New insights into thyroglobulin pathophysiology revealed by the study of a family with congenital goiter.
New insights into thyroglobulin pathophysiology revealed by the study of a family with congenital goiter.
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DOI：
10.1210/jc.2009-2109
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发表时间：
2010-06
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通讯作者：
D. Peteiro-González;Jaemin Lee;J. Rodriguez-Fontan;Isabel Castro-Piedras;J. Cameselle-Teijeiro;Andrés Beiras;Susana B. Bravo;Clara V. Alvarez;D. Hardy;H. Targovnik;Peter Arvan;J. Lado-Abeal
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作者：
D. Peteiro-González;Jaemin Lee;J. Rodriguez-Fontan;Isabel Castro-Piedras;J. Cameselle-Teijeiro;Andrés Beiras;Susana B. Bravo;Clara V. Alvarez;D. Hardy;H. Targovnik;Peter Arvan;J. Lado-Abeal
背景：甲状腺球蛋白（TG）基因突变导致先天性甲状腺功能减退（CH）伴甲状腺肿。对于一些频繁的突变，已经提出了奠基人效应。突变蛋白在细胞内运输中存在缺陷，导致细胞内滞留，伴有类似内质网储存病的超微结构变化。目的通过临床、细胞、分子和遗传学研究，揭示来自西班牙加利西亚缺碘地区因TG突变而出现CH的家族的甲状腺球蛋白病理生理学的新方面。设计包括家庭成员的临床评估，TG基因突变的DNA测序和单倍型分析，受影响受试者甲状腺组织标本的超微结构分析，发现的突变对TG基因转录的影响分析，以及突变蛋白的细胞生产和分泌的体外研究。设置地点包括初级保健和大学医院。结果CH、智力低下和甲状腺肿家族成员c.886C—>t （p.R277X）和g.IVS35+1delG为复合杂合基因。对于c.886C- >T，不能排除奠基者效应，其转录几乎无法检测到。g.IVS35+1delG引起35外显子的框内缺失，产生一种虽然合成但不能分泌的蛋白。超微结构分析显示形态学改变与内质网蓄积病一致。结论新型g.v ivs35 +1delG所产生的较短的甲状腺球蛋白保留在甲状腺细胞内质网内，与p.R227X一起引起严重的甲状腺功能减退并甲状腺肿。p.R277X是最常见的TG突变，由TG外显子7高度突变易发区域引起，不能排除一些病例从加利西亚传入南美洲的可能性。
CONTEXT Thyroglobulin (TG) gene mutations cause congenital hypothyroidism (CH) with goiter. A founder effect has been proposed for some frequent mutations. Mutated proteins have a defect in intracellular transport causing intracellular retention with ultrastructural changes that resemble an endoplasmic reticulum storage disease. OBJECTIVE To reveal new aspects of thyroglobulin pathophysiology through clinical, cellular, molecular, and genetic studies in a family presenting with CH due to TG mutations from Galicia, an iodine-deficient area of Spain. DESIGN The included clinical evaluation of family members, DNA sequencing for TG gene mutation and haplotyping analysis, ultrastructural analysis of thyroid tissue specimens from affected subjects, analysis of effects of mutations found on TG gene transcription, and in vitro studies of cellular production and secretion of mutated proteins. SETTING Locations included primary care and university hospitals. RESULTS Family members with CH, mental retardation, and goiter were compound heterozygous for c.886C-->T (p.R277X) and g.IVS35+1delG. For c.886C-->T, a founder effect cannot be excluded, and its transcription was hardly detectable. g.IVS35+1delG caused an in-frame deletion in exon 35 and produced a protein that, although synthesized, could not be secreted. Ultrastructural analyses showed morphological changes consistent with an endoplasmic reticulum storage disease. CONCLUSION The shorter thyroglobulin resulting from the novel g.IVS35+1delG was retained within the endoplasmic reticulum of thyrocytes, and together with p.R227X caused severe hypothyroidism with goiter. p.R277X, the most commonly described TG mutation, is caused by a TG exon-7 highly mutation-prone region, and the possibility that some cases were introduced to South America from Galicia cannot be excluded.