Novel Missense Variants in <i>PAX8</i> and <i>NKX2-1</i> Cause Congenital Hypothyroidism
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 st...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-01-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/24/1/786 |
| _version_ | 1797625586098634752 |
|---|---|
| author | Menglin Li Zhuo Li Miaomiao Chen Zhiqing Hu Miaojin Zhou Lingqian Wu Chunhua Zhang Desheng Liang |
| author_facet | Menglin Li Zhuo Li Miaomiao Chen Zhiqing Hu Miaojin Zhou Lingqian Wu Chunhua Zhang Desheng Liang |
| author_sort | Menglin Li |
| collection | DOAJ |
| description | 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 <i>PAX8</i> (c.149A > C and c.329G > A) and <i>NKX2-1</i> (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 <i>PAX8</i> and <i>NKX2-1</i> and provide important information for diagnosing, treating, and preventing CH in these families. |
| first_indexed | 2024-03-11T09:58:28Z |
| format | Article |
| id | doaj.art-fd872a3c43cd4d25a86b78c0c5f16fff |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T09:58:28Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-fd872a3c43cd4d25a86b78c0c5f16fff2023-11-16T15:38:28ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-01-0124178610.3390/ijms24010786Novel Missense Variants in <i>PAX8</i> and <i>NKX2-1</i> Cause Congenital HypothyroidismMenglin Li0Zhuo Li1Miaomiao Chen2Zhiqing Hu3Miaojin Zhou4Lingqian Wu5Chunhua Zhang6Desheng Liang7Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, ChinaCenter for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, ChinaCenter for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, ChinaCenter for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, ChinaCenter for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, ChinaCenter for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, ChinaCenter for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, ChinaCenter for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, ChinaPrimary 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 <i>PAX8</i> (c.149A > C and c.329G > A) and <i>NKX2-1</i> (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 <i>PAX8</i> and <i>NKX2-1</i> and provide important information for diagnosing, treating, and preventing CH in these families.https://www.mdpi.com/1422-0067/24/1/786congenital hypothyroidism<i>PAX8</i><i>NKX2-1</i>whole exome sequencing (WES)novel variantsfunctional study |
| spellingShingle | Menglin Li Zhuo Li Miaomiao Chen Zhiqing Hu Miaojin Zhou Lingqian Wu Chunhua Zhang Desheng Liang Novel Missense Variants in <i>PAX8</i> and <i>NKX2-1</i> Cause Congenital Hypothyroidism International Journal of Molecular Sciences congenital hypothyroidism <i>PAX8</i> <i>NKX2-1</i> whole exome sequencing (WES) novel variants functional study |
| title | Novel Missense Variants in <i>PAX8</i> and <i>NKX2-1</i> Cause Congenital Hypothyroidism |
| title_full | Novel Missense Variants in <i>PAX8</i> and <i>NKX2-1</i> Cause Congenital Hypothyroidism |
| title_fullStr | Novel Missense Variants in <i>PAX8</i> and <i>NKX2-1</i> Cause Congenital Hypothyroidism |
| title_full_unstemmed | Novel Missense Variants in <i>PAX8</i> and <i>NKX2-1</i> Cause Congenital Hypothyroidism |
| title_short | Novel Missense Variants in <i>PAX8</i> and <i>NKX2-1</i> Cause Congenital Hypothyroidism |
| title_sort | novel missense variants in i pax8 i and i nkx2 1 i cause congenital hypothyroidism |
| topic | congenital hypothyroidism <i>PAX8</i> <i>NKX2-1</i> whole exome sequencing (WES) novel variants functional study |
| url | https://www.mdpi.com/1422-0067/24/1/786 |
| work_keys_str_mv | AT menglinli novelmissensevariantsinipax8iandinkx21icausecongenitalhypothyroidism AT zhuoli novelmissensevariantsinipax8iandinkx21icausecongenitalhypothyroidism AT miaomiaochen novelmissensevariantsinipax8iandinkx21icausecongenitalhypothyroidism AT zhiqinghu novelmissensevariantsinipax8iandinkx21icausecongenitalhypothyroidism AT miaojinzhou novelmissensevariantsinipax8iandinkx21icausecongenitalhypothyroidism AT lingqianwu novelmissensevariantsinipax8iandinkx21icausecongenitalhypothyroidism AT chunhuazhang novelmissensevariantsinipax8iandinkx21icausecongenitalhypothyroidism AT deshengliang novelmissensevariantsinipax8iandinkx21icausecongenitalhypothyroidism |