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Five New Families with Resistance to Thyroid Hormone not Caused by Mutations in the Thyroid Hormone Receptor ß Gene¹

Departments of Medicine (J.P., R.E.W., P.E.M., S.P., S.R.) and Pediatrics (J.P., S.R.) and the J. P. Kennedy, Jr., Mental Retardation Research Center (S.R.), University of Chicago, Chicago, Illinois 60637-1470; the Department of Medicine, Princess Margaret Hospital (I.T.L.), Hong Kong, China; and the Department of Internal Medicine, University of Missouri (H.H.), Columbia, Missouri 65212

Address all correspondence and requests for reprints to: Dr. Samuel Refetoff, University of Chicago, 5841 South Maryland Avenue, Chicago, Illinois 60637. E-mail: refetoff{at}medicine.uchicago.bsd.edu

Resistance to thyroid hormone (RTH) is a syndrome of variable tissue hyposensitivity to TH. In 191 families, the RTH phenotype has been linked to mutations located in the ligand-binding or hinge domains of the TH receptor (TR) ß gene. The defective TRß 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 TRß gene that encompasses exons 7–10. Isolation of a TRß PAC (P1 derived artificial chromosome) clone provided the intronic sequences necessary to amplify and sequence the entire TRß gene from genomic DNA. Not a single nucleotide substitution, deletion, or insertion was found in all coding and noncoding TRß1- and TRß2-specific and common exons of the five families with RTH reported herein. Furthermore, linkage analysis using polymorphic markers excluded involvement of the TRß and TR genes in two and three of the five families, respectively.

The phenotype of RTH in patients without TRß gene defects was not different from that in patients with RTH due to TRß gene mutations in terms of clinical presentation and reduced responsiveness of the pituitary and peripheral tissues to TH. However, the degree of thyrotroph hyposensitivity to TH appeared to be among the more severe, similar to that of patients with mutant TRßs that have more than 50-fold reduction of T₃ binding affinity and strong dominant negative effect. In these five families and another with non-TR/non-TRß RTH, previously identified in our laboratory, evidence for dominant inheritance was secured in two families, and the appearance of a new defect or recessive inheritance was found in the remaining four families.

RTH without a structural TRß defect occurs in about 10% of families expressing the classic phenotype of TH hyposensitivity, and TRß and TR gene involvement has been excluded in 5%. We postulate that a cofactor that interacts with TR is potentially responsible for the manifestation of RTH in these families. As affected subjects are not infertile, the high prevalence of putative neomutations and the low rate of transmission in this non-TR form of RTH may be due to reduced survival of embryos harboring the defect.

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