RESISTANCE TO THYROTROPIN (TSH) IN 3 FAMILIES IS NOT ASSOCIATED WITH MUTATIONS IN THE TSH RECEPTOR OR TSH

Resistance to TSH (RTSH) is a recently described syndrome of reduced s ensitivity to TSH that manifests as euthyroid hyperthyrotropinemia. It is usually identified at birth during routine neonatal screening for congenital hypothyroidism. In less than 2 yr, 13 subjects with RTSH be longing to 8 families have been reported, and all were shown to harbor mutations in the TSH receptor (TSHR) gene. We now report the occurren ce of RTSH in 3 unrelated families. Contrary to previous reports, the inheritance of RTSH in 2 of the families was dominant rather than rece ssive and was not associated with abnormalities in the TSHR gene. Abno rmalities in the TSHR gene were excluded by sequencing all coding sequ ences, exon/intron junctions, and the promoter region of the gene. Fur thermore, the involvement of the TSHR in the manifestation of the RTSH phenotype was excluded in 2 families by linkage analysis using intrag enic polymorphic markers. We excluded defects in the TSH beta-subunit by sequencing its gene and by showing that the circulating TSH in affe cted subjects from all families had normal bioactivity. Also, no abnor malities were found in the G(s) alpha gene of one family analyzed by G C-clamped denaturing gradient gel electrophoresis. This study shows th at RTSH may be a manifestation of several different genetic defects th at requires the exploration of other candidate genes involved in the T SH-TSHR-G(s) alpha cascade and genes participating in its regulation.