SEQUENCE-ANALYSIS OF THE THYROTROPIN (TSH) RECEPTOR GENE IN CONGENITAL PRIMARY HYPOTHYROIDISM ASSOCIATED WITH TSH UNRESPONSIVENESS

Congenital primary hypothyroidism due to thyrotropin (TSH) unresponsiv eness is a very rare disorder and only a few cases have been documente d previously. To elucidate whether structural abnormalities in the TSH receptor (TSHR) could be a primary underlying mechanism of this disor der, we analyzed nucleotide sequence of the entire coding region of th e TSHR gene in three patients diagnosed with congenital primary hypoth yroidism associated with TSH unresponsiveness. Diagnosis of TSH unresp onsiveness was largely made based on the following criteria: (a) conge nital primary hypothyroidism with autosomal recessive inheritance, (b) a nongoitrous thyroid gland in a normal position with low thyroidal r adioactive iodine uptake, (c) normal in vitro TSH bioactivity or absen t in vivo response to exogenous TSH, and (d) absence of thyroid autoan tibodies. The TSHR cDNA was successfully obtained from RNA of peripher al mononuclear leukocytes with reverse transcription and polymerase ch ain reaction, and was sequenced directly. Comparison of these nucleoti de sequences with the normal TSHR sequence revealed no difference in t he predicted amino acid sequence with a heterozygous polymorphism in c odon 601 in one patient, indicating absence of TSHR structural abnorma lities in these patients. Our results indicate that congenital primary hypothyroidism associated with TSH unresponsiveness is unlikely to be due to mutations in the TSHR-structure gene.