Five families with familial inherited TSH deficiency, reported to date, were examined for the TSHβ gene at the nucleotide level. The first family carries a single base substitution in the 29th codon which lies in the so-called CAGYC region; GGA (glycine) is replaced by AGA (arginine). This substitution induces conformational changes of the β-polypeptide which make it unable to associate with the α-subunit. This mutation generates a new cleavage site for a restriction endonuclease Mael, a new marker that can be used for DNA diagnosis. The second and third families were found to carry the same nucleotide substitution. Also, all three families were associated with an additional single base substitution in intron 2 as a polymorphic change, suggesting that these three families may have originated from the same single founder from Shikoku Island in Japan. The nucleotide sequence from the fourth and fifth families showed no alterations in the TSHβ gene from the about –200 basepair up-stream region to the polyadenylation site.
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