甲状腺过氧化物酶
等位基因
人口
遗传学
突变
背景(考古学)
SNP公司
等位基因频率
单核苷酸多态性
甲状腺
医学
甲状腺功能
内科学
内分泌学
甲状腺球蛋白
基因型
基因
生物
古生物学
环境卫生
作者
Shunji Narumi,Koji Muroya,Yumi Asakura,Masanori Aachi,Tomonobu Hasegawa
摘要
Abstract Context: Inborn errors of thyroid hormone biosynthesis are collectively referred to as thyroid dyshormonogenesis (DH). Seven genes have been implicated in DH, including the dual oxidase 2 gene (DUOX2), the thyroglobulin gene (TG), and the thyroid peroxidase gene (TPO). Objective: We aimed to define the prevalence and phenotypic spectrum of DH with single gene mutations. Subjects and Methods: A population-based cohort of 102 patients with permanent congenital hypothyroidism was enrolled. Fourteen were diagnosed as DH and were analyzed for the seven causative genes including DUOX2, TG, and TPO. Several common mutations were screened in the remaining 88 patients. Pathogenicity of single amino acid mutations was verified in vitro. Results: We identified four, five, and two patients with seemingly biallelic mutations in DUOX2, TG, and TPO, respectively. We also found two patients having one heterozygous DUOX2 mutation and one uncommon single-nucleotide polymorphism (SNP) p.H678R (rs57659670, allele frequency 0.035) and another two patients with homozygous p.H678R. Expression experiments and RT-PCR revealed that p.H678R is a functional SNP with theoretical 40% loss of function, supporting a role of p.H678R in the onset of DH. As for clinical phenotypes, patients with inactive DUOX2 alleles (mutations and/or p.H678R) showed characteristic time-dependent improvement of thyroid function and morphology. All three evaluated patients had a negative result in the perchlorate test. Conclusions: Mutations (or a functional SNP) in DUOX2, TG, or TPO were observed in 93% (95% confidence interval = 70–99%) of DH patients. Inactive DUOX2 alleles cause a broader phenotypic spectrum than currently accepted.
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