Five new families with resistance to thyroid hormone not caused by mutations in the thyroid hormone receptor beta gene

Resistance to thyroid hormone (RTH) is a syndrome of variable tissue hypose nsitivity to TH. In 191 families, the RTH phenotype has been linked to muta tions located in the ligand-binding or hinge domains of the TK receptor (TR ) beta gene. The defective TR beta molecules interfere with the function of the normal TRs to produce dominantly inherited RTH. Of the 65 families with RTH studied in our laboratory, 59 had mutations in the mutagenic region of the TR beta gene that encompasses exons 7-10. Isola tion of a TR beta PAC (P1 derived artificial chromosome) clone provided the intronic sequences necessary to amplify and sequence the entire TR beta ge ne from genomic DNA. Not a single nucleotide substitution, deletion, or ins ertion was found in all coding and noncoding TR beta 1- and TR beta 2-speci fic and common exons of the five families with RTH reported herein. Further more, linkage analysis using polymorphic markers excluded involvement of th e TR beta and TR alpha genes in two and three of the five families, respect ively. The phenotype of RTH in patients without TR beta gene defects was not diffe rent from that in patients with RTH due to TR beta gene mutations in terms of clinical presentation and reduced responsiveness of the pituitary and pe ripheral tissues to TH. However, the degree of thyrotroph hyposensitivity t o TH appeared to be among the more severe, similar to that of patients with mutant TR beta s that have more than 50-fold reduction of T-3 binding affi nity and strong dominant negative effect. In these five families and anothe r with non-TR alpha/non-TR beta RTH, previously identified in our laborator y, evidence for dominant inheritance was secured in two families, and the a ppearance of a new defect or recessive inheritance was found in the remaini ng four families. RTH without a structural TR beta defect occurs in about 10% of families exp ressing the classic phenotype of TH hyposensitivity, and TR beta and TR alp ha gene involvement has been excluded in 5%. We postulate that a cofactor t hat interacts with TR is potentially responsible for the manifestation of R TH in these families. As affected subjects are not infertile, the high prev alence of putative neomutations and the low rate of transmission in this no n-TR form of RTH may be due to reduced survival of embryos harboring the de fect.