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

Abstract

Five families with familial inherited TSH deficiency, reported to date, were examined for the TSH beta 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; GCA (glycine) is replaced by AGA (arginine). This substitution induces conformational changes of the beta-polypeptide which make it unable to associate with the alpha-subunit. This mutation generates a new cleavage site for a restriction endonuclease MaeI, 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 TSH beta gene from the about -200 basepair up-stream region to the polyadenylation site.

Congenital Thyrotropin Deficiency-From Discovery to Molecular Biology, Postgenome and Preventive Medicine-

“…The missense mutation was found to be homozygous in two patients in siblings and heterozygous in their parents whose marriage was consanguineous indicating that the mutation was responsible for the disease, and that the inheritance was recessive. The same mutation was demonstrated in 6 affected members in 5 Japanese families so far examined [6,7,21,22]. Although mutual blood relationships among the families were not clear from the family history, all families originated from a small area in the western part of Shikoku Island in Japan and an identical polymorphism in intron 2 was associated with the mutation in 3 patients in different families.…”

“…Later on we analyzed the TSH β-subunit gene in the first case of congenital isolated TSH deficiency and found a single base substitution from guanine (G) to adenine (A) at position 85 which altered GGA encoding glycine (Gly) (G) to AGA encoding arginine (Arg) (R) at the 29th codon ([G29R]) [6,7,21]. The missense mutation was found to be homozygous in two patients in siblings and heterozygous in their parents whose marriage was consanguineous indicating that the mutation was responsible for the disease, and that the inheritance was recessive.…”

“…About two decades later, introduction of molecular biology techniques paved the way for the gene analyses of the patient. We performed molecular cloning of hTSH β subunit gene [4,5] and demonstrated that a single base substitution in the CAGYC region of the TSH β-subunit was responsible for this disorder [6,7]. Based on our subsequent studies on wild and mutant types of glycoprotein hormones with site directed mutagenesis of the CAGYC region in the β-subunits and CMGCC region in the α-subunit [6,[8][9][10], we hypothesized that the CXGXC motif plays an important role in the biosynthesis of glycoprotein hormones [11].…”

The Etiology of Isolated Thyroid Stimulating Hormone Deficiency

“…Since then at least 10 families, with 17 affected patients, have been reported in Japan, France, Greece and Brazil (3)(4)(5)(6). Mutation in the TSH-p subunit gene, G to Ain the 29th codon in exon 2 (missence mutation) has been reported in Japanese families (3,4).…”

“…Since then at least 10 families, with 17 affected patients, have been reported in Japan, France, Greece and Brazil (3)(4)(5)(6). Mutation in the TSH-p subunit gene, G to Ain the 29th codon in exon 2 (missence mutation) has been reported in Japanese families (3,4). G to T transversion at nucleotide 94 in exon 2 (nonsence mutation) was found families in Greece (5) and nucleotide deletion in codon 105 resulting in a truncated TSHpeptide of only 1 13 amino acids (frameshift mutation) was found families in Brazil (6).…”