中国儿童先天性甲状腺功能减退症的基因学研究进展

陈晓宇; 秦晓松

doi:10.7499/j.issn.1008-8830.2018.03.015

PDF(954 KB)

HTML

中国当代儿科杂志 ›› 2018, Vol. 20 ›› Issue (3) : 243-250. DOI: 10.7499/j.issn.1008-8830.2018.03.015

综述

中国儿童先天性甲状腺功能减退症的基因学研究进展

陈晓宇, 秦晓松

作者信息 +

Advances in genetic research of congenital hypothyroidism in China

CHEN Xiao-Yu, QIN Xiao-Song

Author information +

文章历史 +

摘要

先天性甲状腺功能减退症（先天性甲减）是新生儿最常见的一种内分泌障碍性疾病，是由于甲状腺激素的合成不足而不能满足机体的需求。其发病机制主要分为两种，即甲状腺发育不全和甲状腺内分泌障碍，均可引起甲状腺激素合成过程中相关酶的缺陷而导致甲状腺激素合成不足。近年许多研究者在先天性甲减的基因学方面开展了广泛研究，本文就已发现的与中国人先天性甲减相关的基因学研究进行综述。

Abstract

Congenital hypothyroidism (CH), which results from insufficient thyroid hormone biosynthesis, is one of the most common neonatal endocrine disorders. Thyroid dysgenesis and thyroid dyshormonogenesis are the two causes of CH and either one will lead to deficiencies of enzymes during thyroid hormone biosynthesis and insufficient thyroid hormone biosynthesis. Recently, researchers have performed extensive studies on genetics of CH. This paper reviews genes reported to be associated with CH in China.

导出引用

陈晓宇, 秦晓松. 中国儿童先天性甲状腺功能减退症的基因学研究进展[J]. 中国当代儿科杂志. 2018, 20(3): 243-250 https://doi.org/10.7499/j.issn.1008-8830.2018.03.015

CHEN Xiao-Yu, QIN Xiao-Song. Advances in genetic research of congenital hypothyroidism in China[J]. Chinese Journal of Contemporary Pediatrics. 2018, 20(3): 243-250 https://doi.org/10.7499/j.issn.1008-8830.2018.03.015

参考文献

[1] Chiesa Al, Prieto L, Mendez V, et al. Prevalence and etiology of congenital hypothyroidism detected through an argentine neonatal screening program (1997-2010)[J]. Horm Res Paediatr, 2013, 80(3):185-192.
[2] 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.
[3] 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 Chim Acta, 2016, 462:127-132.
[4] 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.
[5] 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.
[6] Fan X, Fu C, Shen Y, et al. Next-generation sequencing analysis of twelve known causative genes in congenital hypothyroidism[J]. Clin Chim Acta, 2017, 468:76-80.
[7] Wang F, Liu C, Jia X, et al. Next-generation sequencing of NKX2.1, FOXE1, PAX8, NKX2.5, and TSHR in 100 Chinese patients with congenital hypothyroidism and athyreosis[J]. Clin Chim Acta, 2017, 470:36-41.
[8] 袁哲锋, 罗燕斐, 吴亦栋, 等. 先天性甲状腺功能减低症汉族儿童的促甲状腺素受体基因失活突变[J]. 中华儿科杂志, 2007, 45(7):508-512.
[9] Yuan ZF, Mao HQ, Luo YF, et al. Thyrotropin receptor and thyroid transcription factor-1genes variant in Chinese children with congenital hypothyroidism[J]. Endocr J, 2008, 55(2):415-423.
[10] Jiang H, Wu J, Ke S, et al. High prevalence of DUOX2 gene mutations among children with congenital hypothyroidism in central China[J]. Eur J Med Genet, 2016, 59(10):526-531.
[11] 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.
[12] Ramos HE, Carré A, Carré A, et al. Extreme phenotypic variability of thyroid dysgenesis in six new cases of congenital hypothyroidism due to PAX8 gene loss-of-function mutations[J]. Eur J Endocrinol, 2014, 171(4):499-507.
[13] 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[J]. Eur J Endocrinol, 2007, 156(5):521-529.
[14] Liu S, Wang X, Zou H, et al. Identification and characterization of novel PAX8 mutations in congenital hypothyroidism CH in a Chinese population[J]. Oncotarget, 2017, 8(5):8707-8716.
[15] Liu SG, Zhang SS, Zhang LQ, et al. Screening of PAX8 mutations in Chinese patients withcongen ital hypothyroidism[J]. J Endocrinol Invest, 2012, 35(10):889-892.
[16] Zou H, Chai J, Liu S, et al. A De novo PAX8 mutation in a Chinese child with congenital thyroid dysgenesis[J]. Int J Clin Exp Pathol, 2015, 8(9):11434-11439.
[17] Szinnai G. Clinical genetics of congenital hypothyroidism[J]. Endocr Dev, 2014, 26:60-78.
[18] Lazzaro D, Price M, de Felice M, et al. The transcription factor TTF-1 is expressed at the onset of thyroid and lung morphogenesis and in restricted regions of the foetal brain[J]. Development, 1991, 113(4):1093-1104.
[19] Civitareale D, Lonigro R, Sinclair AJ, et al. A thyroid-specific nuclear protein essential for tissue-specific expression of the thyroglobulin promoter[J]. EMBO J, 1989, 8(9):2537-2542.
[20] Nettore I, Ferrara AM, Mirra P, et al. Identification and functional characterization of a novel mutation in the NKX2-1 gene:comparison with the data in the literature[J]. Thyroid, 2013, 23(6):675-682.
[21] De Felice M, Ovitt C, Biffali E, et al. A mouse model for hereditary thyroid dysgenesis and cleft palate[J]. Nat Genet, 1998, 19(4):395-398.
[22] Nettore IC1, 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.
[23] 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.
[24] Liu S, Chai J, Zheng G, et al. Screening of HHEX mutations in Chinese children with thyroid dysgenesis[J]. J Clin Res Pediatr Endocrinol, 2016, 8(1):21-25.
[25] Lamas L, Anderson PC, Fox JW, et al. Consensus sequences for early iodination and hormonogenesis in human thyroglobulin[J]. J Biol Chem, 1989, 264(23):13541-13545.
[26] Hu X, Chen R, Fu C, et al. Thyroglobulin gene mutations in Chinese patients with congenital hypothyroidism[J]. Mol Cell Endocrinol, 2016, 423:60-66.
[27] Fu C, Luo S, Zhang S, et al. Next-generation sequencing analysis of DUOX2 in 192 Chinese subclinical congenital hypothyroidism SCH and CH patients[J]. Clin Chim Acta, 2016, 458:30-34.
[28] Liu S, Zhang S, Li W, et al. Clinical and genetic analysis of a compound heterozygous mutation in the thyroglobulin gene in a Chinese twin family with congenital goiter and hypothyroidism[J]. Twin Res Hum Genet, 2012, 15(1):126-132.
[29] Niu DM, Hsu JH, Chong KW, et al. Six new mutations of the thyroglobulin gene discovered in taiwanese children presenting with thyroid dyshormonogenesis[J]. J Clin Endocrinol Metab, 2009, 94(12):5045-5052.
[30] Cangul H, Aycan Z, Olivera-Nappa A, et al. Thyroid dyshormonogenesis is mainly caused by TPO mutations in consanguineous community[J]. Clin Endocrinol (Oxf), 2013, 79(2):275-281.
[31] Fu C, Xie B, Zhang S, et al. Mutation screening of the TPO gene in a cohort of 192 Chinese patients with congenital hypothyroidism[J]. BMJ Open, 2016, 6(5):e010719.
[32] Niu DM, Hwang B, Chu YK, et al. High prevalence of a novel mutation (2268 ins T) of the thyroid peroxidase gene in Taiwanese patients with total iodide organification defect, and evidence for a founder effect[J]. J Clin Endocrinol Metab, 2002, 87(9):4208-4212.
[33] 黄永兰, 谭敏沂, 蒋翔, 等. 疑似甲状腺素合成障碍性永久性先天性甲状腺功能减低症患儿TPO、DUOX2及DUOXA2基因突变分析[J]. 中华儿科杂志, 2017, 55(3):210-214.
[34] Lee CC, Harun F, Jalaludin MY, et al. Prevalence of c.2268dup and detection of two novel alterations, c.670_672del and c.1186C>T, in the TPO gene in a cohort of Malaysian-Chinese with thyroid dyshormonogenesis[J]. BMJ Open, 2015, 5(1):e006121.
[35] Ma SG, Zheng X, Qiu YL, et al. Compound heterozygous mutations p.T561M and c.2422delT in the TPO gene associated with congenital hypothyroidism[J]. J Pediatr Endocrinol Metab, 2016, 29(5):567-570.
[36] Lee CC, Harun F, Jalaludin MY, et al. Functional analyses of C.2268dup in thyroid peroxidase gene associated with goitrous congenital hypothyroidism[J]. Biomed Res Int, 2014, 2014:370538.
[37] Ma SG, Wu XJ, Liu H, et al. Mutations of the thyroid peroxidase gene in Chinese siblings with congenital goitrous hypothyroidism[J]. Arq Bras Endocrinol Metabol, 2012, 56(9):614-617.
[38] Muzza M, Rabbiosi S, Vigone MC, et al. The clinical and molecular characterization of patients with dyshormonogenic congenital hypothyroidism reveals specific diagnostic clues for DUOX2 defects[J]. J Clin Endocrinol Metab, 2014, 99(3):544-553.
[39] Fu C, Zhang S, Su J, et al. Mutation screening of DUOX2 in Chinese patients with congenital hypothyroidism[J]. J Endocrinol Invest, 2015, 38(11):1219-1224.
[40] Wang F, Lu K, Yang Z, et al. Genotypes and phenotypes of congenital goitre and hypothyroidism caused by mutations in dual oxidase 2 genes[J]. Clin Endocrinol (Oxf), 2014, 81(3):452-457.
[41] Zheng X, Ma SG, Qiu YL, et al. A Novel c.554+5C>T mutation in the DUOXA2 gene combined with p.R885Q mutation in the DUOX2 gene causing congenital hypothyroidism[J]. J Clin Res Pediatr Endocrinol, 2016, 8(2):224-227.
[42] 柴建, 杨晓龙, 郭明贞, 等. 先天性甲状腺功能减退症患儿DUOX2基因突变的研究[J].中国当代儿科杂志, 2015, 17(1):40-44.
[43] Liu S, Zhang W, Zhang L, et al. Genetic and functional analysis of two missense DUOX2 mutations in congenital hypothyroidism and goiter[J]. Oncotarget, 2016, 7:1-9.
[44] 吕志萍, 李桂花, 李文杰, 等. 暂时性甲状腺功能减低症伴甲状腺肿大患儿DUOX2基因突变的研究[J]. 中华儿科杂志, 2011, 49(12):943-946.
[45] Liu S, Liu L, Niu X, et al. A novel missense mutation (I26M) in DUOXA2 causing congenital goiter hypothyroidism impairs NADPH oxidase activity but not protein expression[J]. J Clin Endocrinol Metab, 2015, 100(4):1225-1229.
[46] Zheng X, Ma SG, Guo ML, et al. Compound heterozygous mutations in the DUOX2/DUOXA2 genes cause congenital hypothyroidism[J]. Yonsei Med J, 2017, 58(4):888-890.
[47] Fu C, Zheng H, Zhang S, et al. Mutation screening of the SLC26A4 gene in a cohort of 192 Chinese patients with congenital hypothyroidism[J]. Arch Endocrinol Metab, 2016, 60(4):323-327.