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Michel Polak - One of the best experts on this subject based on the ideXlab platform.
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a novel foxe1 mutation r73s in bamforth lazarus syndrome causing increased Thyroidal gene expression
Thyroid, 2014Co-Authors: Aurore Carre, Rasha T Hamza, Dulanjalee Kariyawasam, Loic Guillot, Raphael Teissier, Elodie Tron, Mireille Castanet, Corinne Dupuy, Mohamed El Kholy, Michel PolakAbstract:Background: Homozygous loss-of-function mutations in the FOXE1 gene have been reported in several patients with partial or complete Bamforth–Lazarus syndrome: congenital hypoThyroidism (CH) with Thyroid Dysgenesis (usually athyreosis), cleft palate, spiky hair, with or without choanal atresia, and bifid epiglottis. Here, our objective was to evaluate potential functional consequences of a FOXE1 mutation in a patient with a similar clinical phenotype. Methods: FOXE1 was sequenced in eight patients with Thyroid Dysgenesis and cleft palate. Transient transfection was performed in HEK293 cells using the thyroglobulin (TG) and Thyroid peroxidase (TPO) promoters in luciferase reporter plasmids to assess the functional impact of the FOXE1 mutations. Primary human thyrocytes transfected with wild type and mutant FOXE1 served to assess the impact of the mutation on endogenous TG and TPO expression. Results: We identified and characterized the function of a new homozygous FOXE1 missense mutation (p.R73S) in a boy w...
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spectrum of human foxe1 ttf2 mutations
Hormone Research in Paediatrics, 2010Co-Authors: Mireille Castanet, Michel PolakAbstract:FOXE1 (or TTF-2) has been recognized as one of the Thyroid Dysgenesis (TD)-related genes based on its early expression at the Thyroid bud stage and on the finding in Foxe1 knock-out mice of a sublingual or absent Thyroid gland. In humans, three homozygous loss-of-function missense mutations located within the forkhead domain have been reported in 5 patients with Bamforth syndrome. This syndrome is a rare inherited condition whose main features are congenital hypoThyroidism (CH) due to TD (usually athyreosis), cleft palate, and spiky hair, with or without choanal atresia and bifid epiglottis. These FOXE1 mutations were typically inherited from heterozygous carrier parents who were usually consanguineous. Recently, a novelmissense mutation was found in a patient with sporadic Bamforth syndrome, inherited via uniparental isodisomy. Altogether these observations strongly suggest that FOXE1 is involved in both familial and sporadic syndromic CH due to TD in association with cleft palate. Nevertheless, despite intensive research, FOXE1 mutations have been identified in only a minority of the affected patients. Recent data suggest that the transcription factor encoded by FOXE1 may act as a susceptibility factor for TD via variations in FOXE1 polyalanine tract length, which may modulate the risk of TD.
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Thyroid hemiagenesis is a rare variant of Thyroid Dysgenesis with a familial component but without pax8 mutations in a cohort of 22 cases
Pediatric Research, 2005Co-Authors: Mireille Castanet, Juliane Leger, Paul Czernichow, Laurence Leenhardt, Aurore Simoncarre, Stanislas Lyonnet, Anna Pelet, Michel PolakAbstract:Thyroid hemiagenesis is a rare form of Thyroid Dysgenesis of which some familial cases have been reported, including one associated with a heterozygous mutation in the Pax8 gene. However, the physiopathology remains not well known. The objectives of this study were 1) to describe the clinical features, 2) to look for familial clustering, and 3) to search for Pax8 mutations in a relatively large cohort of affected patients. A family history of Thyroid Dysgenesis was found in nine patients (40%), whose affected relatives had ectopic Thyroid (n = 4), athyreosis (n = 1), Thyroid hemiagenesis (n = 2), or thyroglossal duct cysts (n = 2). Screening for Pax8 mutations identified abnormal migration profiles by SSCP analysis in 3 patients, but direct sequencing did not show coding region mutations in any of the 22 patients. In conclusion, this study provides the first evidence that Thyroid hemiagenesis can occur as a familial disorder associated with any form of Thyroid Dysgenesis. This finding supports both a common underlying mechanism to the various abnormalities in Thyroid development and a role for genetic factors; however, our results from Pax8 analysis suggest that this gene may not be a key factor.
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pax8 titf1 and foxe1 gene expression patterns during human development new insights into human Thyroid development and Thyroid Dysgenesis associated malformations
The Journal of Clinical Endocrinology and Metabolism, 2005Co-Authors: Sylvia Sura Trueba, Michel Polak, Paul Czernichow, Joelle Auge, Geraldine Mattei, Heather C Etchevers, Jeleena Martinovic, Michel Vekemans, Tania AttiebitachAbstract:Thyroid Dysgenesis (TD) is responsible for most cases of congenital hypoThyroidism, a condition that affects about one in 4000 newborns. Mutations in PAX8, TITF1, or FOXE1 may account for congenital hypoThyroidism in patients with either isolated TD or TD with associated malformations involving kidney, lung, forebrain, and palate. Pax8, titf1, and foxe1 are expressed in the mouse Thyroid bud as soon as it differentiates on the pharyngeal floor. Because the spatio-temporal expression of these genes is unknown in humans, we decided to study them at different stages of human embryonic and fetal development. PAX8 and TITF1 were first expressed in the median Thyroid primordium. Interestingly, PAX8 was also expressed in the thyroglossal duct and the ultimobranchial bodies. Human FOXE1 expression was detected later than in the mouse. PAX8 was also expressed in the developing central nervous system and kidney, including the ureteric bud and the main collecting ducts. TITF1 was expressed in the ventral forebrain and lung. FOXE1 expression was detected in the oropharyngeal epithelium and thymus. In conclusion, the expression patterns described here show some differences from those reported in the mouse. They explain the malformations associated with TD in patients carrying PAX8, TITF1, and FOXE1 gene mutations.
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a novel loss of function mutation in ttf 2 is associated with congenital hypoThyroidism Thyroid agenesis and cleft palate
Human Molecular Genetics, 2002Co-Authors: Mireille Castanet, Juliane Leger, Paul Czernichow, Stanislas Lyonnet, Anna Pelet, Soomi Park, Aaron G Smith, Michel Bost, Krishna Chatterjee, Michel PolakAbstract:Thyroid Dysgenesis is the most common cause of congenital hypoThyroidism (CH) and its genetic basis is largely unknown. Here, we describe the second homozygous missense mutation in TTF-2 (or FOXE1), a transcription factor that has been implicated in Thyroid development. Two male siblings, born to consanguineous parents, presented with CH, athyreosis and cleft palate and were found to be homozygous for a mutation corresponding to a serine to asparagine substitution at codon 57 (S57N) in the forkhead DNA binding domain of TTF-2. Their heterozygous parents were unaffected and this mutation was not found in 31 unrelated cases of athyreosis or normal controls. Consistent with its location, the S57N TTF-2 mutant protein showed impaired DNA binding and partial loss of transcriptional function. Such incomplete loss of TTF-2 function may account for the absence of choanal atresia and bifid epiglottis in our patients, anomalies which were present together with CH and cleft palate in two other individuals with the only other, more deleterious, TTF-2 mutation (A65V) described previously. Our observations support the role of TTF-2 in both Thyroid and palate development but suggest phenotypic heterogeneity of this syndromic form of CH.
Mireille Castanet - One of the best experts on this subject based on the ideXlab platform.
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a novel foxe1 mutation r73s in bamforth lazarus syndrome causing increased Thyroidal gene expression
Thyroid, 2014Co-Authors: Aurore Carre, Rasha T Hamza, Dulanjalee Kariyawasam, Loic Guillot, Raphael Teissier, Elodie Tron, Mireille Castanet, Corinne Dupuy, Mohamed El Kholy, Michel PolakAbstract:Background: Homozygous loss-of-function mutations in the FOXE1 gene have been reported in several patients with partial or complete Bamforth–Lazarus syndrome: congenital hypoThyroidism (CH) with Thyroid Dysgenesis (usually athyreosis), cleft palate, spiky hair, with or without choanal atresia, and bifid epiglottis. Here, our objective was to evaluate potential functional consequences of a FOXE1 mutation in a patient with a similar clinical phenotype. Methods: FOXE1 was sequenced in eight patients with Thyroid Dysgenesis and cleft palate. Transient transfection was performed in HEK293 cells using the thyroglobulin (TG) and Thyroid peroxidase (TPO) promoters in luciferase reporter plasmids to assess the functional impact of the FOXE1 mutations. Primary human thyrocytes transfected with wild type and mutant FOXE1 served to assess the impact of the mutation on endogenous TG and TPO expression. Results: We identified and characterized the function of a new homozygous FOXE1 missense mutation (p.R73S) in a boy w...
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maternal isodisomy for chromosome 9 causing homozygosity for a novel foxe1 mutation in syndromic congenital hypoThyroidism
The Journal of Clinical Endocrinology and Metabolism, 2010Co-Authors: Mireille Castanet, Uma Mallya, Maura Agostini, Erik Schoenmakers, Catherine Mitchell, Stephanie Demuth, Lucy F Raymond, John W R Schwabe, Mark GurnellAbstract:Context: Homozygous loss-of-function mutations in forkhead box E1/Thyroid transcription factor 2 (FOXE1/TTF-2) cause syndromic congenital hypoThyroidism, with Thyroid Dysgenesis, cleft palate, spiky hair, and variable choanal atresia and bifid epiglottis in three cases reported hitherto. We have elucidated the molecular basis of the disorder in a female with a similar clinical phenotype, born to nonconsanguineous parents. Objective and Design: The FOXE1 gene, located on chromosome 9q22, was sequenced in the proband and family members. Microsatellite marker and multiplex ligation probe amplification analyses determined chromosomal inheritance patterns and FOXE1 copy number. Mutant FOXE1 function was predicted by structural modeling and tested in transfection assays. Results: The proband was homozygous for a novel missense (c.412T→C; F137S) FOXE1 mutation, but her mother showed heterozygous and father wild-type alleles for this gene sequence. However, the proband was also homozygous for 10 microsatellite ma...
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spectrum of human foxe1 ttf2 mutations
Hormone Research in Paediatrics, 2010Co-Authors: Mireille Castanet, Michel PolakAbstract:FOXE1 (or TTF-2) has been recognized as one of the Thyroid Dysgenesis (TD)-related genes based on its early expression at the Thyroid bud stage and on the finding in Foxe1 knock-out mice of a sublingual or absent Thyroid gland. In humans, three homozygous loss-of-function missense mutations located within the forkhead domain have been reported in 5 patients with Bamforth syndrome. This syndrome is a rare inherited condition whose main features are congenital hypoThyroidism (CH) due to TD (usually athyreosis), cleft palate, and spiky hair, with or without choanal atresia and bifid epiglottis. These FOXE1 mutations were typically inherited from heterozygous carrier parents who were usually consanguineous. Recently, a novelmissense mutation was found in a patient with sporadic Bamforth syndrome, inherited via uniparental isodisomy. Altogether these observations strongly suggest that FOXE1 is involved in both familial and sporadic syndromic CH due to TD in association with cleft palate. Nevertheless, despite intensive research, FOXE1 mutations have been identified in only a minority of the affected patients. Recent data suggest that the transcription factor encoded by FOXE1 may act as a susceptibility factor for TD via variations in FOXE1 polyalanine tract length, which may modulate the risk of TD.
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polymorphic length of foxe1 alanine stretch evidence for genetic susceptibility to Thyroid Dysgenesis
Human Genetics, 2007Co-Authors: Aurore Carre, Delphine Trochet, Jeanne Amiel, Mireille Castanet, Sylvia Suratrueba, Gabor Szinnai, Guy Van Vliet, Juliane Leger, Paul Czernichow, Virginie ScotetAbstract:Familial cases of congenital hypoThyroidism from Thyroid Dysgenesis (TD) (OMIM 218700) occur with a frequency 15-fold higher than by chance, FOXE1 is one of the candidate genes for this genetic predisposition and contains an alanine tract. Our purpose is to assess the influence of length of the alanine tract of FOXE1 on genetic susceptibility to TD. A case–control association study (based on 115 patients affected by TD and 129 controls genotyped by direct sequencing) and transmission disequilibrium testing (TDT) analyses were performed. The transcriptional activities of FOXE1 constructs containing 14 or 16 alanines were also studied. In the case–control association study, the 16/16 and 16/14 genotypes were inversely associated with TD (OR = 0.39, 95%CI = 0.22–0.68, P = 0.0005), strongly suggesting that the presence of 16 alanines in the tract protect against the occurrence of TD. This association was stronger in the subgroup of patients with ectopic Thyroid (OR = 0.28, 95%CI = 0.13–0.58, P = 0.00015). The protection was confirmed by the TDT analysis performed in 39 trios (χ2 = 4.3, P = 0.0374). Alternatively, the presence of the 14/14 genotype is associated with an increase risk of TD (OR = 2.59, 95%CI = 1.56–4.62, P = 0.0005). The expression studies showed that the transcriptional activities of FOXE1 with 16 alanines were significantly higher (1.55-fold) than FOXE1 containing 14 alanines (P < 0.003), while the nuclear localisation of the proteins was not affected. We conclude that FOXE1 through its alanine containing stretch modulates significantly the risk of TD occurrence, enhancing a mechanism linking an alanine containing transcription factor to disease.
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Thyroid hemiagenesis is a rare variant of Thyroid Dysgenesis with a familial component but without pax8 mutations in a cohort of 22 cases
Pediatric Research, 2005Co-Authors: Mireille Castanet, Juliane Leger, Paul Czernichow, Laurence Leenhardt, Aurore Simoncarre, Stanislas Lyonnet, Anna Pelet, Michel PolakAbstract:Thyroid hemiagenesis is a rare form of Thyroid Dysgenesis of which some familial cases have been reported, including one associated with a heterozygous mutation in the Pax8 gene. However, the physiopathology remains not well known. The objectives of this study were 1) to describe the clinical features, 2) to look for familial clustering, and 3) to search for Pax8 mutations in a relatively large cohort of affected patients. A family history of Thyroid Dysgenesis was found in nine patients (40%), whose affected relatives had ectopic Thyroid (n = 4), athyreosis (n = 1), Thyroid hemiagenesis (n = 2), or thyroglossal duct cysts (n = 2). Screening for Pax8 mutations identified abnormal migration profiles by SSCP analysis in 3 patients, but direct sequencing did not show coding region mutations in any of the 22 patients. In conclusion, this study provides the first evidence that Thyroid hemiagenesis can occur as a familial disorder associated with any form of Thyroid Dysgenesis. This finding supports both a common underlying mechanism to the various abnormalities in Thyroid development and a role for genetic factors; however, our results from Pax8 analysis suggest that this gene may not be a key factor.
Joachim Pohlenz - One of the best experts on this subject based on the ideXlab platform.
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novel mutations in the nkx2 1 gene and the pax8 gene in a boy with brain lung Thyroid syndrome
Experimental and Clinical Endocrinology & Diabetes, 2017Co-Authors: Pia Hermanns, Helmut Grasberger, Samuel Refetoff, Malgorzata Kumorowiczczoch, Joachim PohlenzAbstract:Objective To elucidate the molecular mechanism which causes Thyroid Dysgenesis (TD) in a boy with brain-lung-Thyroid syndrome. Design, patients, measurements We describe a patient with TD, respiratory disease and cerebral palsy who is heterozygous for mutations in two different genes, the PAX8 (p.E234K) and the NKX2.1 (p.A329GfsX108). In vitro studies were performed to functionally characterize these mutations. Congenital hypoThyroidism (CH) was identified by neonatal screening associated with a hypoplastic Thyroid gland. Postpartum he developed a brain-lung-Thyroid syndrome with severe respiratory failure, symptomatic epilepsy and a considerable psychomotor retardation. The DNA-binding capability and the transcriptional activity of the two mutated transcription factors were investigated in vitro. Results The NKX2.1 mutation did not show any transcriptional activity and had almost no DNA-binding. The PAX8 mutation was normally located to the nucleus and showed a normal transactivation and a normal binding to the known downstream targets. Conclusions The molecular defect explaining the phenotype of brain-lung-Thyroid syndrome was identified. To what extent the PAX8 mutation contributes to the phenotype needs to be further investigated. We recommend to screen patients with CH and TD for mutations in all known TD candidate genes.
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two cases of Thyroid Dysgenesis caused by different novel pax8 mutations in the dna binding region in vitro studies reveal different pathogenic mechanisms
Thyroid, 2012Co-Authors: Pia Hermanns, Helmut Grasberger, Samuel Refetoff, Ronald N Cohen, Clemens Freiberg, Helmuthgunther Dorr, Joachim PohlenzAbstract:Background: Mutations in PAX8, a transcription factor gene, cause Thyroid Dysgenesis (TD). The extreme variability of the Thyroid phenotype makes it difficult to identify individuals harboring PAX8 gene mutations. Here we describe two patients with TD and report two novel PAX8 gene mutations (S54R and R133Q). We performed in vitro studies to functionally characterize these mutations. Methods: Using PAX8 expression vectors, we investigated whether the PAX8 mutants localized correctly to the nucleus. To analyze the DNA-binding properties of S54R and R133Q, electrophoretic mobility shift assays were performed. Furthermore, we measured whether the mutant PAX8 proteins were able to activate the thyroglobulin (TG)- and the thyroperoxidase (TPO)-promoters. Results: S54R had an impaired binding to DNA and a negligible activity on the TG- and the TPO-promoters. The DNA-binding property of R133Q, which is located in the highly conserved terminal portion of the PAX8 DNA-binding domain, was normal. Interestingly, it ...
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mutations in the nkx2 5 gene and the pax8 promoter in a girl with Thyroid Dysgenesis
The Journal of Clinical Endocrinology and Metabolism, 2011Co-Authors: Pia Hermanns, Helmut Grasberger, Samuel Refetoff, Joachim PohlenzAbstract:A girl with Thyroid Dysgenesis had two gene mutations resulting in two defective transcriptional factors important for Thyroid development.
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partial deficiency of Thyroid transcription factor 1 produces predominantly neurological defects in humans and mice
Journal of Clinical Investigation, 2002Co-Authors: Joachim Pohlenz, Roy E Weiss, Ronald N Cohen, Alexandra M Dumitrescu, Dorothee Zundel, Ursula Martine, Winfried Schonberger, Eugene Koo, Shioko Kimura, Samuel RefetoffAbstract:Three genes, TTF1, TTF2, and PAX8, involved in Thyroid gland development and migration have been identified. Yet systematic screening for defects in these genes in Thyroid Dysgenesis gave essentially negative results. In particular, no TTF1 gene defects were found in 76 individuals with Thyroid Dysgenesis even though a deletion of this gene in the mouse results in Thyroid and lung agenesis and defective diencephalon. We report a 6-year-old boy with predominant dyskinesia, neonatal respiratory distress, and mild hyperthyrotropinemia. One allele of his TTF1 gene had a guanidine inserted into codon 86 producing a nonsense protein of 407, rather than 371, amino acids. The mutant TTF1 did not bind to its canonical cis-element or transactivate a reporter gene driven by the thyroglobulin promoter, a natural target of TTF1. Failure of the mutant TTF1 to interfere with binding and transactivation functions of the wild-type TTF1 suggested that the syndrome was caused by haploinsufficiency. This was confirmed in mice heterozygous for Ttf1 gene deletion, heretofore considered to be normal. Compared with wild-type littermates, Ttf1(+/-) mice had poor coordination and a significant elevation of serum thyrotropin. Therefore, haploinsufficiency of the TTF1 gene results in a predominantly neurological phenotype and secondary hyperthyrotropinemia.
Samuel Refetoff - One of the best experts on this subject based on the ideXlab platform.
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novel mutations in the nkx2 1 gene and the pax8 gene in a boy with brain lung Thyroid syndrome
Experimental and Clinical Endocrinology & Diabetes, 2017Co-Authors: Pia Hermanns, Helmut Grasberger, Samuel Refetoff, Malgorzata Kumorowiczczoch, Joachim PohlenzAbstract:Objective To elucidate the molecular mechanism which causes Thyroid Dysgenesis (TD) in a boy with brain-lung-Thyroid syndrome. Design, patients, measurements We describe a patient with TD, respiratory disease and cerebral palsy who is heterozygous for mutations in two different genes, the PAX8 (p.E234K) and the NKX2.1 (p.A329GfsX108). In vitro studies were performed to functionally characterize these mutations. Congenital hypoThyroidism (CH) was identified by neonatal screening associated with a hypoplastic Thyroid gland. Postpartum he developed a brain-lung-Thyroid syndrome with severe respiratory failure, symptomatic epilepsy and a considerable psychomotor retardation. The DNA-binding capability and the transcriptional activity of the two mutated transcription factors were investigated in vitro. Results The NKX2.1 mutation did not show any transcriptional activity and had almost no DNA-binding. The PAX8 mutation was normally located to the nucleus and showed a normal transactivation and a normal binding to the known downstream targets. Conclusions The molecular defect explaining the phenotype of brain-lung-Thyroid syndrome was identified. To what extent the PAX8 mutation contributes to the phenotype needs to be further investigated. We recommend to screen patients with CH and TD for mutations in all known TD candidate genes.
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chapter 7 congenital defects of Thyroid hormone synthesis
Genetic Diagnosis of Endocrine Disorders (Second edition), 2016Co-Authors: Helmut Grasberger, Samuel RefetoffAbstract:With a prevalence of one in 3000–4000 newborns, congenital hypoThyroidism (CH) is the most common inborn endocrine disorder and one of the most common preventable causes of mental retardation. While most cases are sporadic and associated with abnormalities of Thyroid gland development and migration (Thyroid Dysgenesis), approximately 15–20% are caused by inherited defects in one of the steps of Thyroid hormone synthesis (Thyroid dyshormonogenesis). When the synthesis defect results in reduced hormone secretion, the ensuing diminished negative feedback on the anterior pituitary thyrotrophs leads to an increase in thyrotropin (TSH) secretion stimulating the Thyroid gland. Consequently, patients are born with an enlarged Thyroid gland (goiter) or develop goiter postnatally, especially when diagnosis and treatment with levothyroxine (L-T4) are delayed.
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two cases of Thyroid Dysgenesis caused by different novel pax8 mutations in the dna binding region in vitro studies reveal different pathogenic mechanisms
Thyroid, 2012Co-Authors: Pia Hermanns, Helmut Grasberger, Samuel Refetoff, Ronald N Cohen, Clemens Freiberg, Helmuthgunther Dorr, Joachim PohlenzAbstract:Background: Mutations in PAX8, a transcription factor gene, cause Thyroid Dysgenesis (TD). The extreme variability of the Thyroid phenotype makes it difficult to identify individuals harboring PAX8 gene mutations. Here we describe two patients with TD and report two novel PAX8 gene mutations (S54R and R133Q). We performed in vitro studies to functionally characterize these mutations. Methods: Using PAX8 expression vectors, we investigated whether the PAX8 mutants localized correctly to the nucleus. To analyze the DNA-binding properties of S54R and R133Q, electrophoretic mobility shift assays were performed. Furthermore, we measured whether the mutant PAX8 proteins were able to activate the thyroglobulin (TG)- and the thyroperoxidase (TPO)-promoters. Results: S54R had an impaired binding to DNA and a negligible activity on the TG- and the TPO-promoters. The DNA-binding property of R133Q, which is located in the highly conserved terminal portion of the PAX8 DNA-binding domain, was normal. Interestingly, it ...
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mutations in the nkx2 5 gene and the pax8 promoter in a girl with Thyroid Dysgenesis
The Journal of Clinical Endocrinology and Metabolism, 2011Co-Authors: Pia Hermanns, Helmut Grasberger, Samuel Refetoff, Joachim PohlenzAbstract:A girl with Thyroid Dysgenesis had two gene mutations resulting in two defective transcriptional factors important for Thyroid development.
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congenital defects of Thyroid hormone synthesis
Genetic Diagnosis of Endocrine Disorders, 2010Co-Authors: Helmut Grasberger, Samuel RefetoffAbstract:Publisher Summary This chapter focuses on the congenital defects in synthesis of Thyroid hormone. Congenital hypoThyroidism (CH) is mentioned to be the most inborn endocrine disorder and one of the most preventable causes of mental retardation. The disorder may be associated with abnormalities of Thyroid gland development and migration (Thyroid Dysgenesis) or the disease can be caused by inherited defects in one of the steps of Thyroid hormone synthesis (Thyroid dyshormonogenesis). The etiological classification of CH is stated to be based on clinical and biochemical evaluation by measurement of serum thyrotropin, thyroxine, triiodothyronine and thyroglobulin by Thyroid ultrasonography and scintigraphy. The identification of key steps involved in Thyroid hormone synthesis can make molecular genetic diagnosis feasible for a majority of dyshormonogenesis patients. The pathophysiology and genetics of specific dyshormonogenesis defect is elaborated. An effective treatment of patients with specific defects is mentioned to be iodide supplementation rather than by levothyroxine and an early molecular diagnosis can predict the necessity for life-long hormone replacement therapy.
Helmut Grasberger - One of the best experts on this subject based on the ideXlab platform.
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novel mutations in the nkx2 1 gene and the pax8 gene in a boy with brain lung Thyroid syndrome
Experimental and Clinical Endocrinology & Diabetes, 2017Co-Authors: Pia Hermanns, Helmut Grasberger, Samuel Refetoff, Malgorzata Kumorowiczczoch, Joachim PohlenzAbstract:Objective To elucidate the molecular mechanism which causes Thyroid Dysgenesis (TD) in a boy with brain-lung-Thyroid syndrome. Design, patients, measurements We describe a patient with TD, respiratory disease and cerebral palsy who is heterozygous for mutations in two different genes, the PAX8 (p.E234K) and the NKX2.1 (p.A329GfsX108). In vitro studies were performed to functionally characterize these mutations. Congenital hypoThyroidism (CH) was identified by neonatal screening associated with a hypoplastic Thyroid gland. Postpartum he developed a brain-lung-Thyroid syndrome with severe respiratory failure, symptomatic epilepsy and a considerable psychomotor retardation. The DNA-binding capability and the transcriptional activity of the two mutated transcription factors were investigated in vitro. Results The NKX2.1 mutation did not show any transcriptional activity and had almost no DNA-binding. The PAX8 mutation was normally located to the nucleus and showed a normal transactivation and a normal binding to the known downstream targets. Conclusions The molecular defect explaining the phenotype of brain-lung-Thyroid syndrome was identified. To what extent the PAX8 mutation contributes to the phenotype needs to be further investigated. We recommend to screen patients with CH and TD for mutations in all known TD candidate genes.
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chapter 7 congenital defects of Thyroid hormone synthesis
Genetic Diagnosis of Endocrine Disorders (Second edition), 2016Co-Authors: Helmut Grasberger, Samuel RefetoffAbstract:With a prevalence of one in 3000–4000 newborns, congenital hypoThyroidism (CH) is the most common inborn endocrine disorder and one of the most common preventable causes of mental retardation. While most cases are sporadic and associated with abnormalities of Thyroid gland development and migration (Thyroid Dysgenesis), approximately 15–20% are caused by inherited defects in one of the steps of Thyroid hormone synthesis (Thyroid dyshormonogenesis). When the synthesis defect results in reduced hormone secretion, the ensuing diminished negative feedback on the anterior pituitary thyrotrophs leads to an increase in thyrotropin (TSH) secretion stimulating the Thyroid gland. Consequently, patients are born with an enlarged Thyroid gland (goiter) or develop goiter postnatally, especially when diagnosis and treatment with levothyroxine (L-T4) are delayed.
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two cases of Thyroid Dysgenesis caused by different novel pax8 mutations in the dna binding region in vitro studies reveal different pathogenic mechanisms
Thyroid, 2012Co-Authors: Pia Hermanns, Helmut Grasberger, Samuel Refetoff, Ronald N Cohen, Clemens Freiberg, Helmuthgunther Dorr, Joachim PohlenzAbstract:Background: Mutations in PAX8, a transcription factor gene, cause Thyroid Dysgenesis (TD). The extreme variability of the Thyroid phenotype makes it difficult to identify individuals harboring PAX8 gene mutations. Here we describe two patients with TD and report two novel PAX8 gene mutations (S54R and R133Q). We performed in vitro studies to functionally characterize these mutations. Methods: Using PAX8 expression vectors, we investigated whether the PAX8 mutants localized correctly to the nucleus. To analyze the DNA-binding properties of S54R and R133Q, electrophoretic mobility shift assays were performed. Furthermore, we measured whether the mutant PAX8 proteins were able to activate the thyroglobulin (TG)- and the thyroperoxidase (TPO)-promoters. Results: S54R had an impaired binding to DNA and a negligible activity on the TG- and the TPO-promoters. The DNA-binding property of R133Q, which is located in the highly conserved terminal portion of the PAX8 DNA-binding domain, was normal. Interestingly, it ...
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mutations in the nkx2 5 gene and the pax8 promoter in a girl with Thyroid Dysgenesis
The Journal of Clinical Endocrinology and Metabolism, 2011Co-Authors: Pia Hermanns, Helmut Grasberger, Samuel Refetoff, Joachim PohlenzAbstract:A girl with Thyroid Dysgenesis had two gene mutations resulting in two defective transcriptional factors important for Thyroid development.
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congenital defects of Thyroid hormone synthesis
Genetic Diagnosis of Endocrine Disorders, 2010Co-Authors: Helmut Grasberger, Samuel RefetoffAbstract:Publisher Summary This chapter focuses on the congenital defects in synthesis of Thyroid hormone. Congenital hypoThyroidism (CH) is mentioned to be the most inborn endocrine disorder and one of the most preventable causes of mental retardation. The disorder may be associated with abnormalities of Thyroid gland development and migration (Thyroid Dysgenesis) or the disease can be caused by inherited defects in one of the steps of Thyroid hormone synthesis (Thyroid dyshormonogenesis). The etiological classification of CH is stated to be based on clinical and biochemical evaluation by measurement of serum thyrotropin, thyroxine, triiodothyronine and thyroglobulin by Thyroid ultrasonography and scintigraphy. The identification of key steps involved in Thyroid hormone synthesis can make molecular genetic diagnosis feasible for a majority of dyshormonogenesis patients. The pathophysiology and genetics of specific dyshormonogenesis defect is elaborated. An effective treatment of patients with specific defects is mentioned to be iodide supplementation rather than by levothyroxine and an early molecular diagnosis can predict the necessity for life-long hormone replacement therapy.