Centro de Investigaciones en Bioquímica Clínica e Inmunología-Consejo Nacional de Investigaciones Científicas y Técnicas, Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, 5000 Córdoba, Argentina.
J Clin Endocrinol Metab. 2011 Jul;96(7):E1100-7. doi: 10.1210/jc.2011-0349. Epub 2011 May 11.
Iodide transport defect (ITD) is an autosomal recessive disorder caused by impaired Na(+)/I(-) symporter (NIS)-mediated active iodide accumulation into thyroid follicular cells. Clinical manifestations comprise a variable degree of congenital hypothyroidism and goiter, and low to absent radioiodide uptake, as determined by thyroid scintigraphy. Hereditary molecular defects in NIS have been shown to cause ITD.
Our objective was to perform molecular studies on NIS in a patient with congenital hypothyroidism presenting a clinical ITD phenotype.
The genomic DNA encoding NIS was sequenced, and an in vitro functional study of a newly identified NIS mutation was performed.
The analysis revealed the presence of an undescribed homozygous C to T transition at nucleotide -54 (-54C>T) located in the 5'-untranslated region in the NIS sequence. Functional studies in vitro demonstrated that the mutation was associated with a substantial decrease in iodide uptake when transfected into Cos-7 cells. The mutation severely impaired NIS protein expression, although NIS mRNA levels remained similar to those in cells transfected with wild-type NIS, suggesting a translational deficiency elicited by the mutation. Polysome profile analysis demonstrated reduced levels of polyribosomes-associated mutant NIS mRNA, consistent with reduced translation efficiency.
We described a novel mutation in the 5'-untranslated region of the NIS gene in a newborn with congenital hypothyroidism bearing a clinical ITD phenotype. Functional evaluation of the molecular mechanism responsible for impaired NIS-mediated iodide concentration in thyroid cells indicated that the identified mutation reduces NIS translation efficiency with a subsequent decrease in protein expression and function.
碘转运缺陷（ITD）是一种常染色体隐性疾病，由钠/碘同向转运体（NIS）介导的活性碘积聚到甲状腺滤泡细胞的功能障碍引起。临床表现包括不同程度的先天性甲状腺功能减退和甲状腺肿，以及甲状腺闪烁显像显示放射性碘摄取低至无。已经表明 NIS 的遗传性分子缺陷会导致 ITD。
我们旨在对患有先天性甲状腺功能减退并表现出 ITD 表型的患者进行 NIS 的分子研究。
对 NIS 的基因组 DNA 进行测序，并对新鉴定的 NIS 突变进行体外功能研究。
分析显示 NIS 序列 5'-非翻译区存在未描述的核苷酸 -54 处的纯合 C 到 T 转换（-54C>T）。体外功能研究表明，该突变与转染 Cos-7 细胞时碘摄取的显著减少相关。该突变严重损害了 NIS 蛋白的表达，尽管 NIS mRNA 水平与转染野生型 NIS 的细胞相似，提示该突变引起翻译缺陷。多核糖体谱分析显示，多核糖体相关突变 NIS mRNA 水平降低，与翻译效率降低一致。
我们在一名患有先天性甲状腺功能减退并伴有 ITD 表型的新生儿中描述了 NIS 基因 5'-非翻译区的一个新突变。对导致甲状腺细胞中 NIS 介导的碘浓度受损的分子机制的功能评估表明，所鉴定的突变降低了 NIS 的翻译效率，随后降低了蛋白表达和功能。
