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

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.

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

10.21203/rs.3.rs-1239485/v1 ◽

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.

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Mutation screening of the thyroid peroxidase gene in a cohort of 55 Portuguese patients with congenital hypothyroidism

Acta Endocrinologica ◽

10.1530/eje.1.01826 ◽

2005 ◽

Vol 152 (2) ◽

pp. 193-198 ◽

Cited By ~ 35

Author(s):

Carina Rodrigues ◽

Paula Jorge ◽

José Pires Soares ◽

Isaura Santos ◽

Regina Salomão ◽

...

Keyword(s):

Congenital Hypothyroidism ◽

Mutation Screening ◽

Gene Mutations ◽

Human Thyroid ◽

Thyroid Peroxidase ◽

Molecular Testing ◽

Missense Mutations ◽

Human Thyroid Peroxidase ◽

Iodide Organification Defect ◽

Organification Defect

Objective: Defects in the human thyroid peroxidase (TPO) gene are reported to be one of the causes of congenital hypothyroidism (CH) due to a total iodide organification defect. The aim of the present study was to determine the nature and frequency of TPO gene mutations in patients with CH, characterised by elevated TSH levels and orthotopic thyroid gland, identified in the Portuguese National Neonatal Screening Programme. Subjects and methods: The sample comprised 55 patients, from 53 unrelated families, with follow-up in the endocrinology clinics of the treatment centres of Porto and Lisbon. Mutation screening in the TPO gene (exons 1–17) was performed by single-strand conformational analysis followed by sequencing of fragments with abnormal migration patterns. Results: Eight different mutations were detected in 13 patients (seven homozygotes and six compound heterozygotes). Novel mutations included three missense mutations, namely 391T > C (S131P), 1274A > G (N425S) and 2512T > A (C838S), as well as the predictable splice mutation 2748G > A (Q916Q/spl?). The undocumented polymorphism 180-47A > C was also detected. Conclusion: The results are in accordance with previous observations confirming the genetic heterogeneity of TPO defects. The proportion of patients in which the aetiology was determined justifies the implementation of this molecular testing in our CH patients with dyshormonogenesis.

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

Acta Endocrinologica ◽

10.1530/eje-15-0959 ◽

2016 ◽

Vol 174 (4) ◽

pp. 453-463 ◽

Cited By ~ 15

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).

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Thyroid Peroxidase Gene Mutations Causing Congenital Hypothyroidism in Three Turkish Families

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem.2009.22.11.1033 ◽

2009 ◽

Vol 22 (11) ◽

Cited By ~ 2

Author(s):

M.N. Ozbek ◽

A.B. Uslu ◽

N. Onenli-Mungan ◽

B. Yuksel ◽

J. Pohlenz ◽

...

Keyword(s):

Congenital Hypothyroidism ◽

Gene Mutations ◽

Thyroid Peroxidase ◽

Peroxidase Gene

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Cochlear Structure and Hearing in Murine Congenital Hypothyroidism Caused by Targeted Gene Mutations in the Mouse Dual Oxidase A1 and A2 Genes

The Laryngoscope ◽

10.1002/lary.22280 ◽

2011 ◽

Vol 121 (S5) ◽

pp. S324-S324

Author(s):

Kedar Kakodkar ◽

Miriam Saadia-Redleaf ◽

Mia Weiss ◽

Helmut Grasberger

Keyword(s):

Congenital Hypothyroidism ◽

Gene Mutations ◽

Dual Oxidase

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The Coexistence of a Novel Inactivating Mutant Thyrotropin Receptor Allele with Two Thyroid Peroxidase Mutations: A Genotype-Phenotype Correlation

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2011-0127 ◽

2011 ◽

Vol 96 (6) ◽

pp. E1001-E1006 ◽

Cited By ~ 11

Author(s):

Chutintorn Sriphrapradang ◽

Yardena Tenenbaum-Rakover ◽

Mia Weiss ◽

Marla S. Barkoff ◽

Osnat Admoni ◽

...

Keyword(s):

Clinical Investigation ◽

Gene Mutations ◽

Structure And Function ◽

Compound Heterozygote ◽

Thyroid Peroxidase ◽

Thyrotropin Receptor ◽

Loss Of Function ◽

Phenotype Correlation ◽

And Function

Context: TSH receptor (TSHR) and thyroid peroxidase (TPO) gene mutations occur independently. This is the first report of their coexistence in the same individuals. Objectives: The objective of the study was to evaluate the genotype-phenotype correlations when mutations in both genes are present alone or together in the same individual. Patients and Methods: Thirty subjects from an extended Arab kindred underwent clinical investigation and molecular studies of the mutant TSHRs. Results: A novel mutant TSHR was identified, involving four nucleotides at three sites on the same allele, c.267G>T (L89L), c.269/270AG>CT (Q90P), and c.790C>T (P264S). In addition, two known TPO gene mutations, G493S and R540X, were identified. Thirteen heterozygotes for the mutant TSHR allele had mild hyperthyrotropinemia. In nine of theses, the coexistence of a TPO mutation in one allele did not magnify the hyperthyrotropinemia. Homozygotes for the mutant TSHR and a compound heterozygote for the TPO mutations presented frank hypothyroidism. In vitro studies showed increasing loss of function for Q90P less than P264S less than Q90P/P264S TSHR mutants, the latter being that expressed in the subjects under investigation. The two interchangeably used WT TSHR vectors, L87 and V87, although functionally identical, differed in structure and function in the presence of the Q90P mutation. Conclusions: TSHR and TPO gene mutations were identified alone and together in individuals of a consanguineous kindred. Homozygotes for the TSHR and a compound heterozygote for the TPO mutations were hypothyroid. The mild hyperthyrotropinemia of heterozygotes for the mutant TSHR allele was not aggravated by the coexistence of a TPO defect in one allele.

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

Molecular Endocrinology ◽

10.1210/me.2007-0085 ◽

2007 ◽

Vol 21 (7) ◽

pp. 1593-1602 ◽

Cited By ~ 69

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.

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Functional analysis of thyroid peroxidase gene mutations resulting in congenital hypothyroidism

Clinical Endocrinology ◽

10.1111/cen.14253 ◽

2020 ◽

Vol 93 (4) ◽

pp. 499-507 ◽

Cited By ~ 1

Author(s):

Defa Zhao ◽

Yang Li ◽

Zhongyan Shan ◽

Weiping Teng ◽

Jing Li ◽

...

Keyword(s):

Functional Analysis ◽

Congenital Hypothyroidism ◽

Gene Mutations ◽

Thyroid Peroxidase ◽

Peroxidase Gene

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Transient Congenital Hypothyroidism Caused by Biallelic Mutations of the Dual Oxidase 2 Gene in Japanese Patients Detected by a Neonatal Screening Program

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2008-0856 ◽

2008 ◽

Vol 93 (11) ◽

pp. 4261-4267 ◽

Cited By ~ 68

Author(s):

Yoshihiro Maruo ◽

Hiroko Takahashi ◽

Ikumi Soeda ◽

Noriko Nishikura ◽

Katsuyuki Matsui ◽

...

Keyword(s):

Congenital Hypothyroidism ◽

Neonatal Screening ◽

Screening Program ◽

Thyroid Peroxidase ◽

Compound Heterozygous ◽

Recessive Trait ◽

Dual Oxidase ◽

Neonatal Screening Program ◽

Biallelic Mutations ◽

Transient Congenital Hypothyroidism

Context: Mutations in dual oxidase (DUOX2) have been proposed as a cause of congenital hypothyroidism. Previous reports suggest that biallelic mutations of DUOX2 cause permanent congenital hypothyroidism and that monoallelic mutations cause transient congenital hypothyroidism. Objective: To clarify the inheritance of hypothyroidism, we looked at the DUOX2 gene in patients with transient congenital hypothyroidism. Design: DUOX2, thyroid peroxidase, Na+/I− symporter and dual oxidase maturation factor 2 genes were analyzed in eight patients with transient congenital hypothyroidism, using the PCR-amplified direct sequencing method. Patients: The eight patients were found by a neonatal screening program. Six of these patients belonged to two independent families; the other two were unrelated. Their serum TSH values varied from 24.8–233.0 mU/liter. Six of the eight patients had a low serum freeT4 level (0.19–0.84 ng/dl). Seven of the eight patients were treated with thyroid hormone replacement therapy, which ceased to be necessary by 9 yr of age. Results: Eight novel mutations were detected in the DUOX2 gene. Four patients in one family were compound heterozygous for p.L479SfsX2 and p.K628RfsX10. Two patients in a second family were compound heterozygous for p.K530X and p.[E876K;L1067S]. The two remaining unrelated patients were also compound heterozygous, for p.H678R/p.L1067S and p.A649E/p.R885Q, respectively. Conclusion: All eight patients had biallelic mutations in the DUOX2 gene. We find that loss of DUOX2 activity results in transient congenital hypothyroidism and that transient congenital hypothyroidism caused by DUOX2 mutations is inherited as an autosomal recessive trait.

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Thyroid Peroxidase Gene Mutation in Patients with Congenital Hypothyroidism in Isfahan, Iran

International Journal of Endocrinology ◽

10.1155/2012/717283 ◽

2012 ◽

Vol 2012 ◽

pp. 1-6 ◽

Cited By ~ 3

Author(s):

Mahin Hashemipour ◽

Fahimeh Soheilipour ◽

Sakineh Karimizare ◽

Hossein Khanahmad ◽

Morteza Karimipour ◽

...

Keyword(s):

Congenital Hypothyroidism ◽

Gene Mutations ◽

Cross Sectional Study ◽

Thyroid Peroxidase ◽

Nucleotide Polymorphisms ◽

Salting Out ◽

Cross Sectional ◽

Peroxidase Gene ◽

Thyroid Dyshormonogenesis ◽

Unknown Gene

Background. Thyroid peroxidase gene (TPO) mutations are one of the most common causes of thyroid dyshormonogenesis in patients with congenital hypothyroidism (CH). In this study, the prevalence of TPO gene mutations in patients with thyroid dyshormonogenesis in Isfahan was investigated.Methods. In this cross-sectional study, genomic DNA of 41 patients with permanent CH due to thyroid dyshormonogenesis was extracted using the salting out method. The 17 exonic regions of the TPO gene were amplified. SSCP technique was performed for scanning of the exonic regions of the TPO gene, except exon 8. DNA sequencing was performed for those with different migration patterns in SSCP by chain termination method. Exon 8 was sequenced directly in all patients. In 4 patients, all fragments were also sequenced.Results. One missense mutationc.2669G>A(NM_000547.5) at exon 15 (14th coding exon) in one patient in homozygous form and seven different single nucleotide polymorphisms (SNPs) in exons 1, 7, 8, 11, and 15 of TPO gene.Conclusion. The TPO gene mutations among CH patients with dyshormonogenesis in Isfahan were less frequent in comparison with other similar studies. It may be due to the presence of other unknown gene mutations which could not be detected by SSCP and sequencing methods.

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