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A Novel Mutation in the TBG Gene Producing Partial Thyroxine-Binding Globulin Deficiency (Glencoe) Identified in 2 Families.

ABSTRACT: BACKGROUND:Thyroxine-binding globulin (TBG) is the major thyroid hormone transport protein in serum. Located on the long arm of the X chromosome, TBG (SERPINA7) gene mutations most commonly produce inherited partial TBG deficiency (TBG-PD). OBJECTIVE:We report a novel TBG variant associated with TBG-PD identified in 2 different families of Ashkenazi origin residing in greater Chicago. METHODS:Family 1: The proband was 12.6 years old when she presented for delayed puberty and was placed on L-T4. Although her serum TSH normalized, her serum T4 remained low. Affected family members had low total T4 and T3, but a normal free T4 index, even when serum TSH concentrations were normal. Family 2: A 71-year-old male presented with a history of a nonfunctioning pituitary adenoma and normal pituitary axes except for low total T4 and T3. His brother had a similar thyroid phenotype. RESULTS:Following direct DNA sequencing, both index patients were found to carry a missense mutation in the TBG gene (c.751T>G) producing p.V215G. The proposita of family 1 was heterozygous and the proband in family 2 was hemizygous for the mutation. Isoelectric focusing showed no alteration in the TBG isoforms and in vitro expression demonstrated a TBG with reduced affinity for T4. CONCLUSIONS:We report a novel mutation in the TBG gene in 2 unrelated families that produces a molecule with reduced affinity for T4 resulting in low serum T4. However, the physical properties of the mutant molecule remained unaltered as determined by isoelectric focusing.

SUBMITTER: Pappa T

PROVIDER: S-EPMC5527229 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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A Novel Mutation in the TBG Gene Producing Partial Thyroxine-Binding Globulin Deficiency (Glencoe) Identified in 2 Families.

Pappa Theodora T Moeller Lars C LC Edidin Deborah V DV Pannain Silvana S Refetoff Samuel S

European thyroid journal 20170202 3

<h4>Background</h4>Thyroxine-binding globulin (TBG) is the major thyroid hormone transport protein in serum. Located on the long arm of the X chromosome, <i>TBG</i> (<i>SERPINA7</i>) gene mutations most commonly produce inherited partial TBG deficiency (TBG-PD).<h4>Objective</h4>We report a novel TBG variant associated with TBG-PD identified in 2 different families of Ashkenazi origin residing in greater Chicago.<h4>Methods</h4>Family 1: The proband was 12.6 years old when she presented for dela ...[more]

PMID: 28785540

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Project description:Thyroxine-binding globulin (TBG), the major carrier of thyroid hormones in human and murine sera, is in the rat a developmentally regulated protein, showing a large surge during post-natal growth followed by virtual disappearance in adults. Here we study as a function of age, from the 19-day embryo to 60 days after birth, the structural and binding characteristics of rat TBG microheterogeneity. Serum obtained throughout development, when pre-incubated with 125I-thyroxine (T4), was shown by isoelectric focusing (IEF; pH range 4-5) to contain six labelled isoforms of TBG, with isoelectric points between 4.25 and 4.55. These isoforms differ in their sialic acid content. The relative labelling densities of the isoforms show age-related changes: in neonates, the bulk of T4 is bound to the most alkaline (least sialylated) TBG isoforms; then, with advancing age, it shifts to the most acidic isoforms. To understand whether this progressive transfer of ligand reflects developmental changes in the relative abundance of isoforms, we submitted sera from rats of different ages to crossed immunoelectrofocusing analysis. We demonstrate that the relative proportions of the TBG isoforms remain fairly constant, independent of the level of total TBG. The most acidic forms always represented the majority (approximately 50%), with the most alkaline ones only representing 15% of total TBG. Experiments based on IEF of charcoal-treated sera, supplemented or not with lipidic serum extracts, further demonstrate that the paradoxical low labelling seen in the neonates for the most abundant highly sialylated isoforms is due to inhibition of their binding abilities by liposoluble components, which are particularly concentrated in the sera at the earlier post-natal ages. These studies represent the first analysis of concentration versus binding functions of rat TBG isoforms in the physiological conditions of normal ontogeny. Our results point to an important influence for the serum environment on the binding properties of TBG isoforms. The physiological significance of such interactions remains to be clarified.

Dataset Information

A Novel Mutation in the TBG Gene Producing Partial Thyroxine-Binding Globulin Deficiency (Glencoe) Identified in 2 Families.

Publications

A Novel Mutation in the TBG Gene Producing Partial Thyroxine-Binding Globulin Deficiency (Glencoe) Identified in 2 Families.

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