Tight Linkage between the Syndrome of Generalized Thyroid Hormone Resistance and the Human c-erbAβ Gene

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Abstract
Multiple cDNAs belonging to the c-erbA gene family encode proteins that bind T3 with high affinity. However, the biological functions of these multiple thyroid hormone receptors have not yet been clarified. Generalized thyroid hormone resistance (GTHR) refers to a human syndrome characterized by tissue refractoriness to the action of thyroid hormones; several studies suggested quantitative or qualitative defects in T3 binding to nuclear receptors in certain kindreds. To investigate the biological functions of the c-erbA genes, c-erbA.alpha. and c-erbA.beta., we tested the hypothesis that an abnormal c-erbA gene product is present in GTHR by examining these genes in members of one kindred. Restriction enzyme analysis failed to identify an abnormal pattern in affected individuals suggesting no rearrangements or large deletions. However, we demonstrated that the gene conferring the GTHR phenotype is tightly linked to the c-erbA.beta. locus on chromosome 3. This linkage strongly suggests that the c-erbA.beta. gene is important in man as a thyroid hormone receptor and identifies a putative c-erbA.beta. mutant phenotype with central nervous system, pituitary, liver, metabolic, and growth abnormalities.