Faculty Opinions recommendation of Congenital hypothyroidism, dwarfism, and hearing impairment caused by a missense mutation in the mouse dual oxidase 2 gene, Duox2.

2007 ◽  
Author(s):  
Hector Targovnik
Keyword(s):  
Missense Mutation ◽  
Hearing Impairment ◽  
Congenital Hypothyroidism ◽  
Dual Oxidase

scholarly journals Goitrous Congenital Hypothyroidism and Hearing Impairment Associated with Mutations in the TPO and SLC26A4/PDS Genes

2006 ◽  
Vol 91 (7) ◽  
pp. 2678-2681 ◽  
Author(s):  
Nicole Pfarr ◽  
Guntram Borck ◽  
Andrew Turk ◽  
Ulrike Napiontek ◽  
Annerose Keilmann ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Hearing Impairment ◽  
Congenital Hypothyroidism ◽  
Sensorineural Deafness ◽  
Primary Hypothyroidism ◽  
Thyroid Peroxidase ◽  
Compound Heterozygous ◽  
Sequence Variant ◽  
Organification Defect

Abstract Context: Pendred syndrome (PS) and thyroid peroxidase (TPO) deficiency are autosomal-recessive disorders that result in thyroid dyshormonogenesis. They share congenital hypothyroidism, goiter, and an iodide organification defect as common features. Whereas the hallmark of PS is sensorineural deafness, other forms of congenital hypothyroidism may also lead to hearing impairment. Therefore, a definite diagnosis may be difficult and require molecular genetic analyses. Case Report: The propositus presented at birth with primary hypothyroidism and goiter. He also had congenital bilateral moderate hearing loss, and PS was suspected. Methods: We sequenced the SLC26A4/PDS and TPO genes in the propositus and tested familial segregation of mutations in all available family members who were phenotypically normal. The functional consequences of the identified pendrin mutation (p.R776C) were studied in vitro. Results: Sequencing of the SLC26A4/PDS gene revealed a single monoallelic missense mutation in the propositus (p.R776C). This mutation, which was inherited from his unaffected mother, has previously been identified in an individual with deafness and an enlarged vestibular aqueduct. Sequencing of the TPO gene revealed compound heterozygosity for a novel nonsense mutation (p.Q235X) and a known missense mutation (p.Y453D). The mutant pendrin (p.R776C) retained its ability to transport iodide in vitro. Conclusions: These results show that the propositus carries three sequence variants in two genes: a monoallelic SLC26A4/PDS sequence variant and compound heterozygous TPO mutations. Our study illustrates that if only a single heterozygous SLC26A4/PDS mutation is found in a patient with goiter and deafness, other genetic explanations should be considered.

Dual oxidase (DUOX) system genes defects in Children with Congenital Hypothyroidism

Endocrinology ◽  
2021 ◽  
Author(s):  
Fengqi Wang ◽  
Li Xiaole ◽  
Ruixin Ma ◽  
Dehua Zhao ◽  
Shiguo Liu
Keyword(s):  
Congenital Hypothyroidism ◽  
Functional Domain ◽  
Target Region ◽  
Pathogenic Variants ◽  
Significant Difference ◽  
Ef Hand ◽  
Dual Oxidase ◽  
Variation Rate ◽  
Relationship Of

Abstract Purpose The objectives of this study were to analyze the distribution of Dual oxidase (DUOX) system genes (containing DUOX2, DUOX1, DUOXA2 and DUOXA1) variants in children with congenital hypothyroidism and their phenotypes. Methods Target region sequencing technology was performed on DUOX system genes among 606 congenital hypothyroidism (CH) subjects covering all the exon and intron regions. Detailed clinical data were collected for statistical analysis. Results A total of 95 suspected pathogenic variants were detected in the DUOX system genes, showing a 39.11% rate in variant carrying (237/606). DUOX2 was with the highest rate in this study. There were statistical difference in maximum adjusted dose and current dose of L-T4 between the DUOX system genes non-mutated group with the mutated group (p<0.001; p<0.001). The cases in DUOX system genes mutated group were more likely to develop into transient CH (χ 2 = 23.155, p<0.001) and more likely to manifested as goiter or gland-in-situ (χ 2 = 66.139, p<0.001). In addition, there was no significant difference in clinical characteristics between DUOX system genes mono-allelic and non mono-allelic. Although 20% of the variants affected the functional domain regions (EF hand, and FAD and NADPH binding sites), there was no significant effect on the phenotype severity whether the variation is located in the functional domain regions. Conclusions Our results showed the high variation rate of DUOX2 in the DUOX system genes among the Chinese CH patients. And the complex genotype-phenotype relationship of DUOX system genes broadened the understanding of CH phenotype spectrum.

scholarly journals High Prevalence of Hearing Impairment in Primary Congenital Hypothyroidism

2020 ◽  
pp. 1-7
Author(s):  
Tal Almagor ◽  
Shoshana Rath ◽  
Dan Nachtigal ◽  
Zohara Sharroni ◽  
Ghadir Elias-Assad ◽  
...  
Keyword(s):  
Hearing Impairment ◽  
Congenital Hypothyroidism ◽  
High Prevalence

scholarly journals Identification of PENDRIN (SLC26A4) Mutations in Patients With Congenital Hypothyroidism and “Apparent” Thyroid Dysgenesis

2014 ◽  
Vol 99 (1) ◽  
pp. E169-E176 ◽  
Author(s):  
Peter Kühnen ◽  
Serap Turan ◽  
Sebastian Fröhler ◽  
Tülay Güran ◽  
Saygin Abali ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Missense Mutation ◽  
Congenital Hypothyroidism ◽  
Thyroid Tissue ◽  
Primary Defect ◽  
Thyroid Dysgenesis ◽  
Homozygous Missense Mutation ◽  
Slc26a4 Gene ◽  
Thyroid Hormone Biosynthesis ◽  
First Time

Context: Congenital hypothyroidism, the most frequent endocrine congenital disease, can occur either based on a thyroid hormone biosynthesis defect or can predominantly be due to thyroid dysgenesis. However, a genetic cause could so far only be identified in less than 10% of patients with a thyroid dysgenesis. Objectives: Exome sequencing was used for the first time to find additional genetic defects in thyroid dysgenesis. Patients and Methods: In a consanguineous family with thyroid dysgenesis, exome sequencing was applied, and findings were further validated by Sanger sequencing in a cohort of 94 patients with thyroid dysgenesis. Results: By exome sequencing we identified a homozygous missense mutation (p.Leu597Ser) in the SLC26A4 gene of a patient with hypoplastic thyroid tissue, who was otherwise healthy. In the cohort of patients with thyroid dysgenesis, we observed a second case with a homozygous missense mutation (p.Gln413Arg) in the SLC26A4 gene, who was additionally affected by severe hearing problems. Both mutations were previously described as loss-of-function mutations in patients with Pendred syndrome and nonsyndromic enlarged vestibular aqueduct. Conclusion: We unexpectedly identified SLC26A4 mutations that were hitherto diagnosed in thyroid dyshormonogenesis patients, now for the first time in patients with structural thyroid defects. This result resembles the historic description of thyroid atrophy in patients with the so-called myxedematous form of cretinism after severe iodine deficiency. Most likely the thyroid defect of the two homozygous SLC26A4 gene mutation carriers represents a kind of secondary thyroid atrophy, rather than a primary defect of thyroid development in the sense of thyroid agenesis. Our study extends the variable clinical spectrum of patients with SLC26A4 mutations and points out the necessity to analyze the SLC26A4 gene in patients with apparent thyroid dysgenesis in addition to the known candidate genes TSHR, PAX8, NKX2.1, NKX2.5, and FOXE1.

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).

Transient congenital hypothyroidism caused by compound heterozygous mutations affecting the NADPH-oxidase domain of DUOX2

2016 ◽  
Vol 29 (3) ◽  
Author(s):  
Atsuko Yoshizawa-Ogasawara ◽  
Kiyomi Abe ◽  
Sayaka Ogikubo ◽  
Satoshi Narumi ◽  
Tomonobu Hasegawa ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Congenital Hypothyroidism ◽  
Nicotinamide Adenine Dinucleotide ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Nicotinamide Adenine ◽  
Compound Heterozygous ◽  
Loss Of Function ◽  
Dual Oxidase ◽  
Compound Heterozygous Mutations ◽  
Transient Congenital Hypothyroidism

AbstractHere, we describe three cases of loss-of-function mutations in the nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase (NOX) domain of dual oxidase 2 (

scholarly journals Biallelic Inactivation of the Dual Oxidase Maturation Factor 2 (DUOXA2) Gene as a Novel Cause of Congenital Hypothyroidism

2008 ◽  
Vol 93 (2) ◽  
pp. 605-610 ◽  
Author(s):  
Ilaria Zamproni ◽  
Helmut Grasberger ◽  
Francesca Cortinovis ◽  
Maria Cristina Vigone ◽  
Giuseppe Chiumello ◽  
...  
Keyword(s):  
Congenital Hypothyroidism ◽  
Critical Role ◽  
Chinese Patient ◽  
Catalytic Core ◽  
Genetic Event ◽  
Hormone Synthesis ◽  
Maturation Factor ◽  
Dual Oxidase ◽  
Organification Defect

Abstract Context: Dual oxidase 2 (DUOX2) is the catalytic core of the H2O2 generator crucial for the iodination of thyroglobulin in thyroid hormone synthesis. DUOX2 deficiency produces congenital hypothyroidism (CH) in humans and mice. We recently cloned a novel gene, the product of which (dual oxidase maturation factor 2; DUOXA2) is required to express DUOX2 enzymatic activity. Objective: Our objective was to identify DUOXA2 mutations as a novel cause of CH due to dyshormonogenesis. Patients: Subjects included 11 CH patients with partial iodine organification defect but negative for other known genetic causes of partial iodine organification defect. Results: One Chinese patient born to nonconsanguineous parents was homozygous for a nonsense mutation (p.Y246X), producing a truncated DUOXA2 protein lacking transmembrane helix 5 and the C-terminal cytoplasmic domain. The mutant protein was inactive in reconstituting DUOX2 in vitro. Pedigree analysis demonstrated recessive inheritance, because heterozygous carriers had normal thyroid function including negative results in neonatal TSH screening. One heterozygous carrier of Y246X was identified in unrelated Chinese controls (n = 92) but not in Caucasian or Japanese controls, indicating that homozygosity for Y246X could be a frequent cause of CH in Chinese. Functional studies suggest that the DUOXA2 paralog (DUOXA1) can partially compensate DUOXA2 deficiency, consistent with the proband having a milder CH phenotype than patients with biallelic DUOX2 nonsense mutations. Conclusions: We report the first mutation in DUOXA2, identified in a patient with CH and dyshormonogenic goiter. Results of our studies provide evidence for the critical role of DUOXA2 in thyroid hormonogenesis. Biallelic DUOXA2 mutations are a novel genetic event in permanent CH.

Long-term sequelae of hearing impairment in congenital hypothyroidism

1996 ◽  
Vol 128 (6) ◽  
pp. 776-783 ◽  
Author(s):  
Joanne Rovet ◽  
Wynsome Walker ◽  
Bonnie Bliss ◽  
Lori Buchanan ◽  
Robert Ehrlich
Keyword(s):  
Hearing Impairment ◽  
Congenital Hypothyroidism

High prevalence of DUOX2 mutations in Japanese patients with permanent congenital hypothyroidism or transient hypothyroidism

2016 ◽  
Vol 29 (7) ◽  
Author(s):  
Kumihiro Matsuo ◽  
Yusuke Tanahashi ◽  
Tokuo Mukai ◽  
Shigeru Suzuki ◽  
Toshihiro Tajima ◽  
...  
Keyword(s):  
Congenital Hypothyroidism ◽  
Japanese Patients ◽  
Sequence Variants ◽  
Transient Hypothyroidism ◽  
High Prevalence ◽  
Dual Oxidase

AbstractDual oxidase 2 (Forty-eight Japanese DH patients were enroled and analysed for sequence variants ofFourteen sequence variants ofOur results suggest that

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