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Tight linkage between the syndrome of generalized thyroid hormone resistance and the human c-erbA beta gene
S J Usala1, A E Bale, N Gesundheit
1National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892.
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 have 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.
Insights
Generalized thyroid hormone resistance (GTHR) is linked to the c-erbA beta gene. This study suggests c-erbA beta mutations cause GTHR, impacting multiple bodily functions.
Area of Science:
- Molecular Biology
- Endocrinology
- Genetics
Background:
- Multiple c-erbA gene family members encode proteins that bind triiodothyronine (T3) with high affinity.
- The precise biological roles of these diverse thyroid hormone receptors remain incompletely understood.
- Generalized thyroid hormone resistance (GTHR) is a human condition marked by cellular insensitivity to thyroid hormone action, often linked to nuclear receptor defects.
Purpose of the Study:
- To investigate the biological functions of c-erbA alpha and c-erbA beta genes.
- To test the hypothesis that GTHR is caused by an abnormal c-erbA gene product.
- To examine the c-erbA genes in members of a kindred affected with GTHR.
Main Methods:
- Restriction enzyme analysis was used to examine gene structure in affected individuals.
- Genetic linkage analysis was performed to determine the chromosomal location of the GTHR-conferring gene.
- Comparison of gene structure and linkage in affected versus unaffected individuals.
Main Results:
- Restriction enzyme analysis revealed no rearrangements or large deletions in the c-erbA genes of affected individuals.
- The gene responsible for the GTHR phenotype was found to be tightly linked to the c-erbA beta locus on chromosome 3.
- This linkage provides strong evidence for the c-erbA beta gene's role as a thyroid hormone receptor in humans.
Conclusions:
- The c-erbA beta gene is strongly implicated as a critical thyroid hormone receptor in humans.
- A mutant c-erbA beta phenotype is suggested as the cause of GTHR, leading to abnormalities in the central nervous system, pituitary, liver, metabolism, and growth.