Purpose

T4-binding globulin (TBG) is the main thyroid hormone (TH) transporter present in human serum. Inherited thyroxine-binding globulin (TBG) deficiency is caused by mutations in the TBG (SERPINA7) gene, which is located on the X chromosome. This study was performed to report and evaluate coding region mutations in TBG gene for partial thyroxine-binding globulin deficiency.

Methods

A pedigree spanning four generations is described in this study. The proband is a female with partial TBG deficiency. All members of this pedigree underwent thyroid function tests, while Sanger sequencing was used to identify the TBG gene mutations. Bioinformatics databases were used to evaluate the deleterious effects of the mutation(s). Two hundred and seven unrelated individuals were used to evaluate the thyroid function of individuals with different TBG mutations. A one-way ANOVA was used to analyze the impact of the TBG mutations on thyroid function.

Results

TBG gene sequencing results revealed that the proband had a novel mutation in codon 27 leading to alanine to valine substitution (p.A27V). This mutation was associated with lower serum T4 levels (p < 0.0001) when compared to the groups that did not carry the mutation. The previously reported p.L283F mutation was also found in the proband. The hemizygous p.L283F individuals presenting with lower T4 serum and TBG levels (p < 0.001) when compared to wildtype males and females. Both mutations were deleterious upon SIFT and PolyPhen-2 evaluation.

Conclusion

Associated with partial thyroxine-binding globulin deficiency, this study reports a novel p.A27V mutation in the TBG gene.

中文翻译：

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TBG 基因编码区突变家族中的部分甲状腺素结合球蛋白缺乏症。

目的

T4 结合球蛋白 (TBG) 是人血清中存在的主要甲状腺激素 (TH) 转运蛋白。遗传性甲状腺素结合球蛋白 (TBG) 缺乏症是由位于 X 染色体上的TBG ( SERPINA7 ) 基因突变引起的。进行这项研究是为了报告和评估部分甲状腺素结合球蛋白缺乏症的TBG基因编码区突变。

方法

本研究描述了跨越四代的谱系。先证者是一名患有部分 TBG 缺乏症的女性。该谱系的所有成员都接受了甲状腺功能测试，而 Sanger 测序则用于鉴定TBG基因突变。生物信息学数据库用于评估突变的有害影响。使用 207 个无关个体来评估具有不同TBG突变的个体的甲状腺功能。使用单向方差分析来分析TBG突变对甲状腺功能的影响。

结果

TBG基因测序结果显示先证者在密码子 27 中有一个新的突变，导致丙氨酸到缬氨酸的取代（p.A27V）。与 未携带突变的组相比，该突变与较低的血清 T4 水平相关 ( p < 0.0001)。在先证者中也发现了先前报道的 p.L283F 突变。 与野生型雄性和雌性相比，半合子 p.L283F 个体的 T4 血清和 TBG 水平较低 ( p < 0.001)。根据 SIFT 和 PolyPhen-2 评估，这两种突变都是有害的。

结论

与部分甲状腺素结合球蛋白缺乏相关，该研究报告了TBG基因中的一个新的 p.A27V 突变。