Growth and Development group, Vall d'Hebron Research Institute (VHIR), Hospital Universitari Vall d'Hebron, Barcelona, Spain.
CIBERER, ISCIII, Madrid, Spain.
J Clin Endocrinol Metab. 2021 Jan 1;106(1):e152-e170. doi: 10.1210/clinem/dgaa711.
Thyroid dyshormonogenesis is a heterogeneous group of hereditary diseases produced by a total/partial blockage of the biochemical processes of thyroid-hormone synthesis and secretion. Paired box 8 (PAX8) is essential for thyroid morphogenesis and thyroid hormone synthesis. We aimed to identify PAX8 variants in patients with thyroid dyshormonogenesis and to analyze them with in vitro functional studies.
Nine pediatric patients with a eutopic thyroid gland were analyzed by the Catalan screening program for congenital hypothyroidism. Scintigraphies showed absent, low, or normal uptake. Only one patient had a hypoplastic gland. On reevaluation, perchlorate discharge test was negative or compatible with partial iodine-organization deficit. After evaluation, 8 patients showed permanent mild or severe hypothyroidism. Massive-sequencing techniques were used to detect variants in congenital hypothyroidism-related genes. In vitro functional studies were based on transactivating activity of mutant PAX8 on a TG-gene promoter and analyzed by a dual-luciferase assays.
We identified 7 heterozygous PAX8 exonic variants and 1 homozygous PAX8 splicing variant in 9 patients with variable phenotypes of thyroid dyshormonogenesis. Five were novel and 5 variants showed a statistically significant impaired transcriptional activity of TG promoter: 51% to 78% vs the wild type.
Nine patients presented with PAX8 candidate variants. All presented with a eutopic thyroid gland and 7 had deleterious variants. The phenotype of affected patients varies considerably, even within the same family; but, all except the homozygous patient presented with a normal eutopic thyroid gland and thyroid dyshormonogenesis. PAX8 functional studies have shown that 6 PAX8 variants are deleterious. Our studies have proven effective in evaluating these variants.
甲状腺激素生物合成和分泌的生化过程完全/部分受阻会导致甲状腺激素生成障碍，这是一组异质性遗传性疾病。配对盒基因 8（PAX8）是甲状腺形态发生和甲状腺激素合成所必需的。本研究旨在鉴定甲状腺激素生成障碍患者的 PAX8 变异体，并通过体外功能研究进行分析。
通过加泰罗尼亚先天性甲状腺功能减退症筛查计划对 9 名存在外位甲状腺的儿科患者进行分析。闪烁显像显示摄取缺失、摄取减少或摄取正常。仅有 1 名患者存在腺体发育不良。重新评估时，过氯酸盐释放试验阴性或提示碘有机化缺陷部分缺失。评估后，8 名患者表现为永久性轻度或重度甲状腺功能减退。采用大规模测序技术检测与先天性甲状腺功能减退相关的基因中的变异体。体外功能研究基于突变 PAX8 对 TG 基因启动子的转录激活活性，并通过双荧光素酶测定进行分析。
我们在 9 名甲状腺激素生成障碍患者中发现了 7 个异质的 PAX8 外显子变异体和 1 个 PAX8 剪接变异体，这些患者具有不同的甲状腺激素生成障碍表型。其中 5 个为新发现的变异体，5 个变异体显示 TG 启动子的转录活性受到显著抑制：与野生型相比为 51%至 78%。
9 名患者携带 PAX8 候选变异体。所有患者均存在外位甲状腺，7 名患者存在有害变异体。受影响患者的表型差异很大，即使在同一家庭中也是如此；但除了纯合子患者外，所有患者均表现为正常的外位甲状腺和甲状腺激素生成障碍。PAX8 功能研究表明，6 个 PAX8 变异体是有害的。我们的研究在评估这些变异体方面是有效的。
