scholarly journals Characterization of a Novel Loss of Function Mutation of PAX8 in a Familial Case of Congenital Hypothyroidism with In-Place, Normal-Sized Thyroid

2004 ◽  
Vol 89 (9) ◽  
pp. 4285-4291 ◽  
Author(s):  
Laurent Meeus ◽  
Brigitte Gilbert ◽  
Catherine Rydlewski ◽  
Jasmine Parma ◽  
Anne Lienhardt Roussie ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Congenital Hypothyroidism ◽  
Novel Mutation ◽  
Gene Promoter ◽  
Loss Of Function ◽  
Thyroid Dysgenesis ◽  
Cis Element ◽  
Ability To Act ◽  
Pax8 Gene ◽  
Functional Analyses

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.

scholarly journals Extreme phenotypic variability of thyroid dysgenesis in six new cases of congenital hypothyroidism due to PAX8 gene loss-of-function mutations

2014 ◽  
Vol 171 (4) ◽  
pp. 499-507 ◽  
Author(s):  
H E Ramos ◽  
A Carré ◽  
L Chevrier ◽  
G Szinnai ◽  
E Tron ◽  
...  
Keyword(s):  
Thyroid Gland ◽  
Congenital Hypothyroidism ◽  
Screening Program ◽  
Phenotypic Variability ◽  
Cross Sectional Study ◽  
The Novel ◽  
Loss Of Function ◽  
Cross Sectional ◽  
Clinical Presentations ◽  
Pax8 Gene

ContextWithin the last two decades, heterozygous loss-of-function PAX8 mutations have been reported in patients with a wide degree of thyroid gland dysfunction and growth despite the presence of identical mutations.ObjectivesTo search for PAX8 mutations in a cohort of patients with congenital hypothyroidism (CH) and various types of thyroid gland defects.DesignA cross-sectional study was conducted in a cohort of patients.SettingThe French neonatal screening program was used for recruiting patients.PatientsA total of 118 patients with CH, including 45 with familial and 73 with sporadic diseases, were included in this study. The thyroid gland was normal in 23 patients had hypoplasia, 25 had hemithyroid agenesis, 21 had athyreosis, and 21 had ectopy.ResultsWe found four different PAX8 mutations (p.R31C, p.R31H, p.R108X, and p.I47T) in ten patients (six patients with CH and four family members), two with sporadic and eight with familial diseases. Imaging studies performed in the index cases showed ectopic thyroid gland (n=2), hypoplasia (n=2), eutopic lobar asymmetry (n=1), and eutopic gland compatible with dyshormonogenesis (n=1). The previously reported p.R31C and the novel p.I47T PAX8 mutations are devoid of activity.ConclusionFour different PAX8 mutations were detected in six index patients with CH (ten total subjects). The p.R31C, p.R31H, and p.R108X mutations have been reported. The novel p.I47T PAX8 mutation presented loss of function leading to CH. Thyroid ectopy was observed in two cases of PAX8 (p.R31H) mutation, a finding that has not been reported previously. We observed a high inter-individual and intra-familial variability of the phenotype in PAX8 mutations, underlining that population genetic studies for CH should include patients with various clinical presentations.

scholarly journals Congenital Hypothyroidism Caused by a PAX8 Gene Mutation Manifested as Sodium/Iodide Symporter Gene Defect

2010 ◽  
Vol 2010 ◽  
pp. 1-3 ◽  
Author(s):  
Wakako Jo ◽  
Katsura Ishizu ◽  
Kenji Fujieda ◽  
Toshihiro Tajima
Keyword(s):  
Thyroid Gland ◽  
Congenital Hypothyroidism ◽  
Sodium Iodide ◽  
Present Report ◽  
Sodium Iodide Symporter ◽  
Loss Of Function ◽  
Laboratory Findings ◽  
Iodide Transport ◽  
Transport Defect ◽  
Pax8 Gene

Loss-of-function mutations of the PAX8 gene are considered to mainly cause congenital hypothyroidism (CH) due to thyroid hypoplasia. However, some patients with PAX8 mutation have demonstrated a normal-sized thyroid gland. Here we report a CH patient caused by a PAX8 mutation, which manifested as iodide transport defect (ITD). Hypothyroidism was detected by neonatal screening and L-thyroxine replacement was started immediately. Although I scintigraphy at 5 years of age showed that the thyroid gland was in the normal position and of small size, his iodide trapping was low. The ratio of the saliva/plasma radioactive iodide was low. He did not have goiter; however laboratory findings suggested that he had partial ITD. Gene analyses showed that the sodium/iodide symporter (NIS) gene was normal; instead, a mutation in the PAX8 gene causing R31H substitution was identified. The present report demonstrates that individuals with defective PAX8 can have partial ITD, and thus genetic analysis is useful for differential diagnosis.

scholarly journals Study of molecular basis of thyroid dysgenesis

2018 ◽  
Vol 14 (2) ◽  
pp. 64-71
Author(s):  
Nina A. Makretskaya ◽  
Olga B. Bezlepkina ◽  
Anna A. Kolodkina ◽  
Alexey V. Kiyaev ◽  
Evgeny V. Vasilyev ◽  
...  
Keyword(s):  
Congenital Hypothyroidism ◽  
Molecular Basis ◽  
Molecular Genetic ◽  
Molecular Genetic Analysis ◽  
Ion Torrent ◽  
Loss Of Function ◽  
Thyroid Dysgenesis ◽  
Different Types ◽  
Generation Sequencing ◽  
Tsh Levels

Congenital hypothyroidism is a heterogeneous group of diseases, which is manifested by loss of function of the thyroid gland that affects infants from birth. 80–85% of cases are due to different types of thyroid dysgenesis. 5 genes have been described that are involved in the pathogenesis of thyroid dysgenesis: TSHR, PAX8, FOXE1, NKX2-1, NKX2-5. Aims. To evaluate the prevalence of mutations in the genes TSHR, PAX8, FOXE1, NKX2-1, NKX2-5 among patients with severe congenital hypothyroidism. Materials and methods. 161 patients (64 boys, 97 girls) with congenital hypothyroidism (TSH levels at neonatal screening or retesting greater than 90 mU/l) were included in the study. 138 subjects had different variants of thyroid dysgenesis, and 23 patients had normal volume of the gland. A next generation sequencing was used for molecular-genetic analysis. Sequencing was performed using PGM semiconductor sequencer (Ion Torrent, Life Technologies, USA) and a panel “Hypothyroidism” (Custom DNA Panel). Assessment of the pathogenicity of sequence variants were carried out according to the latest international guidelines (ACMG, 2015). Results. 13 patients had variants in thyroid dysgenesis genes (8,1%, 13/161): TSHR, n = 6; NKX2-1, n = 3; NKX2-5, n = 1; PAX8, n = 3; FOXE1, n = 0. Conclusions. Mutations in thyroid dysgenesis genes are a rare pathology. The majority of variants among our patients were identified in TSHR.

Genetic Variability of the Paired Box Transcription Factor; PAX8 Gene: Guidance Towards Treatment Strategies in a Cohort of Congenital Hypothyroidism

2021 ◽  
Author(s):  
Sohier S. Abou El-Ella ◽  
Essam Shawky A.E.H. Khattab ◽  
Rehab K. Beddah ◽  
Naglaa Fathy Barseem
Keyword(s):  
Genetic Variability ◽  
Congenital Hypothyroidism ◽  
Novel Mutation ◽  
Treatment Strategies ◽  
Group I ◽  
Egyptian Patients ◽  
Pax8 Gene ◽  
Healthy Control ◽  
And Function ◽  
Thyroid Development

AbstractThe contribution of PAX8 genetic variants to congenital hypothyroidism (CH) is not well understood. We aimed to study the genetic variability of exons 3 and 5 of PAX8 gene among a cohort of children with congenital hypothyroidism in correspondence to their clinical aspect. Blood samples were collected from 117 children (63 girls and 54 boys) with CH and enrolled as cases (Group I). All cases underwent biochemical confirmation with low FT4 and high TSH levels and thyroid gland imaging, along with equal number of matched apparently healthy individuals who served as controls (Group II). Genomic materials for exons 3 and 5 of PAX8 gene were extracted, amplified by PCR, detected by electrophoresis, purified, and sequenced by the Sanger technique through the application of ABI 3730x1 DNA Sequencer. Out of 117 cases, eight different effective PAX8 mutations were detected in exon 3 (G23D, V35I, I34T, Q40P, p.R31C, p.R31H, p.R31A, and p.I47T) in 14 patients with their sonographic findings ranged from normal, hypoplastic to thyroid agenesis. Besides the reported mutations, one novel mutation; R31A was detected in 1 euotopic case. Exon 5 analysis revealed no detected mutations elsewhere. In contrast, all healthy control children showed no mutation and normal sonographic findings. Mutations in exon 3 of PAX8 gene, implies its important role in thyroid development and function, as a first estimate of PA8 mutation rate in Egyptian patients with CH having normal and dysgenetic gland. Using ultrasound is mandatory for diagnosis and guiding the treatment of children with CH.

scholarly journals Mutations in the gene encoding paired box domain (PAX8) are not a frequent cause of congenital hypothyroidism (CH) in Iranian patients with thyroid dysgenesis

2010 ◽  
Vol 54 (6) ◽  
pp. 555-559 ◽  
Author(s):  
Frouzandeh Mahjoubi ◽  
Mona Malek Mohammadi ◽  
Maryam Montazeri ◽  
Masoud Aminii ◽  
Mahin Hashemipour
Keyword(s):  
Transcription Factor ◽  
Congenital Hypothyroidism ◽  
Single Strand Conformation Polymorphism ◽  
Clinical Tests ◽  
Gene Encoding ◽  
Thyroid Dysgenesis ◽  
Pax8 Gene ◽  
And Function ◽  
Conformation Polymorphism ◽  
Iranian Patients

OBJECTIVE: Congenital hypothyroidism (CH) may be caused by defects in the thyroid or in one of the stages in the synthesis of thyroid hormones. Thyroid dysgenesis may be associated with mutation in the paired box transcription factor 8 (PAX8) gene. We attempted to screen PAX8 gene mutation in 50 CH patients with thyroid dysgenesis. SUBJECTS AND METHODS: The patients were classified in two groups as agenesis and ectopic based on biochemical and para clinical tests. By employing PCR, Single Strand Conformation Polymorphism (SSCP) and sequencing, exons 3 to 12 of PAX8 gene with their exon-intron boundaries were studied. RESULTS: No mutation was found in these patients in any of the exons. CONCLUSION: Our results, once again, indicate that the PAX8 mutation rate is very low and can only explain a minority of the cases. Therefore, it is highly needed to further investigate the genes controlling development and function of thyroid.

scholarly journals A Mouse Model Demonstrates a Multigenic Origin of Congenital Hypothyroidism

Endocrinology ◽  
2005 ◽  
Vol 146 (12) ◽  
pp. 5038-5047 ◽  
Author(s):  
Elena Amendola ◽  
Pasquale De Luca ◽  
Paolo Emidio Macchia ◽  
Daniela Terracciano ◽  
Annamaria Rosica ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Thyroid Hormone ◽  
Thyroid Gland ◽  
Congenital Hypothyroidism ◽  
Human Condition ◽  
Thyroid Dysgenesis ◽  
Genes Encoding ◽  
Thyroid Hormone Levels ◽  
Mendelian Transmission ◽  
Is Strain

Congenital hypothyroidism with thyroid dysgenesis (TD) is a frequent human condition characterized by elevated levels of TSH in response to reduced thyroid hormone levels. Congenital hypothyroidism is a genetically heterogeneous disease. In the majority of cases studied, no causative mutations have been identified and very often the disease does not show a Mendelian transmission. However, in approximately 5% of cases, it can be a consequence of mutations in genes encoding the TSH receptor or the transcription factors TITF1, FOXE1, or PAX8. We report here that in mouse models, the combination of partial deficiencies in the Titf1 and Pax8 genes results in an overt TD phenotype that is absent in either of the singly deficient, heterozygous mice. The disease is characterized by a small thyroid gland, elevated levels of TSH, reduced thyroglobulin biosynthesis, and high occurrence of hemiagenesis. The observed phenotype is strain specific, and the pattern of transmission indicates that at least two other genes, in addition to Titf1 and Pax8, are necessary to generate the condition. These results show that TD can be of multigenic origin in mice and strongly suggest that a similar pathogenic mechanism may be observed in humans.

scholarly journals GATA family transcription factors activate lactase gene promoter in intestinal Caco-2 cells

2001 ◽  
Vol 280 (1) ◽  
pp. G58-G67 ◽  
Author(s):  
Rixun Fang ◽  
Lynne C. Olds ◽  
Nilda A. Santiago ◽  
Eric Sibley
Keyword(s):  
Transcription Factors ◽  
Binding Site ◽  
Gene Promoter ◽  
Wild Type ◽  
Gata Factor ◽  
Mobility Shift ◽  
Factor Binding ◽  
Cis Element ◽  
Lactase Gene ◽  
Gata Family

The GATA family of transcription factors regulate tissue-specific patterns of gene expression during development. We have characterized the interaction between GATA proteins and the lactase gene promoter. Nuclear protein bound to the lactase gene GATA region cis element (−97 to −73) was analyzed by electrophoretic mobility shift assays (EMSA) and supershift assays with GATA antibodies. Lactase promoter activities were assayed in Caco-2 cells transfected with wild-type and mutated luciferase promoter-reporter constructs and GATA-4/5/6 expression constructs. EMSA with the GATA region probe yields a specific DNA-protein complex that requires the GATA factor binding site WGATAR. The complex is recognized by GATA-4- and GATA-6-specific antibodies. GATA-4/5/6 expression constructs are able to activate transcription driven by the wild-type promoter, but not by a promoter in which the GATA binding site is mutated, in Caco-2 and nonintestinal QT6 cells. GATA factor binding to the lactase cis element correlates with functional promoter activation. We conclude that each of the GATA family zinc finger proteins expressed in the intestine, GATA-4, -5, and -6, can interact with the lactase promoter GATA element and can function to activate the promoter in Caco-2 cells.

Denaturing High Performance Liquid Chromatography and Bioinformatics - Two Modern Tools for Extracellular Superoxide Dismutase (SOD3) Gene Promoter Analysis

2008 ◽  
Vol 59 (7) ◽  
Author(s):  
Corina Samoila ◽  
Alfa Xenia Lupea ◽  
Andrei Anghel ◽  
Marilena Motoc ◽  
Gabriela Otiman ◽  
...  
Keyword(s):  
High Performance Liquid Chromatography ◽  
Transcription Factors ◽  
Liquid Chromatography ◽  
Dna Sequences ◽  
High Performance ◽  
Zinc Finger Protein ◽  
High Capacity ◽  
Gene Promoter ◽  
Experimental Approaches ◽  
Myeloid Zinc Finger

Denaturing High Performance Liquid Chromatography (DHPLC) is a relatively new method used for screening DNA sequences, characterized by high capacity to detect mutations/polymorphisms. This study is focused on the Transgenomic WAVETM DNA Fragment Analysis (based on DHPLC separation method) of a 485 bp fragment from human EC-SOD gene promoter in order to detect single nucleotide polymorphism (SNPs) associated with atherosclerosis and risk factors of cardiovascular disease. The fragment of interest was amplified by PCR reaction and analyzed by DHPLC in 100 healthy subjects and 70 patients characterized by atheroma. No different melting profiles were detected for the analyzed DNA samples. A combination of computational methods was used to predict putative transcription factors in the fragment of interest. Several putative transcription factors binding sites from the Ets-1 oncogene family: ETS member Elk-1, polyomavirus enhancer activator-3 (PEA3), protein C-Ets-1 (Ets-1), GABP: GA binding protein (GABP), Spi-1 and Spi-B/PU.1 related transcription factors, from the Krueppel-like family: Gut-enriched Krueppel-like factor (GKLF), Erythroid Krueppel-like factor (EKLF), Basic Krueppel-like factor (BKLF), GC box and myeloid zinc finger protein MZF-1 were identified in the evolutionary conserved regions. The bioinformatics results need to be investigated further in others studies by experimental approaches.

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