The TPO mutation screening and genotype-phenotype analysis in 230 Chinese patients with congenital hypothyroidism

Zhang, Ruijia; Sun, Feng; Chen, Feng; Fang, Yun; Yan, Chen‐Yan; Zhang, Chang-Run; Ying, Ying-Xia; Wang, Zheng; Zhang, Cao-Xu; Wu, Feng‐Yao; Han, Bing; Liang, Jun; Zhao, Shuang‐Xia; Song, Huai-Dong

doi:10.1016/j.mce.2020.110761

Cited by 15 publications

(17 citation statements)

References 35 publications

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“…This was performed using filter paper blood spots (obtained through heel prick) obtained 3–5 days after birth. The diagnostic criteria for establishing CH in patients have been described previously [ 19 – 21 ]. This study included unrelated infants with CH ( n = 192).…”

Section: Methodsmentioning

confidence: 99%

Upregulation of GBP1 in thyroid primordium is required for developmental thyroid morphogenesis

Yang

Zhan

Zhou

et al. 2021

Genetics in Medicine

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Purpose Congenital hypothyroidism (CH) is a common congenital endocrine disorder in humans. CH-related diseases such as athyreosis, thyroid ectopy, and hypoplasia are primarily caused by dysgenic thyroid development. However, the underlying molecular mechanisms remain unknown. Methods To identify novel CH candidate genes, 192 CH patients were enrolled, and target sequencing of 21 known CH-related genes was performed. The remaining 98 CH patients carrying no known genes were subjected to exome sequencing (ES). The functions of the identified variants were confirmed using thyroid epithelial cells in vitro and in zebrafish model organisms in vivo. Results Four pathogenic GBP1 variations from three patients were identified. In zebrafish embryos, gbp1 knockdown caused defective thyroid primordium morphogenesis and hypothyroidism. The thyroid cells were stuck together and failed to dissociate from each other to form individual follicles in gbp1-deficient embryos. Furthermore, defects were restored with wild-type human GBP1 (hGBP1) messenger RNA (mRNA) except for mutated hGBP1 (p.H150Y, p.L187P) overexpression. GBP1 promoted β-catenin translocation into the cytosol and suppressed the formation of cellular adhesion complexes. Suppression of cell–cell adhesion restored the thyroid primordium growth defect observed in gbp1-deficient zebrafish embryos. Conclusion This study provides further understanding regarding thyroid development and shows that defective cellular remodeling could cause congenital hypothyroidism.

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Section: Methodsmentioning

confidence: 99%

Upregulation of GBP1 in thyroid primordium is required for developmental thyroid morphogenesis

Yang

Zhan

Zhou

et al. 2021

Genetics in Medicine

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“…A total of 273 CH patients (141 females and 132 males) identified through newborn screening were enrolled in this study. The diagnosis of permanent CH was confirmed in infants based on the following criteria: CH patients with elevated TSH (thyrotropin) levels, with or without T4 (thyroxine) or FT4 (free thyroxine) levels less than the normal range, and the restoration of normal thyroid parameters after receiving replacement therapy with L-thyroxine; however, after stopping treatment, a rise in TSH and a drop in FT4 were observed again (26)(27)(28). Written consent was obtained from the parents of the CH patients, and the study was approved by the Ethics Committee of Shanghai Ninth People's Hospital affiliated with the Shanghai Jiao Tong University School of Medicine.…”

Section: Clinical Subjectsmentioning

confidence: 99%

“…RNA extraction was performed as described previously (27). RNA was prepared using Trizol reagent (Invitrogen, H10522) and the total RNA (1 mg) was reverse transcribed using the cDNA synthesis kit (Takara).…”

Section: Total Rna Extraction and Qpcr (Quantitative Pcr)mentioning

confidence: 99%

Novel Compound Heterozygous Pathogenic Mutations of SLC5A5 in a Chinese Patient With Congenital Hypothyroidism

Zhang

Yang

et al. 2021

Front. Endocrinol.

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Background and ObjectivesDefects in the human sodium/iodide symporter (SLC5A5) gene have been reported to be one of the causes of congenital hypothyroidism (CH). We aimed to identify SLC5A5 mutations in Chinese patients with CH and to evaluate the function of the mutation.MethodsTwo hundred and seventy-three patients with primary CH were screened for mutations in SLC5A5 using next-generation sequencing. We investigated the expression and cellular localization of the novel compound heterozygous mutation in SLC5A5. The functional activity of the mutants was further examined in vitro.ResultsIn 273 patients with CH, two previously undescribed pathogenic mutations p.Gly51AlafsTer45 (G51fs) and p.Gly421Arg (G421R) in a compound heterozygous state in SLC5A5 were identified in a pediatric patient. G51fs was located in the first intercellular loop connecting transmembrane segment I and II, whereas G421R was in the transmembrane segment (TMS) XI. G51fs and G421R resulted in a truncated NIS and reduced protein expression, respectively. In vitro experiments further showed that the normal function of iodine transport of sodium-iodide symporter (NIS) mutants was markedly impaired.ConclusionThe undescribed compound heterozygous mutation of SLC5A5 was discovered in a Chinese CH patient. The mutation led to significantly reduced NIS expression and impaired iodide transport function accompanied by the impaired location of the NIS on the plasma membrane. Our study thus provides further insights into the roles of SLC5A5 in CH pathogenesis.

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“…All patients had undergone newborn CH screening according to the previously described diagnostic criteria for CH. 8,16,17 Twenty-one genes associated with CH were sequenced and analyzed as previously described. 8 Detailed methods are provided in the Supplementary Methods.…”

Section: Patients and Targeted Ngsmentioning

confidence: 99%

Correlation of DUOX2 residual enzymatic activity with phenotype in congenital hypothyroidism caused by biallelic DUOX2 defects

et al. 2021

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DUOX2 is the most frequently mutated gene in patients with congenital hypothyroidism (CH) in China. However, no reliable genotype-phenotype relationship has been found in patients with DUOX2 mutations. In this study, DUOX2 mutations were screened in 266 CH patients, and the enzymatic activity of 89 DUOX2 variants was determined in vitro. Furthermore, the DUOX2 residual activity in 76 CH patients caused by DUOX2 biallelic mutations was calculated. The thyroid-stimulating hormone (TSH) and free thyroxine (FT4) levels were found to be higher and lower in patients with DUOX2 residual activity ≤22%, respectively, compared to patients with residual enzymatic activity >22%. Moreover, we interpreted the pathogenicity of DUOX2 variants by applying the ACMG classification criteria with or without PS3/BS3 evidence.The results indicated that residual DUOX2 enzymatic activity was closely related to the clinical phenotypes of CH patients caused by DUOX2 biallelic mutations. These findings suggest that the residual enzymatic activity of 22% may be a cutoff value for estimating the severity of hypothyroidism in CH patients with biallelic DUOX2 mutations. Well-established functional studies are useful and necessary to evaluate the pathogenicity of DUOX2 variants, improving the accuracy and scope of genetic consultations.

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The TPO mutation screening and genotype-phenotype analysis in 230 Chinese patients with congenital hypothyroidism

Cited by 15 publications

References 35 publications

Upregulation of GBP1 in thyroid primordium is required for developmental thyroid morphogenesis

Upregulation of GBP1 in thyroid primordium is required for developmental thyroid morphogenesis

Novel Compound Heterozygous Pathogenic Mutations of SLC5A5 in a Chinese Patient With Congenital Hypothyroidism

Correlation of DUOX2 residual enzymatic activity with phenotype in congenital hypothyroidism caused by biallelic DUOX2 defects

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