia (FHH). Here, we report two novel CASR mutations affecting the same amino acid (p.N802); one causes ADH and the other atypical FHH.

Patients And Methods: The first patient, an 11-year-old girl suffering from hypocalcemia, developed nephrocalcinosis when she was only 5 years old. The second patient is a 30-year-old woman who presented with mild hypercalcemia. PCR amplification of CASR coding exons and direct sequencing of PCR products were used to identify mutations. Site-directed mutagenesis was used to generate mutated CASR cDNAs in an expression plasmid. Using the MAPK assay system and transient transfection of Cos-7 cells with wild-type (WT) and mutated CASR, we studied the responses of these mutated receptors to extracellular Ca(2+) and to the negative allosteric CASR modulator, NPS2143.

Results: Two heterozygous missense mutations (p.N802I and p.N802S) affecting a residue in the sixth transmembrane domain of CASR were identified. In functional tests, the response of the p.N802S mutant to calcium was typical of an inactivating mutation. However, the p.N802I mutant had 70% of the maximally stimulated WT receptor activity even in the absence of extracellular calcium. This constitutive activity was only partially inhibited by the inhibitor, NPS2143.

Conclusions: The asparagine at amino acid position 802 appears to be essential for the activity of the CASR protein and is implicated in the mechanism of CASR signaling.
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http://dx.doi.org/10.1530/EJE-12-0714DOI Listing
February 2013

[Height and weight delay in growth].

Rev Prat 2011 Oct;61(8):1133-40

Endocrinologie pédiatrique, hôpital de la Mère et de l'Enfant, 87042 Limoges Cedex.

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October 2011

A comparative phenotypic study of kallmann syndrome patients carrying monoallelic and biallelic mutations in the prokineticin 2 or prokineticin receptor 2 genes.

J Clin Endocrinol Metab 2010 Feb 18;95(2):659-69. Epub 2009 Dec 18.

Service d'Endocrinologie, Hôpital Bicêtre, 78 Rue du Général Leclerc, 94275 Le Kremlin Bicêtre, France.

Context: Both biallelic and monoallelic mutations in PROK2 or PROKR2 have been found in Kallmann syndrome (KS).

Objective: The objective of the study was to compare the phenotypes of KS patients harboring monoallelic and biallelic mutations in these genes.

Design And Patients: We studied clinical and endocrine features that reflect the functioning of the pituitary-gonadal axis, and the nonreproductive phenotype, in 55 adult KS patients (42 men and 13 women), of whom 41 had monoallelic mutations and 14 biallelic mutations in PROK2 or PROKR2.

Results: Biallelic mutations were associated with more frequent cryptorchidism (70% vs. 34%, P < 0.05) and microphallus (90% vs. 28%, P < 0.001) and lower mean testicular volume (1.2 +/- 0.4 vs. 4.5 +/- 6.0 ml; P < 0.01) in male patients. Likewise, the testosterone level as well as the basal FSH level and peak LH level under GnRH-stimulation were lower in males with biallelic mutations (0.2 +/- 0.1 vs. 0.7 +/- 0.8 ng/ml; P = 0.05, 0.3 +/- 0.1 vs. 1.8 +/- 3.0 IU/liter; P < 0.05, and 0.8 +/- 0.8 vs. 5.2 +/- 5.5 IU/liter; P < 0.05, respectively). Nonreproductive, nonolfactory anomalies were rare in both sexes and were never found in patients with biallelic mutations. The mean body mass index of the patients (23.9 +/- 4.2 kg/m(2) in males and 26.3 +/- 6.6 kg/m(2) in females) did not differ significantly from that of gender-, age-, and treatment-matched KS individuals who did not carry a mutation in PROK2 or PROKR2. Finally, circadian cortisol levels evaluated in five patients, including one with biallelic PROKR2 mutations, were normal in all cases.

Conclusion: Male patients carrying biallelic mutations in PROK2 or PROKR2 have a less variable and on average a more severe reproductive phenotype than patients carrying monoallelic mutations in these genes. Nonreproductive, nonolfactory clinical anomalies associated with KS seem to be restricted to patients with monoallelic mutations.
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http://dx.doi.org/10.1210/jc.2009-0843DOI Listing
February 2010

Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2.

PLoS Genet 2006 Oct 1;2(10):e175. Epub 2006 Sep 1.

Institut Cochin, INSERM U567, Université René Descartes, Paris, France.

Kallmann syndrome combines anosmia, related to defective olfactory bulb morphogenesis, and hypogonadism due to gonadotropin-releasing hormone deficiency. Loss-of-function mutations in KAL1 and FGFR1 underlie the X chromosome-linked form and an autosomal dominant form of the disease, respectively. Mutations in these genes, however, only account for approximately 20% of all Kallmann syndrome cases. In a cohort of 192 patients we took a candidate gene strategy and identified ten and four different point mutations in the genes encoding the G protein-coupled prokineticin receptor-2 (PROKR2) and one of its ligands, prokineticin-2 (PROK2), respectively. The mutations in PROK2 were detected in the heterozygous state, whereas PROKR2 mutations were found in the heterozygous, homozygous, or compound heterozygous state. In addition, one of the patients heterozygous for a PROKR2 mutation was also carrying a missense mutation in KAL1, thus indicating a possible digenic inheritance of the disease in this individual. These findings reveal that insufficient prokineticin-signaling through PROKR2 leads to abnormal development of the olfactory system and reproductive axis in man. They also shed new light on the complex genetic transmission of Kallmann syndrome.
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http://dx.doi.org/10.1371/journal.pgen.0020175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1617130PMC
October 2006

Characterization of a novel loss of function mutation of PAX8 in a familial case of congenital hypothyroidism with in-place, normal-sized thyroid.

J Clin Endocrinol Metab 2004 Sep;89(9):4285-91

IRIBHM, Université Libre de Bruxelles, Campus Erasme, 808 route de Lennik, B-1070 Bruxelles, Belgium.

Thyroid dysgenesis is the most common cause of congenital hypothyroidism, a relatively frequent disease affecting 1 in 3000-4000 newborns. Whereas most cases are sporadic, mutations in transcription factors implicated in thyroid development have been shown to cause a minority of cases transmitted as monogenic Mendelian diseases. PAX8 is one of these transcription factors, and so far, five mutations have been identified in its paired domain in patients with thyroid dysgenesis. We have identified a novel mutation of PAX8, in the heterozygous state, in a father and his two children both presenting with congenital hypothyroidism associated with an in-place thyroid of normal size at birth. In addition, one of the affected siblings displayed unilateral kidney agenesis. The mutation substitutes a highly conserved serine in position 54 of the DNA-binding domain of the protein (S54G mutation) by a glycine. Functional analyses of the mutant protein (PAX8-S54G) demonstrated that it is unable to bind a specific cis-element of the thyroperoxidase gene promoter in EMSAs and that it has almost completely lost the ability to act in synergy with Titf1 to transactivate transcription from the thyroglobulin promoter/enhancer. These results indicate that loss of function mutations of the PAX8 gene may cause congenital hypothyroidism in the absence of thyroid hypoplasia.
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http://dx.doi.org/10.1210/jc.2004-0166DOI Listing
September 2004