Search for abnormalities of nuclear corepressors, coactivators, and a coregulator in families with resistance to thyroid hormone without mutations inthyroid hormone receptor beta or alpha genes

The syndrome of resistance to thyroid hormone (RTH) is characterized by dec reased tissue responsiveness to thyroid hormones. Inheritance is usually au tosomal dominant due to mutations in the ligand-binding domain or adjacent hinge region of the thyroid hormone receptor beta (TR beta) gene. Six of 65 families with the RTH phenotype studied in our laboratory had normal TR be ta 1 and TR beta 2 gene sequences. Their clinical characteristics were not different from those of subjects with TRP gene mutations. Four of the 6 fam ilies were amenable to Linkage analysis, and TR alpha involvement was exclu ded. Candidate genes were then evaluated for their possible involvement in the RTH phenotype in these 4 families: 2 coactivators [NCoA-1 (SRC-1) and N CoA-3 (AIB-1)], 2 corepressors (NCoR and SMRT), and a coregulator (RXR gamm a). DNA was obtained from 8 affected subjects and 41 of 45 living first deg ree relatives. In 2 of the 4 families, the mode of inheritance could be det ermined by pedigree analysis and was found to be autosomal dominant. Linkag e analyses were performed using polymorphic markers near or within the 5 ca ndidate genes. When analyses were not informative or linkage could not be e xcluded, 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 thr ee and a role for RXR gamma was excluded in two of the four families. Howev er, if the two families without proven dominant mode of inheritance were co mpound heterozygous, only the involvement of NCoA-1 could be excluded in bo th. Roles for NCoR, SMRT, and RXR gamma were excluded in one of these two f amilies. Thus, NCoA-1 and RXR gamma genes were not found to be the cause of RTH in subjects without TR gene mutations even though the absence of NCoA- 1 and RXR gamma 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-TR beta, TR alpha RTH.