Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
Centro de Investigaciones en Bioquímica Clínica e Inmunología - Consejo Nacional de Investigaciones Científicas y Técnicas (CIBICI-CONICET), Córdoba, Argentina.
Front Endocrinol (Lausanne). 2022 May 4;13:868891. doi: 10.3389/fendo.2022.868891. eCollection 2022.
Congenital iodide transport defect (ITD) is an uncommon cause of dyshormonogenic congenital hypothyroidism characterized by the absence of active iodide accumulation in the thyroid gland. ITD is an autosomal recessive disorder caused by loss-of-function variants in the sodium/iodide symporter (NIS)-coding gene.
We aimed to identify, and if so to functionally characterize, novel ITD-causing gene variants in a cohort of five unrelated pediatric patients diagnosed with dyshormonogenic congenital hypothyroidism with minimal to absent Tc-pertechnetate accumulation in the thyroid gland.
The coding region of the gene was sequenced using Sanger sequencing. analysis and functional characterization of a novel synonymous variant were performed.
Sanger sequencing revealed a novel homozygous synonymous gene variant (c.1326A>C in exon 11). analysis revealed that the c.1326A>C variant is potentially deleterious for NIS pre-mRNA splicing. The c.1326A>C variant was predicted to lie within a putative exonic splicing enhancer reducing the binding of splicing regulatory trans-acting protein SRSF5. Splicing minigene reporter assay revealed that c.1326A>C causes exon 11 or exon 11 and 12 skipping during NIS pre-mRNA splicing leading to the NIS pathogenic variants p.G415_P443del and p.G415L32, respectively. Significantly, the frameshift variant p.G415L32 is predicted to be subjected to degradation by nonsense-mediated decay.
We identified the first exonic synonymous gene variant causing aberrant NIS pre-mRNA splicing, thus expanding the mutational landscape of the gene leading to dyshormonogenic congenital hypothyroidism.
先天性碘转运缺陷（ITD）是一种罕见的促甲状腺激素生成性先天性甲状腺功能减退症病因，其特征是甲状腺内无活性碘积聚。ITD 是一种常染色体隐性遗传病，由钠/碘转运体（NIS）编码基因的功能丧失变异引起。
我们旨在鉴定 5 名诊断为促甲状腺激素生成性先天性甲状腺功能减退症的儿科患者中的新的 ITD 致病基因变异，如果存在的话，并对其进行功能特征分析，这些患者的甲状腺中 Tc-过锝酸盐的积聚很少或不存在。
使用 Sanger 测序对 基因的编码区进行测序。对一种新的同义变异进行了 分析和功能特征分析。
Sanger 测序显示一种新的纯合同义 基因变异（c.1326A>C，位于 11 号外显子）。 分析显示，c.1326A>C 变异可能对 NIS 前体 mRNA 的剪接具有破坏性。c.1326A>C 变异被预测位于一个假定的外显子剪接增强子内，降低了剪接调节反式作用蛋白 SRSF5 的结合。剪接 minigene 报告基因实验显示，c.1326A>C 导致 NIS 前体 mRNA 剪接中第 11 外显子或第 11 外显子和 12 外显子跳过，分别导致 NIS 致病性变异 p.G415_P443del 和 p.G415L32。重要的是，移码变异 p.G415L32 预计会被无意义介导的衰变所降解。
我们鉴定了第一个引起异常 NIS 前体 mRNA 剪接的外显子同义 基因变异，从而扩展了导致促甲状腺激素生成性先天性甲状腺功能减退症的 基因的突变景观。
