Mixson A J, Parrilla R, Ransom S C, Wiggs E A, McClaskey J H, Hauser P, Weintraub B D
Molecular and Cellular Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
J Clin Endocrinol Metab. 1992 Oct;75(4):1039-45. doi: 10.1210/jcem.75.4.1400869.
Generalized resistance to thyroid hormone is an inherited disease characterized by unresponsiveness of pituitary and peripheral tissues to thyroid hormone. Genetic analysis of several kindreds linked this syndrome to the gene for the beta-form of the thyroid hormone receptor, and this led to the subsequent identification of various mutations in the ligand-binding domain of this receptor. In this region we now have found 4 new point mutations with reduced T3-binding affinities from separate kindreds by direct sequencing of polymerase chain reaction products. Similar to previously studied kindreds, the reduction in T3 binding of these four kindreds ranged from 2.5- to 5-fold, indicating that these are not neutral polymorphisms. Furthermore, the pattern of inheritance of these 4 kindreds is familial in 2, sporadic in 1, and unknown in 1. To date, 20 distinct mutations have been identified, of which 18 are clustered in 2 distinct topographical regions: 11 are within the tau i/dimerization subdomains of exon 9, and 7 are within the L2 subdomain of exon 10. The 4 newly identified mutations coupled to the 9 mutations our laboratory has previously identified provide new insights into the clinical aspects of generalized resistance to thyroid hormone. Kindreds with mutations in exon 9 compared with those in exon 10 have significantly more problems in language development, as manifested by articulation problems and/or wide discrepancies in verbal and performance IQs. Interestingly, marked variability in language deficiency as well as other clinical patterns were seen not only between kindreds but also within a kindred. Further identification and clinical correlations of new mutations will continue to enhance our understanding of the structure/function relationships and physiological role of the human thyroid hormone receptor.
全身性甲状腺激素抵抗是一种遗传性疾病，其特征为垂体和外周组织对甲状腺激素无反应。对多个家族的基因分析将该综合征与甲状腺激素受体β型的基因联系起来，这随后导致在该受体的配体结合域中鉴定出各种突变。在该区域，我们现在通过对聚合酶链反应产物进行直接测序，从不同家族中发现了4个新的点突变，其T3结合亲和力降低。与先前研究的家族相似，这四个家族的T3结合减少幅度为2.5至5倍，表明这些不是中性多态性。此外，这4个家族的遗传模式中，2个为家族性，1个为散发性，1个未知。迄今为止，已鉴定出20种不同的突变，其中18个聚集在2个不同的地形区域：11个在外显子9的tau i/二聚化亚结构域内，7个在外显子10的L2亚结构域内。新鉴定出的4个突变与我们实验室先前鉴定的9个突变相结合，为全身性甲状腺激素抵抗的临床方面提供了新的见解。与外显子10中的突变相比，外显子9中有突变的家族在语言发育方面存在明显更多问题，表现为发音问题和/或语言智商与操作智商的巨大差异。有趣的是，不仅在家族之间，而且在一个家族内部，都观察到语言缺陷以及其他临床模式存在明显差异。新突变的进一步鉴定及其临床相关性将继续增进我们对人类甲状腺激素受体的结构/功能关系和生理作用的理解。
