先天性甲状腺功能减退症伴甲状腺肿大患儿DUOX2基因突变研究

Study of DUOX2 gene mutation of patients with the congenital hypothyroidism with goiter

目的先天性甲状腺功能减退(CH)是小儿最常见内分泌疾病之一。在已经发现的多种由于甲状腺激素合成与分泌的酶基因突变而导致CH中,以常染色体隐性方式遗传的DUOX2基因突变越来越受到国外学者关注,然而目前国内却没有该方面研究。研究中国人群CH患者常见的DUOX2基因突变类型和特点,不仅有利于CH患者的早期诊断或症状前诊断,而且有利于开展产前诊断,提高出生人口素质。方法本研究利用来自8例甲状腺肿大CH患者为研究对象,对DUOX2基因的全部外显子进行基因突变筛查,结合测序验证及生物信息学分析,研究中国人群CH患者常见的DUOX2基因突变类型和特点。结果 8例甲状腺肿大CH患者均没有发现DUOX2基因致病突变。但是在这些样本中,检测到3个氨基酸的改变,经过生物信息学分析后发现这些氨基酸的改变均位于DUOX2基因的非保守性位点,为新的多态性的改变,而不是引起CH的致病突变。在样本2中,DUOX2基因第三外显子中脯氨酸被亮氨酸取代,即DUOX2 c227 C>T(P76L),样本5中DUOX2基因第十三外显子发生同义突变,即DUOX2 c1621 C>A(R541R),样本6中,DUOX2基因第二十六外显子中赖氨酸被精氨酸取代,即DUOX2 c3532 A>G(K1178R)。结论 DUOX2基因在中国先天性甲状腺功能减退症伴甲状腺肿大的患儿中突变率极低,并不是引起伴甲状腺肿大的CH的常见致病基因。

Objective： Congenital hypothyroidism（CH） is the most common inborn endocrine disorder.Many mutations in the genes which are essential for thyroid hormone synthesis and secretion have been proposed as a cause of congenital hypothyroidism and the mutation of DUOX2 gene which is inherited in an autosomal recessive fashion has received considerable attention.Nevertheless,no study to date has evaluated in Han Chinese population.The investigations about the common types and characteristics of the mutation of DUOX2 gene in Han Chinese patients who had the congenital hypothyroidism are useful for not only early diagnosis and presymptomatic diagnosis of congenital hypothyroidism but also carrying out prenatal diagnosis and improving newborn population quality.Methods： We enrolled 8 patients who had congenital hypothyroidism with goiter.The exons of DUOX2 gene were sequenced and mutations were detected by DNA sequence analysis and bioinformatics analysis.We investigated the common types and characteristics of the gene mutation of DUOX2 gene in Han Chinese patients who had the congenital hypothyroidism.Results： No mutations of the DUOX2 gene were found in the 8 patients.However,3 variants were detected,which are not in the consevered region in the DUOX2 gene and are the novel SNPs after bioinformatic analysis.Proline are replaced by Leucine in the exon 3[DUOX2c227 CT（P76L）] in the sample 2,samesenese variant in the exon13[DUOX2 c1621 CA（R541R）]in the sample 5,and Lysine changed to Arginine[DUOX2 c3532 AG（K1178R）] in the exon 26 in the sample 6.Conclusion： The mutation rate of DUOX2 gene is very low in Han Chinese patients who had the congenital hypothyroidism with goiter and the gene is not common disease causing gene which is associated with congenital hypothyroidism.