Hyperthyroxinaemia: Abnormal Binding of T4 by an Inherited Albumin Variant

Lalloz, M. R. A.; Byfield, P. G. H.; Himsworth, R. L.

doi:10.1111/j.1365-2265.1983.tb03181.x

Cited by 53 publications

(26 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although this condition had been widely reported in the medical literature (1)(2)(3)(4)(5)(6)(7)(8), the molecular basis of FDH was not known until the identification of a single point mutation in the HSA gene of several FDH individuals resulting in the substitution of histidine for arginine at amino acid position 218 (9). This result was confirmed by another study in which the same mutation was identified in FDH individuals from eight unrelated families (10).…”

supporting

confidence: 75%

Mutations in a Specific Human Serum Albumin Thyroxine Binding Site Define the Structural Basis of Familial Dysalbuminemic Hyperthyroxinemia

Petersen

Jameson

et al. 1996

Journal of Biological Chemistry

View full text Add to dashboard Cite

The familial dysalbuminemic hyperthyroxinemia (FDH) phenotype results from a natural human serum albumin (HSA) mutant with histidine instead of arginine at amino acid position 218. This mutation results in an enhanced affinity for thyroxine. Site-directed mutagenesis and a yeast protein expression system were used to synthesize wild type HSA and FDH HSA as well as several other HSA mutants. Studies on the binding of thyroxine to these HSA species using equilibrium dialysis and quenching of tryptophan 214 fluorescence suggest that the FDH mutation affects a single thyroxine binding site located in the 2A subdomain of HSA. Sitedirected mutagenesis of HSA and thyroxine analogs were used to obtain information about the mechanism of thyroxine binding to both wild type and FDH HSA. These studies suggest that the guanidino group of arginine at amino acid position 218 in wild type HSA is involved in an unfavorable binding interaction with the amino group of thyroxine, whereas histidine at amino acid position 218 in FDH HSA is involved in a favorable binding interaction with thyroxine. Neither arginine at amino acid position 222 nor tryptophan at amino acid position 214 appears to favorably influence the binding of thyroxine to wild type HSA. Familial dysalbuminemic hyperthyroxinemia (FDH),1 an autosomal dominant condition in which the total thyroxine level in serum is elevated while the free thyroxine level is normal, results from the presence of an abnormal human serum albumin (HSA) with an enhanced affinity for thyroxine (1). Although this condition had been widely reported in the medical literature (1-8), the molecular basis of FDH was not known until the identification of a single point mutation in the HSA gene of several FDH individuals resulting in the substitution of histidine for arginine at amino acid position 218 (9). This result was confirmed by another study in which the same mutation was identified in FDH individuals from eight unrelated families (10). Recently, it was shown that recombinantly produced FDH HSA has an enhanced affinity for thyroxine similar to that seen for natural FDH HSA (11), a result that confirmed that all of the information necessary to generate the FDH phenotype is contained in the FDH mutation.The binding of thyroxine to HSA has been extensively studied (12-23), yet the molecular basis of this interaction remains obscure. Early studies used equilibrium dialysis to measure the binding of radiolabeled thyroxine and radiolabeled thyroxine analogs to HSA. Interpretation of these results was complicated by the observation of several binding components, which were difficult to resolve. For example, some of these studies assigned four equal binding sites for thyroxine with dissociation constants (K d ) of 6.6 M (12-14), whereas other studies resolved the binding data into two sites with The aforementioned results indicated that HSA has multiple thyroxine binding sites, whereas the existence of a specific thyroxine binding site in the 2A subdomain of HSA was suggested by other observations. ...

show abstract

supporting

confidence: 75%

Mutations in a Specific Human Serum Albumin Thyroxine Binding Site Define the Structural Basis of Familial Dysalbuminemic Hyperthyroxinemia

Petersen

Jameson

et al. 1996

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Although earlier studies based on electrophoretic, chemical, and immunological properties have associated the TT 4 abnormality to a HSA variant (Lee et al, 1979;Stockigt et al, 1981;Silverberg and Premachandra, 1982;Lalloz et al, 1983;Weiss et al, 1995), the precise defect was identified only in 1994 (Petersen et al, 1994;Sunthornthepvarakul et al, 1994). In particular, the missense mutation Arg218His produces a HSA variant (named FDH-2) with 10-to 15-fold higher affinity for T 4 than the wild-type molecule, and a 5-fold increase in affinity for T 3 (Sunthornthepvarakul et al, 1994;Petersen et al, 1996;Petitpas et al, 2003).…”

Section: Familial Dysalbuminemic Hyperthyroxinemia and Familial Dysalmentioning

confidence: 95%

Human serum albumin: From bench to bedside

Fanali

Masi

Trezza

et al. 2012

Molecular Aspects of Medicine

1,468

1,452

View full text Add to dashboard Cite

“…The total tri-iodothyronine (T 3 ) (tT 3 ) and thyroidstimulating hormone (TSH) concentrations, usually, are normal (1)(2)(3)(4)(5)(6). These discrepancies are due to the presence of an abnormal serum albumin that exhibits enhanced binding of T 4 , and patients with FDH are clinically euthyroid (7)(8)(9)(10). Although FDH has been widely reported in the medical literature and accounts for the most common cause of genetic euthyroid hyperthyroxinemia in western countries, particularly among hispanics of Puerto Rican origin (11)(12)(13), to our knowledge no case has been reported in individuals of Chinese or African origin.…”

Section: Introductionmentioning

confidence: 99%

A point mutation in the albumin gene in a Chinese patient with familial dysalbuminemic hyperthyroxinemia

Tang

Yang²,

Choo³

et al. 1999

European Journal of Endocrinology

View full text Add to dashboard Cite

Familial dysalbuminemic hyperthyroxinemia (FDH) is an autosomal dominant disorder characterized by euthyroid hyperthyroxinemia. However, FDH has not been reported in Chinese or African patients. Here, we report the first case of FDH in a Chinese patient. A 69-year-old Chinese man was found to have increased serum total T 4 concentrations (198-242 nmol/l; normal range 58-148 nmol/l) and free T 4 concentrations (>58 pmol/l; T 4 analog method, normal range 9-28 pmol/l). Serum total T 3 and TSH concentrations were normal. The patient was misdiagnosed as hyperthyroid and was later suspected to have a TSH-producing tumor by the finding of a pituitary microadenoma, which was eventually proven to be a non-functional pituitary 'incidentaloma'. Electrophoretic analysis of the patient's serum proteins demonstrated enhanced albumin binding of [ 125 I]T 4 . Serum free T 4 concentrations were normal (16-19 pmol/l, normal range 9-26 pmol/l) when a two-step method was used. Direct sequencing of the albumin gene showed a guanine to adenosine transition in the second nucleotide of codon 218, resulting in a substitution of histidine (CAC) for the normal arginine (CGC) in one of the two alleles in the patient. The point mutation was further confirmed by HphI digestion of exon 7 of the albumin gene. The patient's son was not affected. Our studies demonstrated that the point mutation of the albumin gene in a Chinese patient with FDH was similar to that found in western white families, but differed from that in a Japanese family in whom a guanine to cytosine transition at the same position was found.

show abstract

Hyperthyroxinaemia: Abnormal Binding of T4 by an Inherited Albumin Variant

Cited by 53 publications

References 28 publications

Mutations in a Specific Human Serum Albumin Thyroxine Binding Site Define the Structural Basis of Familial Dysalbuminemic Hyperthyroxinemia

Mutations in a Specific Human Serum Albumin Thyroxine Binding Site Define the Structural Basis of Familial Dysalbuminemic Hyperthyroxinemia

Human serum albumin: From bench to bedside

A point mutation in the albumin gene in a Chinese patient with familial dysalbuminemic hyperthyroxinemia

Contact Info

Product

Resources

About