Tight linkage of the human c-erbAβ gene with the syndrome of generalized thyroid hormone resistance is present in multiple kindreds

Generalized thyroid hormone resistance recently was reported to map in a single kindred to the same chromosomal region as the c-erbAβ gene, which codes for a putative thyroid hormone receptor. Restriction fragment length polymorphisms (RFLPs) of c-erbAβ were linked with GTHR in three kindreds with variable neuropsychologic dysfunction; two unrelated kindreds have been reported to possess different single base mutations in the T binding domain of c-erbAβ. In order to ascertain if tight linkage with c-erbAβ could be generalized to other families with this syndrome, we performed RFLP analysis in a separate laboratory on an unrelated family with GTHR which lacks the neuropsychologic defects or short stature often associated with GTHR (Kindred WR). RFLPs were identified after Bam HI and Eco RV digestion of DNA from leukocytes from 14 family members. The Bam HI RFLPs were 2.8 and 5.3 kb bands, and the Eco RV RFLPs were 1.6 and 3.3 kb bands. These RFLPs cosegregated with the GTHR phenotype and 11 family members were informative when both RFLPs were employed. The logarithm of the odds ratio between GTHR and c-erbAβ was 3.67, and therefore GTHR mapped to the c-erbAβ locus in this kindred. Allelic-specific hybridization with a probe constructed to identify the C to A mutation at nucleotide position 1643 (previously identified in one other kindred) suggested that our family has a different c-erbAβ abnormality. Although GTHR appears to be commonly associated with alterations in the human c-erbAβ gene, different kindreds may inherit different genetic defects.