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Deoxyribonucleic Acid Analyses of Five Families with Familial Inherited Thyroid Stimulating Hormone Deficiency^*

YOSHIHIDE HAYASHIZAK, YOSHIKI HIRAOKA, KEITA TATSUMI, TOMOKO HASHIMOTO, JUN-ICHI FURUYAMA, KIYOSHI MIYAI, KAORU NISHIJO, MIKIO MATSUURA, HITOSHI KOHNO, A. LABBE and KENICHI MATSUBARA

Institute for Molecular and Cellular Biology, Osaka University (Y.Ha., Y.Hi., K.T., K.M.) Yamada-oka 1–3, Suita, Osaka 565;
the Department of Genetics, Hyogo College of Medicine (T.H., J.F.) Mukogawa-cho 1–1, Nishinomiya, Hyogo 663;
the Department of Laboratory Medicine, Osaka University Medical School (K. T.,K.M.) Fukusjima-ku, Osaka 535;
Kagawa Children's Hospital (K.N.) 2603 Zentsuji-cho, Zentsuji, Kagawa 765;
the Department of Pediatrics, Nihon University School of Medicine (M.M.) 1-8-13 Kanda, Surugadai, Chiyoda-ku, Tokyo 101;
Fukuoka City Children's Hospital Medical Center (H.K.) 2-5-1 Tojin-machi, Chuo-ku, Fukuoka 810, Japan;
the Department of Pediatrics, Hotel-Dieu (A.L.) Clermont Ferrand 63000, France

Address all correspondence and requests for reprints to: Y. Hayashizaki, Department of Bioscience, National Cardiovascular Center Research Institute, 7-1 Fujishiro-dai 5-chome, Suita, Osaka 565, Japan.

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 -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.

^* This work was supported by grant from the Ministry of Education, Science, and Culture of Japan (to K.M. and Y.H.) and grants from the Japan Intractable Disease Research Foundation (to Y.H.).

Special Postdoctoral Fellow of the Japan Society for the Promotion of Science.

Received December 8, 1989.

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