A Novel Mutation in the TBG Gene Producing Partial Thyroxine-Binding Globulin Deficiency (Glencoe) Identified in 2 Families. Issue 3 (2nd July 2017)

• Record Type: Journal Article
• Authors: Pappa, Theodora; Moeller, Lars C.; Edidin, Deborah V.; Pannain, Silvana; Refetoff, Samuel
• Is Part Of: European thyroid journal. Volume 6:Issue 3(2017)
• Page Start: 138
• Page End: 142
• Publication Date: 2017-07-02
• Subjects: Mutation -- Thyroxine-binding globulin -- Thyroxine-binding globulin deficiency -- T4-binding affinity; Thyroid gland -- Diseases -- Periodicals; Thyroid Diseases -- Periodicals; 612.44
• DOI: 10.1159/000455097
• Languages: English
• ISSNs: 2235-0640

Abstract

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.