Resistance to thyrotropin (TSH) in three families is not associated with mutations in the TSH receptor or TSH

Abstract

Resistance to TSH (RTSH) is a recently described syndrome of reduced sensitivity 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 belonging to 8 families have been reported, and all were shown to harbor mutations in the TSH receptor (TSHR) gene. We now report the occurrence of RTSH in 3 unrelated families. Contrary to previous reports, the inheritance of RTSH in 2 of the families was dominant rather than recessive and was not associated with abnormalities in the TSHR gene. Abnormalities in the TSHR gene were excluded by sequencing all coding sequences, exon/intron junctions, and the promoter region of the gene. Furthermore, the involvement of the TSHR in the manifestation of the RTSH phenotype was excluded in 2 families by linkage analysis using intragenic polymorphic markers. We excluded defects in the TSH beta-subunit by sequencing its gene and by showing that the circulating TSH in affected subjects from all families had normal bioactivity. Also, no abnormalities were found in the Gs alpha gene of one family analyzed by GC-clamped denaturing gradient gel electrophoresis. This study shows that RTSH may be a manifestation of several different genetic defects that requires the exploration of other candidate genes involved in the TSH-TSHR-Gs alpha cascade and genes participating in its regulation.