Identification of Two Missense Mutations in DUOX1 (p.R1307Q) and DUOXA1 (p.R56W) That Can Cause Congenital Hypothyroidism Through Impairing H2O2 Generation

Liu, Shiguo; Han, Wenxiu; Zang, Yali; Zang, Hongwei; Wang, Fang; Jiang, Pei; Wei, Hongwei; Liu, Xiangju; Wang, Yangang; Ma, Xu

doi:10.3389/fendo.2019.00526

Cited by 15 publications

(5 citation statements)

References 28 publications

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“…Similarly, Flp-In 293 cells expressing DUOX1 were transfected with V5-tagged DUOXA1 variants. One identified variant, p.R56Q, previously reported to have compromised H2O2 production (32) showed significantly decreased H2O2 production (Figure 2C).…”

Section: Non-hematopoietic Fungal Recognitionmentioning

confidence: 92%

Immunogenetics associated with severe coccidioidomycosis

Hsu¹,

Korzeniowska²,

Aguilar³

et al. 2022

JCI Insight

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Disseminated coccidioidomycosis (DCM) is caused by Coccidioides, pathogenic fungi endemic to the Southwestern United States and Mexico. Illness occurs in approximately 30% of those infected, <1% of whom develop disseminated disease. To address why some individuals allow dissemination, we enrolled DCM patients and performed whole-exome sequencing. In an exploratory set of 67 DCM patients, two had haploinsufficient STAT3 mutations, while defects in b-glucan sensing and response were seen in 34/67 (50.7%) cases. Damaging CLEC7A (n=14) and PLCG2 (n=11) variants were associated with impaired production of b-glucan-stimulated TNF-a from peripheral blood mononuclear cells compared to healthy controls (P<0.005). Using ancestry-matched controls, damaging CLEC7A and PLCG2 variants were over-represented in DCM (P=0.0206, P=0.015, respectively) including CLEC7A Y238* (P=0.0105) and PLCG2 R268W (P=0.0025). A validation cohort of 111 DCM patients confirmed PLCG2 R268W (P=0.0276), CLEC7A I223S (P=0.044), and CLEC7A Y238* (P=0.0656). Stimulation with a DECTIN-1 agonist induced DUOX1/DUOXA1-derived H2O2 in transfected cells. Heterozygous DUOX1 or DUOXA1 variants which impaired H2O2 production were overrepresented in discovery and validation cohorts. Patients with DCM have impaired b-glucan sensing or response affecting TNF-a and H2O2 production. Impaired Coccidioides recognition and decreased cellular response are associated with disseminated coccidioidomycosis.

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Section: Non-hematopoietic Fungal Recognitionmentioning

confidence: 92%

Immunogenetics associated with severe coccidioidomycosis

Hsu¹,

Korzeniowska²,

Aguilar³

et al. 2022

JCI Insight

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“…The sodium/iodide symporter (NIS) is an integral membrane transporter that mediates active iodine transportation into the thyroid cells, which is then incorporated into TG [39]. For this process, H 2 O 2 is required, which is produced by Dual oxidase 1 (DUOX1) [40]. Furthermore, we included the marker Zo-1, in order to investigate the presence of tight junctions in our organoid model.…”

Section: Characterization Of Ptc and Raird Organoidsmentioning

confidence: 99%

Patient-Derived Papillary Thyroid Cancer Organoids for Radioactive Iodine Refractory Screening

Sondorp

Ogundipe

Groen

et al. 2020

Cancers

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Patients with well-differentiated thyroid cancer, especially papillary thyroid cancer (PTC), are treated with surgical resection of the thyroid gland. This is followed by post-operative radioactive iodine (I131), resulting in total thyroid ablation. Unfortunately, about 15-33% of PTC patients are unable to take up I131, limiting further treatment options. The aim of our study was to develop a cancer organoid model with the potential for pre-treatment diagnosis of these I131-resistant patients. PTC tissue from thirteen patients was used to establish a long-term organoid model. These organoids showed a self-renewal potential for at least five passages, suggesting the presence of cancer stem cells. We demonstrated that thyroid specific markers, a PTC marker, and transporters/receptors necessary for iodine uptake and thyroid hormone production were expressed on a gene and protein level. Additionally, we cultured organoids from I131-resistant PTC material from three patients. When comparing PTC organoids to radioactive iodine (RAI)-refractory disease (RAIRD) organoids, a substantial discordance on both a protein and gene expression level was observed, indicating a treatment prediction potential. We showed that patient-derived PTC organoids recapitulate PTC tissue and a RAIRD phenotype. Patient-specific PTC organoids may enable the early identification of I131-resistant patients, in order to reduce RAI overtreatment and its many side effects for thyroid cancer patients.

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“…The highest positive selection probability (96%) was identified in the peroxidase-like region of Duox1 . The peroxidase activity of TPO and DUOX1 is essential for TH biosynthesis and mutations in the respective genes are well known for their potential to cause hypothyroidism 57 , 58 . Therefore, the positively selected genomic sites might have contributed to the distinct naked mole-rats’ thyroid gland morphology and function.…”

Section: Discussionmentioning

confidence: 99%

Comparative analysis of thyroid hormone systems in rodents with subterranean lifestyle

Gerhardt

Begall

Frädrich

et al. 2023

Sci Rep

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African mole-rats are subterranean rodents inhabiting underground burrows. This habitat entails risks of overheating, hypoxia, and scarce food availability. Consequently, many subterranean species have evolved low basal metabolism and low body temperature, but the regulation of these traits at the molecular level were unknown. Measurements of serum thyroid hormone (TH) concentrations in African mole-rats have revealed a unique TH phenotype, which deviates from the typical mammalian pattern. Since THs are major regulators of metabolic rate and body temperature, we further characterised the TH system of two African mole-rat species, the naked mole-rat (Heterocephalus glaber) and the Ansell’s mole-rat (Fukomys anselli) at the molecular level in a comparative approach involving the house mouse (Mus musculus) as a well-studied laboratory model in TH research. Most intriguingly, both mole-rat species had low iodide levels in the thyroid and naked mole-rats showed signs of thyroid gland hyperplasia. However, contrary to expectations, we found several species-specific differences in the TH systems of both mole-rat species, although ultimately resulting in similar serum TH concentrations. These findings indicate a possible convergent adaptation. Thus, our study adds to our knowledge for understanding adaptations to the subterranean habitat.

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Identification of Two Missense Mutations in DUOX1 (p.R1307Q) and DUOXA1 (p.R56W) That Can Cause Congenital Hypothyroidism Through Impairing H2O2 Generation

Cited by 15 publications

References 28 publications

Immunogenetics associated with severe coccidioidomycosis

Immunogenetics associated with severe coccidioidomycosis

Patient-Derived Papillary Thyroid Cancer Organoids for Radioactive Iodine Refractory Screening

Comparative analysis of thyroid hormone systems in rodents with subterranean lifestyle

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