Theodora Pappa1, Lars C Moeller2, Deborah V Edidin3, Silvana Pannain1, Samuel Refetoff1,4,5. 1. Department of Medicine, The University of Chicago, Chicago, IL, USA. 2. Department of Department of Endocrinology and Division of Laboratory Research, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. 3. Department of Pediatrics, Feinberg School of Medicine Northwestern University, Chicago, IL, USA. 4. Department of Pediatrics, The University of Chicago, Chicago, IL, USA. 5. Department of Committee on Genetics, The University of Chicago, Chicago, IL, USA.
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.
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.
Authors: Y Hayashi; Y Mori; O E Janssen; T Sunthornthepvarakul; R E Weiss; K Takeda; M Weinberg; H Seo; G I Bell; S Refetoff Journal: Mol Endocrinol Date: 1993-08
Authors: Theodora Pappa; Alfonso Massimiliano Ferrara; Samuel Refetoff Journal: Best Pract Res Clin Endocrinol Metab Date: 2015-09-30 Impact factor: 4.690