Gerardo Hernán Carro, Mariano Martín, Sofía Savy, Victoria Peyret, Romina Celeste Geysels, Francisco Andrés Montes, Carlos Eduardo Bernal Barquero, Valentina Ricci, María Eugenia Masnata, Ana María Masini-Repiso, Patricia Papendieck, Mariana Lorena Tellechea, Ana Elena Chiesa, Juan Pablo Nicola
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引用次数: 0
Abstract
Introduction: The sodium/iodide symporter (NIS) mediates active iodide accumulation in the thyroid follicular cell. Biallelic loss-of-function variants in the NIS-coding SLC5A5 gene cause congenital dyshormonogenic hypothyroidism due to a defect in the accumulation of iodide, which is required for thyroid hormonogenesis.
Objective: We aimed to identify, and if so to functionally characterize, novel pathogenic SLC5A5 gene variants in a patient diagnosed with severe congenital dyshormonogenic hypothyroidism characterized by undetectable radioiodide accumulation in a eutopic thyroid gland, as well as in the salivary glands.
Methods: The coding region of the SLC5A5 gene was sequenced using whole-exome sequencing. In silico analysis and in vitro functional characterization of missense SLC5A5 gene variants were performed.
Results: Proposita's whole-exome sequencing revealed a novel pair of compound heterozygous missense variants in the SLC5A5 gene, c.1,627G>A (p.G543R) and c.1,684T>A (p.L562M). The parents were heterozygous carriers of the variants as determined by Sanger sequencing of the SLC5A5 gene. The p.G543R variant in the homozygous state has previously been associated with congenital hypothyroidism. The novel p.L562M variant was not reported in the Genome Aggregation Consortium dataset. In silico analysis of the pathogenic impact of the p.L562M variant yielded inconclusive results. Functional in vitro studies showed that the p.L562M variant reduces iodide accumulation due to defective expression of the mutant NIS protein at the plasma membrane. Notably, the aliphatic residue Leu at position 562 in the carboxy terminus of the protein, which is highly conserved in NIS orthologues, is required for NIS plasma membrane expression.
Conclusions: We report novel compound heterozygous missense SLC5A5 gene variants causing defective iodide accumulation, thus leading to congenital dyshormonogenic hypothyroidism.
钠/碘同调体(NIS)在甲状腺滤泡细胞中介导活跃的碘积累。nis编码SLC5A5基因的双等位基因功能缺失变异可导致先天性甲状腺功能减退症,这是由于碘的积累缺陷造成的,而碘是甲状腺激素生成所必需的。目的:我们的目的是识别,如果是的话,新的致病SLC5A5基因变异在诊断为严重先天性甲状腺功能减退症的患者,其特征是在异位甲状腺和唾液腺中无法检测到放射性碘积累。方法:采用全外显子组测序法对SLC5A5基因编码区进行测序。对SLC5A5错义基因变异进行了计算机分析和体外功能鉴定。结果:Proposita的全外显子组测序发现了SLC5A5基因c. 1627g > a (p.G543R)和c. 1684t > a (p.L562M)对新的复合杂合错义变异。通过SLC5A5基因的Sanger测序,父母是变异的杂合携带者。纯合子状态的p.G543R变异先前与先天性甲状腺功能减退有关。新的p.L562M变异未在基因组聚集联盟数据集中报道。对p.L562M变异致病性影响的计算机分析结果不确定。体外功能研究表明,p.L562M突变体由于在质膜上突变的NIS蛋白表达缺陷而减少了碘的积累。值得注意的是,位于该蛋白羧基端562位的脂肪残基Leu在NIS同源物中高度保守,是NIS质膜表达所必需的。结论:我们报道了一种新的复合杂合错义SLC5A5基因变异,导致碘积累缺陷,从而导致先天性甲状腺功能减退症。
期刊介绍:
Frontiers in Endocrinology is a field journal of the "Frontiers in" journal series.
In today’s world, endocrinology is becoming increasingly important as it underlies many of the challenges societies face - from obesity and diabetes to reproduction, population control and aging. Endocrinology covers a broad field from basic molecular and cellular communication through to clinical care and some of the most crucial public health issues. The journal, thus, welcomes outstanding contributions in any domain of endocrinology.
Frontiers in Endocrinology publishes articles on the most outstanding discoveries across a wide research spectrum of Endocrinology. The mission of Frontiers in Endocrinology is to bring all relevant Endocrinology areas together on a single platform.