title: A new point mutation in the 3,5,3'-triiodothyronine-binding domain of the c-erbA beta thyroid hormone receptor is tightly linked to generalized thyroid hormone resistance.
abstract: Two different mutations in the c-erbA beta thyroid hormone receptor have recently been reported as genetic abnormalities responsible for the syndrome of generalized thyroid hormone resistance (GTHR). We have now found in a third kindred, D, in which GTHR is inherited as a dominant disease, a new point mutation in the T3-binding domain of c-erbA beta. A guanine to cytosine base substitution at nucleotide position 1305, which altered codon-335 from glutamine (CAG) to histidine (CAC), was found in one allele of 10 affected members and was not found in 6 unaffected members. This C-1305 sequence was not present in 106 random alleles, indicating that it was a mutation in c-erbA beta, and it was tightly linked to GTHR in kindred D, with a maximum logarithm of the odds score of 4.19 at a recombination fraction of 0. The tight linkage result confirms that GTHR maps to the c-erbA beta locus in multiple kindreds. In view of the tight linkage between the C-1305 mutation and GTHR, and that this mutation is a nonconservative alteration in a crucial region of the T3-binding domain, it is probably the genetic defect in kindred D responsible for GTHR. The kindred D receptor appears to result in a different phenotype of tissue resistance compared to the previously reported kindred. A receptor with a mutation in the carboxy-terminus of c-erbA beta.
authors.affiliation: Department of Medicine, East Carolina University School of Medicine, Greenville, North Carolina 27858-4354.
authors.forename: S J
authors.initials: SJ
authors.lastname: Usala
authors.forename: J B
authors.initials: JB
authors.lastname: Menke
authors.forename: T L
authors.initials: TL
authors.lastname: Watson
authors.forename: W E
authors.initials: WE
authors.lastname: Bérard
authors.forename: C
authors.initials: C
authors.lastname: Bradley
authors.forename: A E
authors.initials: AE
authors.lastname: Bale
authors.forename: R W
authors.initials: RW
authors.lastname: Lash
authors.forename: B D
authors.initials: BD
authors.lastname: Weintraub
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D003596:Cytosine; D015252:Deoxyribonucleases, Type II Site-Specific; D004351:Drug Resistance / Q000235:genetics; D004700:Endocrine System Diseases / Q000235:genetics*; D005260:Female; D006801:Humans; D008126:Lod Score; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010902:Pituitary Gland / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D011988:Receptors, Thyroid Hormone / Q000235:genetics*; D013577:Syndrome; D013963:Thyroid Hormones / Q000097:blood / Q000494:pharmacology*; D013973:Thyrotropin-Releasing Hormone; D014284:Triiodothyronine / Q000378:metabolism*
chemical_list: D011518:Proto-Oncogene Proteins; D011988:Receptors, Thyroid Hormone; D013963:Thyroid Hormones; D014284:Triiodothyronine; D013973:Thyrotropin-Releasing Hormone; D003596:Cytosine; C025630:CAGCTG-specific type II deoxyribonucleases; D015252:Deoxyribonucleases, Type II Site-Specific