GNAS遗传变异在先天性甲状腺功能减低症人群中的分子流行病学研究

Genetic variation, which is closely related to the pathological classification, phenotypic characteristics and clinical outcomes of congenital hypothyroidism(CH), is an important pathogenic factor of CH. Complexity and diversity of CH-related genetic variation and unclear pathogenic mechanism hinder the precise prevention and treatment of CH. Our previous studies found that mutation of GNAS was high-frequency in Chinese CH population, but molecular epidemiological data and genotype-phenotype relationship of GNAS variation were not studied, and the pathogenesis was unknown. Our previous studies also found that novel mutation of GNAS, p.I103T, reduced the production of cAMP. It implied that mutation of p.I103T may reduce the TSH sensitivity by disturbing cAMP signaling pathway. We will study genetic variation, epidemiological characteristics and genetic model of GNAS variation in CH population. We will also study the pathogenesis of GNAS mutation by studying the p.I103T mutation. Our study may provide theoretical basis for the precise prevention, treatment and genetic intervention of CH.

遗传变异是先天性甲低（CH）的重要致病因素，且与CH患者的病理分类、表型特征及临床转归等密切相关，但CH相关遗传变异复杂多样且致病机制不明，成为阻碍CH精准防治的瓶颈。项目组前期发现在中国CH人群中GNAS基因突变高发，但相关分子流行病学数据、基因型-表型关系谱及致病机制未见报道。预实验发现GNAS新颖突变p.I103T导致cAMP的生成减少，提示该突变可能通过干扰cAMP信号通路的转导能力，降低细胞对TSH的敏感性，从而导致CH发生。课题组拟以CH人群为研究对象，描绘CH人群GNAS遗传变异谱，探索GNAS遗传变异的流行病学特征和遗传模式，同时以p.I103T突变作为切入点研究GNAS突变的致病机制，为CH的精准防治和遗传学干预提供理论依据。

本项目建立了一组先天性甲减（CH）的专病队列，采用了高通量测序方法对包括GNAS在内的多种基因的遗传变异情况进行了调查，结果提示GNAS变异在CH人群中的发生率较低，约为6.66%，而GNAS甲基化异常罕见，不同地区的CH人群GNAS变异情况或许存在较大的差异。CH人群中GNAS变异遗传自母亲，并以杂合错义突变为主要类型，可随机分布在GNAS整个基因序列的任何位置。发生GNAS变异的CH人群甲状腺大小和位置多为正常，此类人群的血清TSH浓度明显高于其它变异的CH人群，CH表型较DUOX2变异人群更为严重，主要体现在血清TSH浓度显著升高以及需服用更高的药物剂量来维持甲状腺激素处于正常范围。因GNAS遗传变异导致的CH为永久性CH，需终身服用L-T4进行替代治疗。GNAS基因的新颖突变p.I103T和p.F340L均能导致甲状腺激素合成依赖的cAMP信号通路中的关键第二信使cAMP生成减少，p.F340L突变通过影响GNAS基因编码产物Gsα蛋白的表达水平来干扰cAMP信号通路，p.I103T通过影响Gsα蛋白活性来干扰cAMP信号通路，但需进一步实验论证。本项目的实施有助于探索CH人群中GNAS变异情况和GNAS变异人群的流行病学特点，对遗传学咨询和干预以及临床诊治具有一定的指导意义。