Genetic testing of PAX8 mutations associated with thyroid dysgenesis in Chinese congenital hypothyroidism patients
Abstract
Introduction: Thyroid dysgenesis (TD) is the main cause of congenital hypothyroidism (CH), affecting nearly 1 in 2000–3000 newborns worldwide, as the most common neonatal endocrine disorder. Paired box gene 8 (PAX8), expressed during all stages of thyroid follicular cell, plays a key role in thyroid morphogenesis by a complex regulatory network. In conclusion, the genetic mechanism of PAX8 mutant in TD is still ambiguous; therefore, further research is needed.
Material and methods: Blood samples were collected from 289 TD patients in Shandong Province, China. Genomic DNA was extracted from peripheral blood. All the exons of PAX8 along with their exon-intro boundaries were amplified by PCR and analysed by Sanger sequencing.
Results: We identified three novel PAX8 nonsense mutations in three patients by sequence analysis of PAX8: Patient 1 (c.285C>G, p.Tyr95Ter), Patient 2 (c.747T>G, p.Tyr249Ter), and Patient 3 (c.786C>A, p.Tyr262Ter). All the three patients carrying PAX8 variants had obvious clinical phenotypes of thyroid anomaly, such as hypoplasia and athyreosis.
Conclusion: We conducted the largest worldwide PAX8 mutation screening so far in TD patients. Three presumably pathogenic PAX8 mutations were detected in 289 TD cases for the first time, showing the mutation rate of PAX8 is 1.04% in Chinese TD patients. In addition, our study expands the gene mutation spectrum of TD.
Keywords: thyroid dysgenesispaired box gene 8mutationSanger sequencing
References
- Targovnik HM, Scheps KG, Rivolta CM. Defects in protein folding in congenital hypothyroidism. Mol Cell Endocrinol. 2019 [Epub ahead of print]; 501: 110638.
- Santos-Silva R, Rosário M, Grangeia A, et al. Genetic analyses in a cohort of Portuguese pediatric patients with congenital hypothyroidism. J Pediatr Endocrinol Metab. 2019; 32(11): 1265–1273.
- Nilsson M, Fagman H. Development of the thyroid gland. Development. 2017; 144(12): 2123–2140.
- Abu-Khudir R, Larrivée-Vanier S, Wasserman JD, et al. Disorders of thyroid morphogenesis. Best Pract Res Clin Endocrinol Metab. 2017; 31(2): 143–159.
- Nilsson M, Fagman H. Mechanisms of thyroid development and dysgenesis: an analysis based on developmental stages and concurrent embryonic anatomy. Curr Top Dev Biol. 2013; 106: 123–170.
- Fernández LP, López-Márquez A, Santisteban P. Thyroid transcription factors in development, differentiation and disease. Nat Rev Endocrinol. 2015; 11(1): 29–42.
- Fagman H, Nilsson M. Morphogenesis of the thyroid gland. Mol Cell Endocrinol. 2010; 323(1): 35–54.
- Sun F, Zhang JX, Yang CY, et al. The genetic characteristics of congenital hypothyroidism in China by comprehensive screening of 21 candidate genes. Eur J Endocrinol. 2018; 178(6): 623–633.
- Ma R, Latif R, Davies TF. Thyroid follicle formation and thyroglobulin expression in multipotent endodermal stem cells. Thyroid. 2013; 23(4): 385–391.
- Carré A, Stoupa A, Kariyawasam D, et al. Mutations in BOREALIN cause thyroid dysgenesis. Hum Mol Genet. 2017; 26(3): 599–610.
- Panneerselvam A, Kannan A, Mariajoseph-Antony LF, et al. PAX proteins and their role in pancreas. Diabetes Res Clin Pract. 2019; 155: 107792.
- Codutti L, van Ingen H, Vascotto C, et al. The solution structure of DNA-free Pax-8 paired box domain accounts for redox regulation of transcriptional activity in the pax protein family. J Biol Chem. 2008; 283(48): 33321–33328.
- Plachov D, Chowdhury K, Walther C, et al. Pax8, a murine paired box gene expressed in the developing excretory system and thyroid gland. Development. 1990; 110(2): 643–651.
- Pasca di Magliano M, Di Lauro R, Zannini M. Pax8 has a key role in thyroid cell differentiation. Proc Natl Acad Sci U S A. 2000; 97(24): 13144–13149.
- Nettore IC, Cacace V, De Fusco C, et al. The molecular causes of thyroid dysgenesis: a systematic review. J Endocrinol Invest. 2013; 36(8): 654–664.
- De Felice M, Di Lauro R. Thyroid development and its disorders: genetics and molecular mechanisms. Endocr Rev. 2004; 25(5): 722–746.
- Srichomkwun P, Admoni O, Refetoff S, et al. A Novel Mutation (S54C) of the PAX8 Gene in a Family with Congenital Hypothyroidism and a High Proportion of Affected Individuals. Horm Res Paediatr. 2016; 86(2): 137–142.
- Raman P, Koenig RJ. Pax-8-PPAR-γ fusion protein in thyroid carcinoma. Nat Rev Endocrinol. 2014; 10(10): 616–623.
- Macchia PE, Lapi P, Krude H, et al. PAX8 mutations associated with congenital hypothyroidism caused by thyroid dysgenesis. Nat Genet. 1998; 19(1): 83–86.
- Vilain C, Rydlewski C, Duprez L, et al. Autosomal dominant transmission of congenital thyroid hypoplasia due to loss-of-function mutation of PAX8. J Clin Endocrinol Metab. 2001; 86(1): 234–238.
- Kumorowicz-Czoch M, Madetko-Talowska A, Dudek A, et al. Genetic analysis of the paired box transcription factor (PAX8) gene in a cohort of Polish patients with primary congenital hypothyroidism and dysgenetic thyroid glands. J Pediatr Endocrinol Metab. 2015; 28(7-8): 735–743.
- Al Taji E, Biebermann H, Límanová Z, et al. Screening for mutations in transcription factors in a Czech cohort of 170 patients with congenital and early-onset hypothyroidism: identification of a novel PAX8 mutation in dominantly inherited early-onset non-autoimmune hypothyroidism. Eur J Endocrinol. 2007; 156(5): 521–529.
- Ramos HE, Nesi-França S, Boldarine VT, et al. Clinical and molecular analysis of thyroid hypoplasia: a population-based approach in southern Brazil. Thyroid. 2009; 19(1): 61–68.
- Cangul H, Morgan NV, Forman JR, et al. Novel TSHR mutations in consanguineous families with congenital nongoitrous hypothyroidism. Clin Endocrinol (Oxf). 2010; 73(5): 671–677.
- Lanzerath K, Bettendorf M, Haag C, et al. Screening for Pax8 mutations in patients with congenital hypothyroidism in South-West Germany. Horm Res. 2006; 66(2): 96–100.
- Liu SG, Zhang SS, Zhang LQ, et al. Screening of PAX8 mutations in Chinese patients with congenital hypothyroidism. J Endocrinol Invest. 2012; 35(10): 889–892.
- Zou H, Chai J, Liu S, et al. A De novo PAX8 mutation in a Chinese child with congenital thyroid dysgenesis. Int J Clin Exp Pathol. 2015; 8(9): 11434–11439.
![](https://journals.viamedica.pl/plugins/generic/popups/images/icons/close.png)