scholarly journals Mutational screening of the TPO and DUOX2 genes in Argentinian children with congenital hypothyroidism due to thyroid dyshormonogenesis.

2022 ◽  
Author(s):  
Maricel F. Molina ◽  
Patricia Papendieck ◽  
Gabriela Sobrero ◽  
Viviana A. Balbi ◽  
Fiorella S. Belforte ◽  
...  
Keyword(s):  
Congenital Hypothyroidism ◽  
Bioinformatic Analysis ◽  
Thyroid Stimulating Hormone ◽  
Motor Deficits ◽  
Thyroid Peroxidase ◽  
Solute Carrier Family ◽  
Dual Oxidase ◽  
Thyroid Dyshormonogenesis ◽  
Solute Carrier ◽  
And Function

Abstract Purpose Primary congenital hypothyroidism (CH) is the most common endocrine disease in children and one of the preventable causes of both cognitive and motor deficits. We present a genetic and bioinformatics investigation of rational clinical design in 16 Argentine patients suspected of CH due to thyroid dyshormonogenesis (TDH). Methods Next-Generation Sequencing approach was used to identify variants in Thyroid Peroxidase (TPO) and Dual Oxidase 2 (DUOX2) genes. A custom panel targeting 7 genes associated with TDH [(TPO, Iodothyrosine Deiodinase I (IYD), Solute Carrier Family 26 Member 4 (SLC26A4), Thyroglobulin (TG), (DUOX2), Dual Oxidase Maturation Factor 2 (DUOXA2), Solute Carrier Family 5 Member 5 (SLC5A5)] and 4 associated with thyroid dysembryogenesis [PAX8, FOXE1, NKX2-1, Thyroid Stimulating Hormone Receptor (TSHR)] has been designed. Additionally, bioinformatic analysis and structural modeling were carried out to predict the disease-causing potential variants. Results Five novel variants have been identified, two in TPO: c.2749-2A>C and c.2752_2753delAG, [p.Ser918Cysfs*62] and three variants in DUOX2 gene: c.425C>G [p.Pro142Arg]; c.790delC [p.Leu264Cysfs*57] and c.2695delC [p.Gln899Serfs*21]. Seventeen identified TPO, DUOX2 and IYD variants were previously described. We identified potentially pahogenic bi-allelic variants in TPO and DUOX2 in 8 and 2 patients, respectively. We also detected a potentially pathogenic mono-allelic variant in TPO and DUOX2 in 4 and 1 patients respectively. Only two patients were heterozygous for digenic variants in TPO/IYD and in TPO/DUOX2 genes. Conclusions 22 variants have been identified associated with TDH. All described novel mutations occur in domains important for protein structure and function, predicting the TDH phenotype.

scholarly journals Increased Prevalence of TG and TPO Mutations in Sudanese Children With Congenital Hypothyroidism

2019 ◽  
Vol 105 (5) ◽  
pp. 1564-1572 ◽  
Author(s):  
Ryan J Bruellman ◽  
Yui Watanabe ◽  
Reham S Ebrhim ◽  
Matthew K Creech ◽  
Mohamed A Abdullah ◽  
...  
Keyword(s):  
Congenital Hypothyroidism ◽  
Molecular Basis ◽  
Genetic Selection ◽  
Gene Mutations ◽  
Thyroid Peroxidase ◽  
Acid Extraction ◽  
Thyroid Function Tests ◽  
Genetic Sequencing ◽  
Dual Oxidase ◽  
And Function

Abstract Context Congenital hypothyroidism (CH) is due to dyshormonogenesis in 10% to 15% of subjects worldwide but accounts for 60% of CH cases in the Sudan. Objective To investigate the molecular basis of CH in Sudanese families. Design Clinical phenotype reporting and serum thyroid hormone measurements. Deoxyribonucelic acid extraction for whole-exome sequencing and Sanger sequencing. Setting University research center. Patients Twenty-six Sudanese families with CH. Intervention Clinical evaluation, thyroid function tests, genetic sequencing, and analysis. Our samples and information regarding samples from the literature were used to compare TG (thyroglobulin) and TPO (thyroid peroxidase) mutation rates in the Sudanese population with all populations. Results Mutations were found in dual-oxidase 1 (DUOX1), dual-oxidase 2 (DUOX2), iodotyrosine deiodinase (IYD), solute-carrier (SLC) 26A4, SLC26A7, SLC5A5, TG, and TPO genes. The molecular basis of the CH in 7 families remains unknown. TG mutations were significantly higher on average in the Sudanese population compared with the average number of TG mutations in other populations (P < 0.05). Conclusions All described mutations occur in domains important for protein structure and function, predicting the CH phenotype. Genotype prediction based on phenotype includes low or undetectable thyroglobulin levels for TG gene mutations and markedly higher thyroglobulin levels for TPO mutations. The reasons for higher incidence of TG gene mutations include gene length and possible positive genetic selection due to endemic iodine deficiency.

scholarly journals Natural course of congenital hypothyroidism by dual oxidase 2 mutations from the neonatal period through puberty

2016 ◽  
Vol 174 (4) ◽  
pp. 453-463 ◽  
Author(s):  
Yoshihiro Maruo ◽  
Keisuke Nagasaki ◽  
Katsuyuki Matsui ◽  
Yu Mimura ◽  
Asami Mori ◽  
...  
Keyword(s):  
Congenital Hypothyroidism ◽  
Screening Program ◽  
Direct Sequencing ◽  
Japanese Patients ◽  
Psychomotor Development ◽  
Thyroid Peroxidase ◽  
Maturation Factor ◽  
Dual Oxidase ◽  
Novel Alleles ◽  
Biallelic Mutations

AimWe previously reported that biallelic mutations in dual oxidase 2 (DUOX2) cause transient hypothyroidism. Since then, many cases with DUOX2 mutations have been reported. However, the clinical features and prognosis of individuals with DUOX2 defects have not been clarified.ObjectiveWe investigated the prognosis of patients with congenital hypothyroidism (CH) due to DUOX2 mutations.PatientsTwenty-five patients were identified by a neonatal screening program and included seven familial cases. Their serum TSH values ranged from 18.9 to 734.6 mU/l. Twenty-two of the patients had low serum free thyroxine (fT4) levels (0.17–1.1 ng/dl). Twenty-four of the patients were treated with L-thyroxine.MethodsWe analyzed the DUOX2, thyroid peroxidase, Na+/I− symporter, and dual oxidase maturation factor 2 genes of these 25 patients by PCR-amplified direct sequencing. An additional 11 genes were analyzed in 11 of the 25 patients using next-generation sequencing.ResultsAll patients had biallelic DUOX2 mutations, and seven novel alleles were detected. Fourteen of the patients were able to discontinue replacement therapy, and seven were receiving reduced L-thyroxine doses. Normalization of thyroglobulin lagged several years behind the completion of treatment. Two patients showed permanent hypothyroidism. Except for one case of a learning disability, growth and psychomotor development were normal.ConclusionThe prognosis of Japanese patients with DUOX2 defects was usually transient CH. Delayed improvement of thyroglobulin indicates that these patients have subclinical hypothyroidism. Hypothyroidism did not recur in patients during the study period (up to 18 years old).

scholarly journals Two novel missense mutations in the thyroid peroxidase gene, R665W and G771R, result in a localization defect and cause congenital hypothyroidism

2002 ◽  
pp. 491-498 ◽  
Author(s):  
K Umeki ◽  
T Kotani ◽  
J Kawano ◽  
T Suganuma ◽  
I Yamamoto ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Congenital Hypothyroidism ◽  
Cellular Localization ◽  
Thyroid Peroxidase ◽  
Missense Mutations ◽  
Thyroid Hormone Biosynthesis ◽  
Thyroid Dyshormonogenesis ◽  
Hormone Biosynthesis ◽  
Iodide Organification Defect ◽  
Organification Defect

OBJECTIVE: Thyroid peroxidase (TPO) deficiency is one of the causes of thyroid dyshormonogenesis, because TPO plays a key role in thyroid hormone biosynthesis. To determine the frequency and pattern of TPO abnormalities, we have been screening TPO genes of patients with congenital goitrous hypothyroidism. SUBJECTS AND METHODS: TPO genes of a patient with congenital goitrous hypothyroidism and her parents were directly sequenced, and two novel missense mutations (R665W and G771R) were found. The former was derived from her father and the latter from her mother. R665 and G771 were well conserved in the peroxidase superfamily. When mRNAs containing each of the mutations were transfected into CHO-K1 cells, each cell showed faint TPO enzyme activity. However, immunofluorescence and immunoelectron microscopic analyses revealed that neither of the mutated TPOs reached the plasma membrane. CONCLUSIONS: Two novel missense mutations in the TPO gene were found. TPO proteins encoded by these mutated alleles showed abnormal cellular localization; namely, localization on the plasma membrane was disturbed. The loss of plasma membrane localization in mutated TPOs brought about the iodide organification defect, which was diagnosed as congenital hypothyroidism.

The effect of including other psychotropic medications into a long-term bipolar disorder lithium treatment on thyroid function

2019 ◽  
Vol 35 (2) ◽  
pp. 111-119
Author(s):  
Agnieszka Kraszewska ◽  
Ewa Ferensztajn-Rochowiak ◽  
Janusz Rybakowski
Keyword(s):  
Bipolar Disorder ◽  
Lithium Treatment ◽  
Antidepressant Drugs ◽  
Thyroid Volume ◽  
Thyroid Stimulating Hormone ◽  
Structure And Function ◽  
Thyroid Peroxidase ◽  
Free Triiodothyronine ◽  
And Function

Background/Aims. Long-term bipolar disorder (BD) treatment with lithium exerts a significant effect on thyroid structure and function. Compared with BD patients who do not take lithium, patients treated with lithium have higher concentrations of thyroid-stimulating hormone (TSH) and free thyroxine (FT4), lower concentrations of free triiodothyronine (FT3), higher thyroid volume and higher occurrence of goitre. The aim of the study was to compare thyroid structure and function in relation to the inclusion of other mood stabilisers and antidepressants into a lithium treatment. Method. The studied group consisted of eighty BD patients (27 male, 53 female) aged 24–85 years, receiving a prophylactic lithium treatment for the average of 19 ± 9 years. Fifteen patients underwent lithium monotherapy; in 17, lithium was administered concurrently with carbamazepine; in 17, concurrently with quetiapine; and in 11, concurrently with valproate. In 20 subjects, lithium was administered concurrently with antidepressants. Results. In comparison with patients on lithium monotherapy, in patients who took lithium and antidepressant drugs, the concentrations of TSH were significantly higher, while in patients who took lithium and carbamazepine the concentrations of FT4 were lower. The concentrations of thyroid peroxidase antibodies (TPOAb) were significantly higher in patients who took lithium concurrently with antidepressants and concurrently with valproate. The highest frequency of goitre (70%) was observed in patients who took lithium concurrently with antidepressants. Conclusions. The obtained results may suggest a significant effect of including other mood stabilisers and antidepressants into a long-term lithium treatment on thyroid structure and function. A limitation of the study is the small size of the groups.

The effect of long-term lithium administration on thyroid function and structure as compared with monotherapy by other mood stabilising drugs – a preliminary study

2020 ◽  
Vol 35 (3-4) ◽  
pp. 169-176
Author(s):  
Agnieszka Kraszewska ◽  
Ewa Ferensztajn-Rochowiak ◽  
Janusz Rybakowski
Keyword(s):  
Antidepressant Drugs ◽  
Thyroid Volume ◽  
Thyroid Stimulating Hormone ◽  
Structure And Function ◽  
Thyroid Peroxidase ◽  
Free Triiodothyronine ◽  
Long Term Treatment ◽  
Preliminary Study ◽  
And Function

Aims: Long-term treatment with lithium in patients with bipolar disorder (BD) exerts a significant effect on thyroid structure and function. Previously, it was found that adding to lithium other mood stabilising or antidepressant drugs can also be important. The aim of this preliminary study was to compare thyroid structure and function in patients with BD receiving long-term lithium monotherapy with monotherapy using other mood stabilising drugs, such as carbamazepine, valproates or quetiapine. Method: Forty-one BD patients were studied (13 male, 28 female) aged 28–80 years. In 15, monotherapy with lithium was given; in 10 – with carbamazepine; and in 8 – with valproate and quetiapine. In all patients, the thyroid-stimulating hormone (TSH), free thyroxine (fT3) free triiodothyronine (fT4), and the antibodies against thyroid peroxidase (TPOAb), thyroglobulin (TGAb) and TSH receptors (TSHRAb) were estimated. Goiter was diagnosed when the thyroid volume exceeded 18 cm3 in women and 25 cm3 in men. Results: The groups were of similar age; however, the duration of quetiapine therapy was shorter than lithium or carbamazepine. Comparing to patients on lithium monotherapy, the median of TSH concentration was lower in patients on quetiapine, and the median of TPOAB lower in patients on valproates. The highest frequency of goiter (47%) was observed in patients receiving lithium. Conclusions: The results obtained may suggest that among the studied mood stabilisers, lithium exerts the biggest goiter-inducing effect. The differences between groups as to thyroid hormones and antibodies were not significant. The limitation of the study was a small number of studied patients.

scholarly journals Maternal Primary Carnitine Deficiency and a Novel Solute Carrier Family 22 Member 5 (SLC22A5) Mutation

2021 ◽  
Vol 9 ◽  
pp. 232470962110195
Author(s):  
Michael Jakoby ◽  
Amruta Jaju ◽  
Aundrea Marsh ◽  
Andrew Wilber
Keyword(s):  
Stop Codon ◽  
Premature Stop Codon ◽  
Thyroid Stimulating Hormone ◽  
Carnitine Deficiency ◽  
Reproductive Age ◽  
Acid Oxidation ◽  
Solute Carrier Family ◽  
Loss Of Function ◽  
Solute Carrier ◽  
Primary Carnitine Deficiency

Primary carnitine deficiency (PCD) is a rare autosomal recessive disorder caused by loss of function mutations in the solute carrier family 22 member 5 ( SLC22A5) gene that encodes a high-affinity sodium-ion–dependent organic cation transporter protein (OCTN2). Reduced carnitine transport results in diminished fatty acid oxidation in heart and skeletal muscle and carnitine wasting in urine. We present a case of PCD diagnosed in an adult female after a positive newborn screen (NBS) for PCD that was not confirmed on follow-up testing. The mother was referred for evaluation of persistent fatigue and possible hypothyroidism even though all measurements of thyroid-stimulating hormone were well within the range of 0.4 to 2.5 mIU/L expected for reproductive-age women. She was found to have unequivocally low levels of both total carnitine and carnitine esters, and genetic testing revealed compound heterozygosity for 2 SLC22A5 mutations. One mutation (c.34G>A [p.Gly12Ser]) is a known missense mutation with partial OCTN2 activity, but the other mutation (c.41G>A [p.Trp14Ter]) is previously unreported and results in a premature stop codon and truncated OCTN2. This case illustrates that some maternal inborn errors of metabolism can be identified by NBS and that maternal carnitine levels should be checked after a positive NBS test for PCD.

Congenital Hypothyroidism, Dwarfism, and Hearing Impairment Caused by a Missense Mutation in the Mouse Dual Oxidase 2 Gene, Duox2

2007 ◽  
Vol 21 (7) ◽  
pp. 1593-1602 ◽  
Author(s):  
Kenneth R. Johnson ◽  
Coleen C. Marden ◽  
Patricia Ward-Bailey ◽  
Leona H. Gagnon ◽  
Roderick T. Bronson ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Congenital Hypothyroidism ◽  
Genetic Model ◽  
Mutant Mice ◽  
Tectorial Membrane ◽  
Thyroid Peroxidase ◽  
Hormone Synthesis ◽  
Thyroid Hormone Synthesis ◽  
Organ Systems ◽  
Dual Oxidase

Abstract Dual oxidases generate the hydrogen peroxide needed by thyroid peroxidase for the incorporation of iodine into thyroglobulin, an essential step in thyroid hormone synthesis. Mutations in the human dual oxidase 2 gene, DUOX2, have been shown to underlie several cases of congenital hypothyroidism. We report here the first mouse Duox2 mutation, which provides a new genetic model for studying the specific function of DUOX2 in the thyroid gland and in other organ systems where it is hypothesized to play a role. We mapped the new spontaneous mouse mutation to chromosome 2 and identified it as a T>G base pair change in exon 16 of Duox2. The mutation changes a highly conserved valine to glycine at amino acid position 674 (V674G) and was named “thyroid dyshormonogenesis” (symbol thyd) to signify a defect in thyroid hormone synthesis. Thyroid glands of mutant mice are goitrous and contain few normal follicles, and anterior pituitaries are dysplastic. Serum T4 in homozygotes is about one-tenth the level of controls and is accompanied by a more than 100-fold increase in TSH. The weight of adult mutant mice is approximately half that of littermate controls, and serum IGF-I is reduced. The cochleae of mutant mice exhibit abnormalities characteristic of hypothyroidism, including a delayed formation of the inner sulcus and tunnel of Corti and an abnormally thickened tectorial membrane. Hearing thresholds of adult mutant mice are on average 50–60 decibels (dB) above those of controls.

Genome-Wide Expression Analysis Suggests Hypoxia-Triggered Hyper-Coagulation Leading to Venous Thrombosis at High Altitude

2018 ◽  
Vol 118 (07) ◽  
pp. 1279-1295 ◽  
Author(s):  
Prabhash Jha ◽  
Anita Sahu ◽  
Amit Prabhakar ◽  
Tarun Tyagi ◽  
Tathagata Chatterjee ◽  
...  
Keyword(s):  
Gene Expression ◽  
High Altitude ◽  
Differential Expression ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Bioinformatic Analysis ◽  
Rnase A ◽  
Additional Risk Factor ◽  
Solute Carrier Family ◽  
Solute Carrier

AbstractVenous thromboembolism (VTE), a multi-factorial disease, is the third most common cardiovascular disease. Established genetic and acquired risk factors are responsible for the onset of VTE. High altitude (HA) also poses as an additional risk factor, predisposing individuals to VTE; however, its molecular mechanism remains elusive. This study aimed to identify genes/pathways associated with the pathophysiology of deep vein thrombosis (DVT) at HA. Gene expression profiling of DVT patients, who developed the disease, either at sea level or at HA-DVT locations, resulted in differential expression of 378 and 875 genes, respectively. Gene expression profiles were subjected to bioinformatic analysis, followed by technical and biological validation of selected genes using quantitative reverse transcription-polymerase chain reaction. Both gene ontology and pathway analysis showed enrichment of genes involved in haemostasis and platelet activation in HA-DVT patients with the most relevant pathway being ‘response to hypoxia’. Thus, given the environmental condition the differential expression of hypoxia-responsive genes (angiogenin, ribonuclease, RNase A family, 5; early growth response 1; lamin A; matrix metallopeptidase 14 [membrane-inserted]; neurofibromin 1; PDZ and LIM domain 1; procollagen-lysine 1, 2-oxoglutarate 5-dioxygenase 1; solute carrier family 6 [neurotransmitter transporter, serotonin], member 4; solute carrier family 9 [sodium/hydrogen exchanger], member 1; and TEK tyrosine kinase, endothelial) in HA-DVT could be a determining factor to understand the pathophysiology of DVT at HA.

Sign in / Sign up

Export Citation Format

Share Document