Thyroxine-Binding Globulin Quantitative Trait Locus

A number sign (#) is used with this entry because of evidence that the level of thyroxine-binding globulin in serum is conferred by variation in the SERPINA7 gene (314200) on chromosome Xq22.

Description

Inherited abnormalities in the level of serum TBG have been classified as complete deficiency (TBG-CD), partial deficiency (TBG-PD), and excess (TBG-E). Patients are euthyroid (summary by Mori et al., 1995).

Clinical Features

TBG defects that lead to a deficiency or an excess of TBG do not lead to major metabolic alterations in affected individuals. The diagnosis of TBG-CD is suspected in clinically euthyroid individuals with low total serum thyroid hormone concentrations and normal thyroid-stimulating hormone (TSH) levels. TBG defects are clinically fully expressed in hemizygous males and rarely in Turner syndrome or homozygous females, whereas in heterozygous females TBG deficiency is usually partial. Due to dosage compensation, normally achieved through the random inactivation of one of the two X chromosomes, heterozygous females usually show intermediate TBG levels between affected and unaffected males. However, on occasion, inactivation may be selective for one of the alleles resulting in a phenotype indistinguishable from that in affected males (summary by Mannavola et al., 2006).

Whereas inherited TBG abnormalities are usually manifested fully in hemizygous males and partially in heterozygous females, Okamoto et al. (1996) found a female manifesting complete TBG deficiency. She was heterozygous for a TBG allele associated with complete TBG deficiency and a normal TBG allele. Selective inactivation was found to be the cause of her complete TBG deficiency phenotype by BstXI digestion of amplified products following digestion with a methylation-sensitive enzyme, HpaII.

Inheritance

TBG Deficiency

Nikolai and Seal (1966) studied 2 low TBG families in which X-linkage was possible.

Marshall et al. (1966) described an extensively studied family in which the findings of low TBG were most consistent with X-linkage. Female carriers showed an intermediate level of TBG.

X-linked inheritance was strongly supported by the finding of deficiency of TBG in a patient with the XO Turner syndrome (Refetoff and Selenkow, 1968). The maternal grandfather and a half brother were also TBG-deficient and at least 3 females, including the mother, had intermediate levels.

Avruskin et al. (1972) found associated retarded mental and motor development in 4 males in 3 sibships of a family with low TBG in a pattern consistent with X-linked recessive inheritance. They suggested close linkage of 2 separate mutant loci, but an allele at the TBG locus with the neurologic features as a pleiotropic effect seemed at least equally possible.

Genetic studies by Jenkins and Steffes (1987) indicated X-linked inheritance, with no suggestion of autosomal inheritance.

TBG Excess

Beierwaltes and Robbins (1959) found high TBG in a father and his only daughter. Both of his sons had normal TBG levels. The daughter's level was not as high as the father's. X-linked dominant inheritance was suggested.

Jones and Seal (1967) reported a family with elevated TBG in 9 persons in 3 generations, again in a pattern suggesting X-linkage. They suggested gene duplication as the mechanism of the elevation.

Population Genetics

In Rome, Sorcini et al. (1980) found a frequency of TBG deficiency of 1 in 3,600 (4 in 14,280) newborns. Recognition is important because the infants may be falsely judged hypothyroid and given unnecessary treatment.

In Minnesota, Jenkins and Steffes (1987) identified 99 cases of TBG deficiency (90 males and 9 females) among low-T4 infants after newborn hypothyroid screening. The data indicated that inherited TBG deficiency occurs in at least 1 in 5,000 newborns (1 in 2,800 males) and that mild and more pronounced forms are found in approximately equal proportions.

Mannavola et al. (2006) stated that the incidence of complete TBG deficiency is extremely variable, being higher in Japanese populations (1:1,200-1:1,900 newborns/year) than in Caucasians (1:5,000-1:15,000 newborns/year).

Molecular Genetics

In affected members of 3 of 8 families with complete TBG deficiency, Mori et al. (1990) identified a missense mutation in the TBG gene (L227P; 314200.0001).

In a male from Montreal with partial TBG deficiency, Janssen et al. (1991) identified a missense mutation in the TBG gene (A113P; 314200.0006).

In a Japanese family with TBG excess, Mori et al. (1995) found evidence that the TBG gene was present in duplicate in hemizygous males; in a second family, they presented evidence that the gene was present in triplicate in males with inherited TBG excess. Thus, gene amplification was the apparent basis (314200.0011).

History

It was considered evidence of a possible autosomal dominant form of TBG deficiency that some persons showed an increase in TBG level with administration of estrogen, suggesting that the mutation may concern a regulator gene rather than a structural gene. Evidence for autosomal dominant transmission of TBG deficiency was presented by Nicoloff et al. (1964) and by Kraemer and Wiswell (1968). Nicoloff et al. (1964) observed 6 cases (3 males, 3 females) of low TBG in 3 sibships of 2 generations of a family. No male-to-male transmission was observed. Kraemer and Wiswell (1968) reported 3 brothers with absent TBG; their father, paternal uncle and paternal grandmother had low values, whereas the mother and several other relatives on her side had normal values. In studies of 99 cases of TBG deficiency ascertained through a newborn hypothyroid screening program, Jenkins and Steffes (1987) found no suggestion of autosomal inheritance.