Abstract：【Objective】To investigate the gene mutations of TSHR, PAX8, TTF1, TTF2 and NKX2.5 in children with congenital hypothyroidism (CH), and to analyze the types and characteristics of gene mutations, so as to provide reference for early screening and clinical gene diagnosis of neonates.【Methods】Genomic DNA was extracted from 14 children with CH and all exons of TSHR, PAX8, TTF1, TTF2 and NKX2.5 genes were amplified by PCR. The amplified products were sequenced by second generation sequencing.【Results】The mutation sites were detected in 9 children with CH. Five suspicious pathogenic gene mutations were found in TSHR gene, two suspicious pathogenic gene mutations were found in PAX8 gene, one suspicious pathogenic gene mutation was found in TTF1 gene and TTF2 gene respectively, and no suspicious pathogenic gene mutation was found in NKX2.5 gene.【Conclusions】The known candidate genes TSHR, PAX8, TTF1 and TTF2 in children with CH all have gene mutations and further enlarged the mutation spectrum of TSHR gene. However, the specific relationship between genotype and phenotype is still unclear, and a large number of functional experiments are needed to verify it.
陈晓宇, 秦晓松, 刘建华, 刘勇. 14例先天性甲状腺功能减退症患儿TSHR、PAX8、TTF1、TTF2、NKX2.5基因二代测序分析[J]. 医学临床研究, 2019, 36(6): 1096-1099.
CHEN Xiao-yu, QIN Xiao-song, LIU Jian-hua,et al. Second Generation Sequencing of TSHR, PAX8, TTF1, TTF2 and NKX2.5 Genes in 14 Children with Congenital Hypothyroidism. JOURNAL OF CLINICAL RESEARCH, 2019, 36(6): 1096-1099.
[1] Park SM, Chatterjee VK.Genetics of congenital hypothyroidism[J].J Med Genet,2005, 42(5) : 379-389.
[2] Anastasovska V,Kocova M.Ethnicity and incidence of congenital hypothyroidism in the capital of Macedonia[J].J Pediatr Endocrinol Metab,2017, 30(4): 405-409.
[3] Anjum A,Afzal MF,Iqbal SM,et al.Congenital hypothyroidism in neonates[J].Indian J Endocrinol Metab,2014, 18(2): 213-216.
[4] Nettore IC, Cacace V, De Fusco C,et al.The molecular causes of thyroid dysgenesis: a systematic review[J].J Endocrinol Invest,2013, 36(8):654-664.
[5] Stein SA, Oates EL, Hall CR, et al. Identification of a point mutation in the thyrotropin receptor of the hyt/hyt hypothyroid mouse[J].Mol Endocrinol,1994, 8(2):129-138.
[6] Qiu YL, Ma SG, Liu H,et al. Two novel TSHR gene mutations (p.R528C and c.392+4del4) associated with congenital hypothyroidism[J].Endocr Res,2016, 41(3) :180-184.
[7] Lábadi , Grassi ES, Gellén B,et al. Loss-of-function variants in a hungarian cohort reveal structural insights on TSH receptor maturation and signaling[J].J Clin Endocrinol Metab,2015, 100(7):E1039-E1045.
[8] Persani L, Calebiro D, Cordella D, et al. Genetics and phenomics of hypothyroidism due to TSH resistance[J].Mol Cell Endocrinol,2010,322(1-2) :72-82.
[9] Chang WC, Liao CY, Chen WC, et al. R450H TSH receptor mutation in congenital hypothyroidism in Taiwanese children[J].Clin Chim Acta,2012, 413(11-12):1004-1007.
[10] Mascia A, Nitsch L, Di Lauro R,et al.Hormonal control of the transcription factor Pax8 and its role in the regulation of thyroglobulin gene expression in thyroid cells[J].J Endocrinol,2002, 172(1) :163-176.
[11] Plachov D, Chowdhury K, Walther C. Walther et al. PAX8.A murine paired box gene expressed in the developing excretory system and thyroid gland[J].Development,1990, 110(2):643-651.
[12] Fu C, Chen R, Zhang S, et al. PAX8 pathogenic variants in Chinese patients with congenital hypothyroidism[J].Clin Chim Acta,2015, 450:322-326.
[13] Fu C, Wang J, Luo S, et al. Next-generation sequencing analysis of TSHR in 384 Chinese subclinical congenital hypothyroidism (CH) and CH patients[J].Clin Chin Acta,2016, 462:127-132.
[14] Vassart G, Dumont JE.The thyrotropin receptor and the regulation of thyrocyte function and growth[J].Endocr Rev,1992, 3(3) :596-611.
[15] Sunthornthepvarakui T,Gottschalk ME,Hayashi Y,et al.Brief report: resistance to thyrotropin caused by mutations in the thyrotropin-receptor gene[J].N Engl J Med,1995, 332(3) :155-160.
2019, Vol. 36 
