Gene amplification as a common cause of inherited thyroxine-binding globulin excess: Analysis of one familial and two sporadic cases

T-4-binding globulin (TBG) is the major thyroid hormone transport protein i n humans. Inherited abnormalities in the level of serum TBG have been class ified as partial deficiency, complete deficiency and excess. A single nucle otide deletion or substitution in the TBG gene, located on Xq22, has been d etected in partial and complete deficiencies. As for inherited TBG excess, the gene amplification has been recognized in two Japanese families recentl y. In this study, an additional three Japanese families, one familial (F-I) and two sporadic TBG excess (F-II, F-III), were analyzed. Serum TBG levels in hemizygous males were 73, 47 and 42 mu g/ml, three- to two-fold the nor mal value. The molecule had normal properties in terms of heat stability an d isoelectric focussing pattern. The gene dosage of TBG was evaluated by co amplification with autosomal beta Globin or X-chromosomal Duchenne Muscular Dystrophy (DMD) and subsequent quantitation by HPLC. The TBG/beta Globin r atios of the affected male and female of F-I were 3.09- and 3.86-times, res pectively, compared to that of the normal males. The TBG/DMD ratios were 2. 93- and 2.09-times, respectively. These results are compatible with three c opies of the TBG gene on the affected X-chromosome. Similarly, a twofold in crease in gene dosage was demonstrated in the affected males of sporadic ca ses. Their mothers with normal TBG values had the same TBG gene dosage as n ormal females, suggesting that de novo gene duplication arose in gametes pr obably during meiosis. Amplification of the TBG gene was not recognized in these three families by in situ hybridization of prometaphase chromosomes. Though the mechanism remains unproved, gene amplification of TBG was consid ered to be a common cause for inherited TBG excess.