Novel Missense Variants in PAX8 and NKX2-1 Cause Congenital Hypothyroidism

Li, Menglin; Li, Zhuo; Chen, Miaomiao; Hu, Zhiqing; Zhou, Miaojin; Wu, Lingqian; Zhang, Chunhua; Liang, Desheng

doi:10.3390/ijms24010786

Open AccessArticle

Novel Missense Variants in PAX8 and NKX2-1 Cause Congenital Hypothyroidism

by

Menglin Li

,

Zhuo Li

,

Miaomiao Chen

,

Zhiqing Hu

,

Miaojin Zhou

,

Lingqian Wu

,

Chunhua Zhang

^* and

Desheng Liang

^*

Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China

^*

Authors to whom correspondence should be addressed.

Int. J. Mol. Sci. 2023, 24(1), 786; https://doi.org/10.3390/ijms24010786

Submission received: 6 October 2022 / Revised: 29 December 2022 / Accepted: 30 December 2022 / Published: 2 January 2023

(This article belongs to the Special Issue Molecular Mechanism of Hypothyroidism)

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Abstract

Primary congenital hypothyroidism (CH) is a common neonatal endocrine disorder characterized by elevated concentrations of thyroid stimulating hormone (TSH) and low concentrations of free thyroxine (FT4). PAX8 and NKX2-1 are important transcription factors involved in thyroid development. In this study, we detected three novel variants in PAX8 (c.149A > C and c.329G > A) and NKX2-1 (c.706A > G) by whole exome sequencing (WES) in three unrelated CH patients with variable phenotypes. The results of Western blot and immunofluorescence analysis showed that the three variants had no effect on protein expression and subcellular localization. However, the results of the electrophoretic mobility shift assay (EMSA) and dual-luciferase reporter assay suggested that the three variants in PAX8 and NKX2-1 both affected their DNA-binding ability and reduced their transactivation capacity. Moreover, a dominant-negative effect in K236E−NKX2-1 was identified by dual-luciferase reporter assay. To sum up, our findings extend our knowledge of the current mutation spectrum of PAX8 and NKX2-1 and provide important information for diagnosing, treating, and preventing CH in these families.

Keywords: congenital hypothyroidism; PAX8; NKX2-1; whole exome sequencing (WES); novel variants; functional study; dominant-negative effect

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MDPI and ACS Style

Li, M.; Li, Z.; Chen, M.; Hu, Z.; Zhou, M.; Wu, L.; Zhang, C.; Liang, D. Novel Missense Variants in PAX8 and NKX2-1 Cause Congenital Hypothyroidism. Int. J. Mol. Sci. 2023, 24, 786. https://doi.org/10.3390/ijms24010786

AMA Style

Li M, Li Z, Chen M, Hu Z, Zhou M, Wu L, Zhang C, Liang D. Novel Missense Variants in PAX8 and NKX2-1 Cause Congenital Hypothyroidism. International Journal of Molecular Sciences. 2023; 24(1):786. https://doi.org/10.3390/ijms24010786

Chicago/Turabian Style

Li, Menglin, Zhuo Li, Miaomiao Chen, Zhiqing Hu, Miaojin Zhou, Lingqian Wu, Chunhua Zhang, and Desheng Liang. 2023. "Novel Missense Variants in PAX8 and NKX2-1 Cause Congenital Hypothyroidism" International Journal of Molecular Sciences 24, no. 1: 786. https://doi.org/10.3390/ijms24010786

APA Style

Li, M., Li, Z., Chen, M., Hu, Z., Zhou, M., Wu, L., Zhang, C., & Liang, D. (2023). Novel Missense Variants in PAX8 and NKX2-1 Cause Congenital Hypothyroidism. International Journal of Molecular Sciences, 24(1), 786. https://doi.org/10.3390/ijms24010786

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Novel Missense Variants in PAX8 and NKX2-1 Cause Congenital Hypothyroidism

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