Characterization of Mutations in the FOXE1 Gene in a Cohort of Unrelated Malaysian Patients with Congenital Hypothyroidism and Thyroid Dysgenesis

Abstract Background: Thyroid dysgenesis (TD) is the main cause of congenital hypothyroidism (CH). As variants of the transcription factor Gli-similar 3 (GLIS3) have been associated with CH and GLIS3 is one of candidate genes of TD, we screened and characterized GLIS3 mutations in Chinese patients with CH and TD.Methods: To detect mutations, we sequenced all GLIS3 exons in the peripheral blood genomic DNA isolated from 50 patients with TD and 100 healthy individuals. Wild-type and mutant expression vectors of Glis3 were constructed. Quantitative real-time PCR, western blotting, and double luciferase assay were performed to investigation the effect of the mutations on GLIS3 protein function and transcriptional activation.Results: Two novel heterozygous missense mutations, c.2710G>A (p.G904R) and c.2507C>A (p.P836Q), were detected in two unrelated patients. Functional studies revealed that p.G904R expression was 59.95% lower and p.P836Q was 31.23% lower than wild-type GLIS3 mRNA expression. The p.G904R mutation also resulted in lower GLIS3 protein expression compared with that encoded by wild-type GLIS3. Additionally, the luciferase reporter assay revealed that p.G904R mediated impaired transcriptional activation compared with the wild-type protein (p < 0.05) but did not have a dominant-negative effect on the wild-type protein.Conclusions: We for the first time screened and characterized the function of GLIS3 mutations in Chinese individuals with CH and TD. Our study not only broadens the GLIS3 mutation spectrum, but also provides further evidence that GLIS3 defects cause TD.

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Abstract #1004316: Thyroid Dysgenesis and Congenital Hypothyroidism: A Case Study and Literature Review

Endocrine Practice ◽

10.1016/j.eprac.2021.04.852 ◽

2021 ◽

Vol 27 (6) ◽

pp. S181

Author(s):

Zara Z. Alvi ◽

Hassan Mehmood ◽

Farhad Hasan

Keyword(s):

Literature Review ◽

Congenital Hypothyroidism ◽

Thyroid Dysgenesis

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Incidence of congenital hypothyroidism in the city of Uberaba/Minas Gerais and etiological evaluation of the affected subjects

Arquivos Brasileiros de Endocrinologia & Metabologia ◽

10.1590/s0004-27302012000500005 ◽

2012 ◽

Vol 56 (5) ◽

pp. 305-312 ◽

Cited By ~ 3

Author(s):

Heloísa Marcelina da Cunha Palhares ◽

Lilian Carla Silva ◽

Luciene Mayumi Sato ◽

Beatriz Hallal Jorge Lara ◽

Sybele de Souza Castro Miranzi ◽

...

Keyword(s):

Congenital Hypothyroidism ◽

Screening Program ◽

Minas Gerais ◽

The State ◽

Thyroid Dysgenesis ◽

Outpatient Unit ◽

Transient Hypothyroidism ◽

Molecular Studies ◽

Definition Of ◽

The City

OBJECTIVE: The objective of this study was to determine the incidence and etiology of congenital hypothyroidism (CH) in Uberaba, MG. SUBJECTS AND METHODS: From 2001 to 2010, by reviewing patient files from a public reference outpatient unit. The screening program covered 88% of live-born children. RESULTS: CH was diagnosed in 16 children, representing an incidence of 1:2,017 live-born children screened. The etiological evaluation was done in 15 children and revealed seven cases of thyroid dysgenesis, seven of dyshormonogenesis, and one case of transient hypothyroidism. One child moved away from the state before etiological investigation was carried out. CONCLUSION: We concluded that both the incidence of CH and of dyshormonogenesis as the main causes of CH were increased in the investigated region, but molecular studies are necessary for a better definition of etiology.

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Novel THRB mutation analysis in congenital hypothyroidism with thyroid dysgenesis

Journal of Cellular Biochemistry ◽

10.1002/jcb.27264 ◽

2018 ◽

Vol 119 (11) ◽

pp. 9474-9482 ◽

Cited By ~ 3

Author(s):

Zhixia Zhou ◽

Chengyu Yang ◽

Fuyan Lv ◽

Wenmiao Liu ◽

Shengli Yan ◽

...

Keyword(s):

Congenital Hypothyroidism ◽

Mutation Analysis ◽

Thyroid Dysgenesis

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Twenty years later: a reevaluation of the contribution of plasma thyroglobulin to the diagnosis of thyroid dysgenesis in infants with congenital hypothyroidism

Clinical Biochemistry ◽

10.1016/j.clinbiochem.2004.03.011 ◽

2004 ◽

Vol 37 (9) ◽

pp. 818-822 ◽

Cited By ~ 22

Author(s):

Anissa Djemli ◽

Marc Fillion ◽

Jaafar Belgoudi ◽

Raymond Lambert ◽

Edgard E. Delvin ◽

...

Keyword(s):

Congenital Hypothyroidism ◽

Thyroid Dysgenesis ◽

Plasma Thyroglobulin

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Mutations in the Gene EncodingThyroid Transcription Factor-1 (TTF-1) Are Not a Frequent Cause of Congenital Hypothyroidism (CH) with Thyroid Dysgenesis

Thyroid ◽

10.1089/thy.1997.7.383 ◽

1997 ◽

Vol 7 (3) ◽

pp. 383-387 ◽

Cited By ~ 49

Author(s):

PAOLA LAPI ◽

PAOLO EMIDIO MACCHIA ◽

LUCA CHIOVATO ◽

ELIO BIFFALI ◽

LIDIA MOSCHINI ◽

...

Keyword(s):

Transcription Factor ◽

Congenital Hypothyroidism ◽

Thyroid Dysgenesis ◽

Transcription Factor 1

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

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2013-2619 ◽

2014 ◽

Vol 99 (1) ◽

pp. E169-E176 ◽

Cited By ~ 30

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.

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Molecular Analysis of Congenital Hypothyroidism in Saudi Arabia: SLC26A7 Mutation Is a Novel Defect in Thyroid Dyshormonogenesis

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2017-02202 ◽

2018 ◽

Vol 103 (5) ◽

pp. 1889-1898 ◽

Cited By ~ 16

Author(s):

Minjing Zou ◽

Ali S Alzahrani ◽

Ali Al-Odaib ◽

Mohammad A Alqahtani ◽

Omer Babiker ◽

...

Keyword(s):

Saudi Arabia ◽

Congenital Hypothyroidism ◽

Screening Program ◽

Genetic Defects ◽

Newborn Screening Program ◽

Endocrine Disorder ◽

Thyroid Dysgenesis ◽

Thyroid Dyshormonogenesis ◽

Biallelic Mutations ◽

Saudi Patients

Abstract Context Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder, affecting one in 3000 to 4000 newborns. Since the introduction of a newborn screening program in 1988, more than 300 cases have been identified. The underlying genetic defects have not been systematically studied. Objective To identify the mutation spectrum of CH-causing genes. Methods Fifty-five patients from 47 families were studied by next-generation exome sequencing. Results Mutations were identified in 52.7% of patients (29 of 55) in the following 11 genes: TG, TPO, DUOX2, SLC26A4, SLC26A7, TSHB, TSHR, NKX2-1, PAX8, CDCA8, and HOXB3. Among 30 patients with thyroid dyshormonogenesis, biallelic TG mutations were found in 12 patients (40%), followed by biallelic mutations in TPO (6.7%), SLC26A7 (6.7%), and DUOX2 (3.3%). Monoallelic SLC26A4 mutations were found in two patients, one of them coexisting with two tandem biallelic deletions in SLC26A7. In 25 patients with thyroid dysgenesis, biallelic mutations in TSHR were found in six patients (24%). Biallelic mutations in TSHB, PAX 8, NKX2-1, or HOXB3 were found once in four different patients. A monoallelic CDCA8 mutation was found in one patient. Most mutations were novel, including three TG, two TSHR, and one each in DUOX2, TPO, SLC26A7, TSHB, NKX2-1, PAX8, CDCA8, and HOXB3. SLC26A7 and HOXB3 were novel genes associated with thyroid dyshormonogenesis and dysgenesis, respectively. Conclusions TG and TSHR mutations are the most common genetic defects in Saudi patients with CH. The prevalence of other disease-causing mutations is low, reflecting the consanguineous nature of the population. SLC26A7 mutations appear to be associated with thyroid dyshormonogenesis.

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