Reutrakul S, Sadow P M, Pannain S, Pohlenz J, Carvalho G A, Macchia P E, Weiss R E, Refetoff S
Department of Medicine, University of Chicago, Illinois 60637-1470, USA.
J Clin Endocrinol Metab. 2000 Oct;85(10):3609-17. doi: 10.1210/jcem.85.10.6873.
The syndrome of resistance to thyroid hormone (RTH) is characterized by decreased tissue responsiveness to thyroid hormones. Inheritance is usually autosomal dominant due to mutations in the ligand-binding domain or adjacent hinge region of the thyroid hormone receptor beta (TRbeta) gene. Six of 65 families with the RTH phenotype studied in our laboratory had normal TRbeta1 and TRbeta2 gene sequences. Their clinical characteristics were not different from those of subjects with TRbeta gene mutations. Four of the 6 families were amenable to linkage analysis, and TRalpha involvement was excluded. Candidate genes were then evaluated for their possible involvement in the RTH phenotype in these 4 families: 2 coactivators [NCoA-1 (SRC-1) and NCoA-3 (AIB-1)], 2 corepressors (NCoR and SMRT), and a coregulator (RXRgamma). DNA was obtained from 8 affected subjects and 41 of 45 living first degree relatives. In 2 of the 4 families, the mode of inheritance could be determined by pedigree analysis and was found to be autosomal dominant. Linkage analyses were performed using polymorphic markers near or within the 5 candidate genes. When analyses were not informative or linkage could not be excluded, direct sequencing of the genes in question was performed. Involvement of NCoA-1 was excluded in all four families assuming autosomal dominant inheritance. Roles for NCoR, SMRT, and NCoA-3 were excluded in three and a role for RXRgamma was excluded in two of the four families. However, if the two families without proven dominant mode of inheritance were compound heterozygous, only the involvement of NCoA-1 could be excluded in both. Roles for NCoR, SMRT, and RXRgamma were excluded in one of these two families. Thus, NCoA-1 and RXRgamma genes were not found to be the cause of RTH in subjects without TR gene mutations even though the absence of NCoA-1 and RXRgamma is the cause of RTH in mice. Involvement of other candidate genes in the mediation of thyroid hormone action as well as intracellular hormone transport needs to be explored in these families with non-TRbeta, TRalpha RTH.
甲状腺激素抵抗综合征（RTH）的特征是组织对甲状腺激素的反应性降低。由于甲状腺激素受体β（TRβ）基因的配体结合域或相邻铰链区发生突变，其遗传方式通常为常染色体显性遗传。在我们实验室研究的65个具有RTH表型的家族中，有6个家族的TRβ1和TRβ2基因序列正常。他们的临床特征与具有TRβ基因突变的受试者无异。这6个家族中有4个适合进行连锁分析，并且排除了TRα的参与。然后对这4个家族中可能与RTH表型有关的候选基因进行评估：2种共激活因子[NCoA-1（SRC-1）和NCoA-3（AIB-1）]、2种共抑制因子（NCoR和SMRT）以及1种辅调节因子（RXRγ）。从8名受影响的受试者和45名在世的一级亲属中的41人获取了DNA。在这4个家族中的2个家族中，遗传方式可通过系谱分析确定，发现为常染色体显性遗传。使用5个候选基因附近或内部的多态性标记进行连锁分析。当分析无信息价值或无法排除连锁关系时，对相关基因进行直接测序。假设为常染色体显性遗传，在所有4个家族中均排除了NCoA-1的参与。在4个家族中的3个家族中排除了NCoR、SMRT和NCoA-3的作用，在4个家族中的2个家族中排除了RXRγ的作用。然而，如果这两个未证实为显性遗传方式的家族是复合杂合子，那么在这两个家族中都只能排除NCoA-1的参与。在这两个家族中的一个家族中排除了NCoR、SMRT和RXRγ的作用。因此，即使在小鼠中NCoA-1和RXRγ的缺失是RTH的病因，但在没有TR基因突变的受试者中，未发现NCoA-1和RXRγ基因是RTH的病因。在这些非TRβ、TRα RTH的家族中，需要探索其他候选基因在甲状腺激素作用介导以及细胞内激素转运中的作用。
