The Experts below are selected from a list of 186 Experts worldwide ranked by ideXlab platform
Samuel Refetoff - One of the best experts on this subject based on the ideXlab platform.
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free thyroxine concentrations in sera of individuals with Familial Dysalbuminemic Hyperthyroxinemia a comparison of three methods of measurement
Thyroid, 2020Co-Authors: Samuel Refetoff, Neal H Scherberg, Chao Yuan, Michael J McphaulAbstract:Background: Euthyroid individuals with Familial Dysalbuminemic Hyperthyroxinemia (FDH) have often falsely elevated serum free thyroxine (fT4) concentrations determined by different automated immunoassays. Methods: We measured serum fT4 using direct dialysis coupled with tandem mass spectrometry (fT4 DDMS) in individuals with the common albumin gene mutation (ALB R218H) from 14 FDH families and compared them with results obtained by direct immunometric assay (fT4 DIMM) and free thyroxine index (fT4I). Results: While all 14 individuals with FDH had elevated total serum T4, the fT4 measured by DIMM was elevated in 12, by fT4I in 5, and by DDMS in 1. Conclusion: The latter method greatly reduced the discordance of fT4 results relative to thyrotropin in FDH.
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Familial Dysalbuminemic Hyperthyroxinemia in a 4 year old girl with hyperactivity palpitations and advanced dental age how gold standard assays may be misleading
Journal of Pediatric Endocrinology and Metabolism, 2015Co-Authors: Abha Choudhary, Samuel Refetoff, Chutintorn Sriphrapradang, Zoltan AntalAbstract:Here we report the case of a young girl who had vague signs and symptoms potentially attributable to hyperthyroidism and was found to have autoimmune thyroiditis and Hyperthyroxinemia. The elevated serum free thyroxine levels were persistent when measured by both standard assays and equilibrium dialysis/high-pressure liquid chromatography-tandem mass spectrometry. The clinical symptoms, with discordant thyroid test results, created a diagnostic dilemma that led initially to unnecessary additional evaluations. She was ultimately found to have Familial Dysalbuminemic Hyperthyroxinemia (FDH) and required no therapy. This case highlights the inherent difficulties in evaluating children, who typically have vague signs and symptoms of thyroid dysfunction, when, in addition, they have an unrelated acquired (autoimmune) as well as a genetic (FDH) defect. The benefit of including testing for immediate members of the family is emphasized.
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a novel mutation in the albumin gene r218s causing Familial Dysalbuminemic Hyperthyroxinemia in a family of bangladeshi extraction
Thyroid, 2014Co-Authors: Solomon Maximo Greenberg, Roy E Weiss, Alfonso Massimiliano Ferrara, Everton S Nicholas, Alexandra M Dumitrescu, Vivian Cody, Samuel RefetoffAbstract:Background: Familial Dysalbuminemic Hyperthyroxinemia (FDH) is a common cause of euthyroid Hyperthyroxinemia. Clinical recognition of FDH is crucial for preventing unnecessary therapy in clinically euthyroid patients with abnormal thyroid function tests. Our goal was to identify the cause of abnormal serum tests of thyroid function in a Canadian family of Bangladeshi extraction. Patients: The proposita was found to have elevated free thyroxine (fT4) and free triiodothyronine (fT3) with nonsuppressed thyrotropin (TSH) on screening blood work. After detailed studies excluding hyperthyroidism and resistance to thyroid hormone, blood was obtained from all members of her immediate family for further investigation. Methods: We conducted laboratory analyses and sequencing of candidate genes. Results: Two members of this family have FDH, caused by a not previously identified mutation in the albumin gene. This mutation, located in exon 7 of the gene (652A>C), produces a single amino acid substitution in the protein molecule (R218S). The mutant albumin is associated with a ninefold increase in serum total T4 and a twofold increase in serum total reverse T3 compared to patients with normal albumin. Modeling data for the R218S variant are compatible with the increased binding affinity of this variant albumin for T4. Conclusions: The R218S substitution reported here causes FDH that, in terms of the magnitude of serum iodothyronine elevation, is intermediate to the two previously reported mutations at codon 218 FDH: R218H being more mild and R218P more severe.
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Circulating Antibodies to T4 Causing Discordant Tests of Thyroid Function: A Case Report
Galenos Yayinevi, 2014Co-Authors: Gülşah Elbüken, Samuel Refetoff, Züleyha Karaca, Fatih Tanrıverdi, Kürşad Unluhizarci, Fahrettin KeleştimurAbstract:The presence of elevated free thyroxine (fT4) hormone level with non-suppressed thyroid-stimulating hormone (TSH) level is called as “inappropriate secretion of TSH’’. TSH-secreting adenoma, resistance to thyroid hormone (RTH), iodothyronine deiodinase defect or false elevation of measured free serum T4 as in Familial Dysalbuminemic Hyperthyroxinemia (FDH) and the presence of autoantibodies to T4 may be the cause of this entity. We report a case that presented with high serum fT4 and TSH levels associated with autoantibodies to T4. Turk Jem 2014; 1: 19-22\u
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congenital hypothyroidism in a child with unsuspected Familial Dysalbuminemic Hyperthyroxinemia caused by a mutation r218h in the human albumin gene
The Journal of Pediatrics, 2001Co-Authors: Joachim Pohlenz, Roy E Weiss, Peter M Sadow, Thomas Koffler, Winfried Schonberger, Samuel RefetoffAbstract:We found Familial Dysalbuminemic Hyperthyroxinemia (FDH) in a 5-month-old boy with congenital hypothyroidism (CH) who had a blood thyrotropin (TSH) level of 479 mU/L but normal total serum thyroxine (T4) and higher than normal total triiodothyronine (T3) levels. Thyroid hormone substitution began at 5 weeks of age when T4 and T3 concentrations were below normal. Until the age of 5 months, treatment with levothyroxine was suboptimal on the basis of high serum TSH levels despite above-normal T4 levels. FDH was confirmed by isoelectric focusing and testing of other family members. DNA analysis of the patient revealed R218H, a mutation in the serum albumin gene associated with FDH, which was also present in the patient's euthyroid father and brother. Thyroid scans, serum thyroglobulin measurements, and free T4 measurements using equilibrium dialysis or 2-step immunoassay methods can identify thyroid hormone-binding protein defects and simplify the diagnosis and treatment of infants with CH.
Nadhipuram V. Bhagavan - One of the best experts on this subject based on the ideXlab platform.
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Structural Investigations of a New Familial
2014Co-Authors: Dysalbuminemic Hyperthyroxinemia Genotype, Jimmy B Feix, Osamu Isozaki, Nadhipuram V. BhagavanAbstract:Background: In a previous study, we found that the amino acid substitution R218H in human serum albu-min (HSA) was the cause of Familial Dysalbuminemic Hyperthyroxinemia (FDH) in several Caucasian patients. Subsequently the substitution R218P was shown to be the cause of FDH in several members of a Japanese family. This study attempts to resolve discrepancies in the only other study of R218P HSA and identifies two new Japanese R218P FDH patients unrelated to those described previously. Methods and Results: Recombinant R218H, R218P, and wild-type HSA were synthesized in yeast, and the affinities of these HSA species for L- and D-thyroxine were determined using fluorescence spectroscopy. The dissociation constants for the binding of wild-type
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structural basis of albumin thyroxine interactions and Familial Dysalbuminemic Hyperthyroxinemia
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Isabelle Petitpas, Charles E Petersen, Chungeun Ha, A A Bhattacharya, Patricia A. Zunszain, J Ghuman, Nadhipuram V. Bhagavan, Stephen CurryAbstract:Human serum albumin (HSA) is the major protein component of blood plasma and serves as a transporter for thyroxine and other hydrophobic compounds such as fatty acids and bilirubin. We report here a structural characterization of HSA–thyroxine interactions. Using crystallographic analyses we have identified four binding sites for thyroxine on HSA distributed in subdomains IIA, IIIA, and IIIB. Mutation of residue R218 within subdomain IIA greatly enhances the affinity for thyroxine and causes the elevated serum thyroxine levels associated with Familial Dysalbuminemic Hyperthyroxinemia (FDH). Structural analysis of two FDH mutants of HSA (R218H and R218P) shows that this effect arises because substitution of R218, which contacts the hormone bound in subdomain IIA, produces localized conformational changes to relax steric restrictions on thyroxine binding at this site. We have also found that, although fatty acid binding competes with thyroxine at all four sites, it induces conformational changes that create a fifth hormone-binding site in the cleft between domains I and III, at least 9 A from R218. These structural observations are consistent with binding data showing that HSA retains a high-affinity site for thyroxine in the presence of excess fatty acid that is insensitive to FDH mutations.
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Familial Dysalbuminemic Hyperthyroxinemia may result in altered warfarin pharmacokinetics
Chemico-Biological Interactions, 2000Co-Authors: Charles E Petersen, Krishna Harohalli, David S Park, Nadhipuram V. BhagavanAbstract:Abstract Two distinct genotypes that result in the amino acid substitutions R218P and R218H in subdomain 2A of human serum albumin (HSA) have been identified as the cause of Familial Dysalbuminemic Hyperthyroxinemia (FDH). These substitutions increase the affinity of subdomain 2A for thyroxine by approximately 10-fold elevating plasma thyroxine levels in affected individuals. While many studies have examined the binding of thyroxine to FDH HSA, the binding of FDH HSA to drugs has not been widely investigated. The widely administered drug warfarin was selected as a model compound to study FDH HSA/drug interactions since it binds to subdomain 2A and its pharmacokinetics are dramatically influenced by HSA binding. Using two independent methods, fluorescence spectroscopy and equilibrium dialysis with radioactive warfarin, the binding of recombinant R218P, R218H, R218M and wild type HSA to warfarin was measured. Both methods showed an approximately 5-fold decrease in the affinity of R218P, R218H and R218M HSA for warfarin relative to wild type HSA. The K d values determined by fluorescence spectroscopy for wild type, R218H, R218P and R218M HSA binding to warfarin were 1.35, 5.38, 5.61, and 8.34 μM, respectively. The values determined by equilibrium dialysis were 5.36, 29.5, 14.5, and 23.4 μM, respectively. Based on the above findings one would expect the free serum warfarin concentration in homozygous R218P and R218H FDH patients to be elevated about 5-fold, resulting in about a 5-fold reduction in the serum half-life of the drug.
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structural investigations of a new Familial Dysalbuminemic Hyperthyroxinemia genotype
Clinical Chemistry, 1999Co-Authors: Charles E Petersen, Osamu Isozaki, Krishna Harohalli, David S Park, Jimmy B Feix, Nadhipuram V. BhagavanAbstract:Background: In a previous study, we found that the amino acid substitution R218H in human serum albumin (HSA) was the cause of Familial Dysalbuminemic Hyperthyroxinemia (FDH) in several Caucasian patients. Subsequently the substitution R218P was shown to be the cause of FDH in several members of a Japanese family. This study attempts to resolve discrepancies in the only other study of R218P HSA and identifies two new Japanese R218P FDH patients unrelated to those described previously. Methods and Results: Recombinant R218H, R218P, and wild-type HSA were synthesized in yeast, and the affinities of these HSA species for l- and d-thyroxine were determined using fluorescence spectroscopy. The dissociation constants for the binding of wild-type, R218P, and R218H HSA to l-thyroxine were 1.44 × 10−6, 2.64 × 10−7, and 2.49 × 10−7 mol/L, respectively. The circular dichroism spectra of thyroxine bound to R218H and R218P HSA were markedly different, indicating that the structure of the thyroxine/HSA complex is different for either protein. Conclusions: The K d values for l-thyroxine bound to R218P and R218H HSA determined in this study were similar. The extremely high serum total-thyroxine concentrations reported previously for R218P FDH patients (10-fold higher than those reported for R218H FDH patients) are not consistent with the K d values determined in this study. Possible explanations for these discrepancies are discussed.
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mutations in a specific human serum albumin thyroxine binding site define the structural basis of Familial Dysalbuminemic Hyperthyroxinemia
Journal of Biological Chemistry, 1996Co-Authors: Charles E Petersen, David M Jameson, Nadhipuram V. BhagavanAbstract: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. Site-directed 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.
Katsumi Yoshida - One of the best experts on this subject based on the ideXlab platform.
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Familial Dysalbuminemic Hyperthyroxinemia in a japanese man caused by a point albumin gene mutation r218p
Japanese Clinical Medicine, 2016Co-Authors: Yoshinori Osaki, Yoshitaka Hayashi, Yoshinori Nakagawa, Katsumi Yoshida, Hiroshi Ozaki, Hiroshi FukazawaAbstract:Familial Dysalbuminemic Hyperthyroxinemia (FDH) is a Familial autosomal dominant disease caused by mutation in the albumin gene that produces a condition of euthyroid Hyperthyroxinemia. In patients with FDH, serum-free thyroxine (FT4) and free triiodothyronine (FT3) concentrations as measured by several commercial methods are often falsely increased with normal thyrotropin (TSH). Therefore, several diagnostic steps are needed to differentiate TSH-secreting tumor or generalized resistance to thyroid hormone from FDH. We herein report a case of a Japanese man born in Aomori prefecture, with FDH caused by a mutant albumin gene (R218P). We found that a large number of FDH patients reported in Japan to date might have been born in Aomori prefecture and have shown the R218P mutation. In conclusion, FDH needs to be considered among the differential diagnoses in Japanese patients born in Aomori prefecture and showing normal TSH levels and elevated FT4 levels.
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artifactually elevated serum free thyroxine levels measured by equilibrium dialysis in a pregnant woman with Familial Dysalbuminemic Hyperthyroxinemia
Thyroid, 2004Co-Authors: Saeko Hoshikawa, Yoshinori Nakagawa, Kouki Mori, Nobuko Kaise, Sadayoshi Ito, Katsumi YoshidaAbstract:Familial Dysalbuminemic Hyperthyroxinemia (FDH) is a Familial autosomal dominant syndrome caused by abnormal albumin with an increased affinity for thyroxine (T4). Two types of mutations in the albumin gene, replacing the normal arginine 218 with a histidine (R218H) or a proline (R218P), have been reported to cause FDH. Here, we report a pregnant Japanese woman with FDH caused by the mutant albumin R218P. She had extremely elevated total T4 levels but normal TSH. While the majority of T4was bound to albumin, T4 binding to thyroxine-binding globulin (TBG) was progressively increased throughout pregnancy. Her infant also had elevated serum T4 but normal thyrotropin (TSH). The presence of a guanine to cytosine transition in the second nucleotide of codon 218 of the albumin gene, resulting in a substitution of proline for the normal arginine (R218P), was revealed in the proband. Serum free thyroxine (FT4) levels were increased when measured with some commercial kits including equilibrium dialysis followed by ...
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artifactually elevated serum free thyroxine levels measured by equilibrium dialysis in a pregnant woman with Familial Dysalbuminemic Hyperthyroxinemia
Thyroid, 2004Co-Authors: Saeko Hoshikawa, Yoshinori Nakagawa, Kouki Mori, Nobuko Kaise, Sadayoshi Ito, Katsumi YoshidaAbstract:Familial Dysalbuminemic Hyperthyroxinemia (FDH) is a Familial autosomal dominant syndrome caused by abnormal albumin with an increased affinity for thyroxine (T4). Two types of mutations in the albumin gene, replacing the normal arginine 218 with a histidine (R218H) or a proline (R218P), have been reported to cause FDH. Here, we report a pregnant Japanese woman with FDH caused by the mutant albumin R218P. She had extremely elevated total T4 levels but normal TSH. While the majority of T4was bound to albumin, T4 binding to thyroxine-binding globulin (TBG) was progressively increased throughout pregnancy. Her infant also had elevated serum T4 but normal thyrotropin (TSH). The presence of a guanine to cytosine transition in the second nucleotide of codon 218 of the albumin gene, resulting in a substitution of proline for the normal arginine (R218P), was revealed in the proband. Serum free thyroxine (FT4) levels were increased when measured with some commercial kits including equilibrium dialysis followed by radioimmunoassay (RIA) but not when determined by RIA after ultrafiltration of sera. These results indicate an increased T4 binding to TBG during pregnancy in the patients with FDH. Furthermore, our results suggest that normal serum FT4 determined by equilibrium dialysis is not an ultimate standard for the diagnosis of FDH in the patients with the mutant albumin R218P.
Roy E Weiss - One of the best experts on this subject based on the ideXlab platform.
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a novel mutation in the albumin gene r218s causing Familial Dysalbuminemic Hyperthyroxinemia in a family of bangladeshi extraction
Thyroid, 2014Co-Authors: Solomon Maximo Greenberg, Roy E Weiss, Alfonso Massimiliano Ferrara, Everton S Nicholas, Alexandra M Dumitrescu, Vivian Cody, Samuel RefetoffAbstract:Background: Familial Dysalbuminemic Hyperthyroxinemia (FDH) is a common cause of euthyroid Hyperthyroxinemia. Clinical recognition of FDH is crucial for preventing unnecessary therapy in clinically euthyroid patients with abnormal thyroid function tests. Our goal was to identify the cause of abnormal serum tests of thyroid function in a Canadian family of Bangladeshi extraction. Patients: The proposita was found to have elevated free thyroxine (fT4) and free triiodothyronine (fT3) with nonsuppressed thyrotropin (TSH) on screening blood work. After detailed studies excluding hyperthyroidism and resistance to thyroid hormone, blood was obtained from all members of her immediate family for further investigation. Methods: We conducted laboratory analyses and sequencing of candidate genes. Results: Two members of this family have FDH, caused by a not previously identified mutation in the albumin gene. This mutation, located in exon 7 of the gene (652A>C), produces a single amino acid substitution in the protein molecule (R218S). The mutant albumin is associated with a ninefold increase in serum total T4 and a twofold increase in serum total reverse T3 compared to patients with normal albumin. Modeling data for the R218S variant are compatible with the increased binding affinity of this variant albumin for T4. Conclusions: The R218S substitution reported here causes FDH that, in terms of the magnitude of serum iodothyronine elevation, is intermediate to the two previously reported mutations at codon 218 FDH: R218H being more mild and R218P more severe.
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Familial Dysalbuminemic Hyperthyroxinemia a rare example of albumin polymorphism and its rapid molecular diagnosis
Journal of Pediatric Endocrinology and Metabolism, 2002Co-Authors: Theodore W Avruskin, Christina S Juan, Roy E WeissAbstract:Familial Dysalbuminemic Hyperthyroxinemia (FDH) is the most common cause of euthyroid Hyperthyroxinemia, although a rare example of albumin polymorphism. FDH is inherited in an autosomal dominant manner and is characterized by enhanced binding of thyroxine to a mutant form of albumin, probably at Site 1, subdomain 11A. Previous laboratory tests of FDH have been cumbersome, rarely available, and required demonstration of anti-albumin precipitable T4, isoelectric focusing of serum for albumin in presence of labeled T4 and, occasionally, comparison of the concentrations of metabolites of T4 that have different binding affinities to the abnormal albumin. Recent studies have shown that the same mutation in the albumin gene that results in FDH has been found in 13 unrelated families. A G-->A transition in codon 218 of the albumin gene resulted in the replacement of arginine with histidine. An intragenic Sac-1 polymorphic site was found in association with the specific FDH mutation, suggesting a founder effect. FDH in our Hispanic family was confirmed by isoelectric focusing of serum. Results of thyroid function tests in our affected patients were typical for the phenotype: high total T4 and normal total T3. Genomic DNA was amplified by PCR using a mismatched oligonucleotide primer that produced a unique restriction site (Dra III) only if the DNA sample contained the mutation in codon 218: CGC (Arg) to CAC (His). In affected individuals of this family expression of the FDH phenotype was associated with the presence of His218 in one of the two alleles. Analysis linking the FDH mutation to the Sac-1 polymorphism in this family was not informative. DNA analysis is a rapid and simple method to diagnose FDH in individuals with euthyroid Hyperthyroxinemia.
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congenital hypothyroidism in a child with unsuspected Familial Dysalbuminemic Hyperthyroxinemia caused by a mutation r218h in the human albumin gene
The Journal of Pediatrics, 2001Co-Authors: Joachim Pohlenz, Roy E Weiss, Peter M Sadow, Thomas Koffler, Winfried Schonberger, Samuel RefetoffAbstract:We found Familial Dysalbuminemic Hyperthyroxinemia (FDH) in a 5-month-old boy with congenital hypothyroidism (CH) who had a blood thyrotropin (TSH) level of 479 mU/L but normal total serum thyroxine (T4) and higher than normal total triiodothyronine (T3) levels. Thyroid hormone substitution began at 5 weeks of age when T4 and T3 concentrations were below normal. Until the age of 5 months, treatment with levothyroxine was suboptimal on the basis of high serum TSH levels despite above-normal T4 levels. FDH was confirmed by isoelectric focusing and testing of other family members. DNA analysis of the patient revealed R218H, a mutation in the serum albumin gene associated with FDH, which was also present in the patient's euthyroid father and brother. Thyroid scans, serum thyroglobulin measurements, and free T4 measurements using equilibrium dialysis or 2-step immunoassay methods can identify thyroid hormone-binding protein defects and simplify the diagnosis and treatment of infants with CH.
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Familial Dysalbuminemic Hyperthyroxinemia in a swiss family caused by a mutant albumin r218p shows an apparent discrepancy between serum concentration and affinity for thyroxine
The Journal of Clinical Endocrinology and Metabolism, 2000Co-Authors: Silvana Pannain, Neal H Scherberg, Roy E Weiss, Michael Feldman, Urs Eiholzer, Samuel RefetoffAbstract:Familial Dysalbuminemic Hyperthyroxinemia (FDH), is the most common cause of inherited increase in serum total T4 (TT4) in the Caucasian population. It is caused by a mutation (R218H) in the human serum albumin (HSA) gene, resulting in 10-fold higher affinity for T4 and, in heterozygous affected subjects, a TT4 level 2-fold higher than that in subjects expressing the wild-type HSA only. We now report FDH in a Swiss family, caused by HSA R218P, previously reported in subjects of Japanese origin. In this form of FDH, serum TT4 levels are 14- to 20-fold the normal mean, confirmed by measurements in serum extracts. TrT3 and TT3, concentrations are 7- and 2-fold above the mean, respectively. Thus, to maintain a normal free T4 level, the calculated affinity constant (Ka) of HSA R218P should be about 16-fold higher than that of HSA R218H. Surprisingly, the Ka values measured at saturation were similar: 5.4 x 10(6) and 6.4 x 10(6) mol/L(-1) for HSA R218H, respectively. To determine how subjects with HSA R218P and R218P maintain a euthyroid state despite the markedly high serum TT4, the concentration of dialyzable T4 was measured at increasing amounts of TT4. At a TT4 level equivalent to that found in the subjects with HSA R218P, the absolute FT4 concentrations were 40, 432, and 1970 pmol/L for sera expressing HSAs R218P, R218H, and wild type, respectively. Thus, the affinity of HSA R218P for T4 must be higher than that of R218H to produce an 11-fold difference in FT4 at the same concentration ofTT4 This difference was obliterated at saturating concentrations of TT4 used for the determination of Ka values by the method of Scatchard.
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linkage of Familial Dysalbuminemic Hyperthyroxinemia to the albumin gene in a large amish kindred
The Journal of Clinical Endocrinology and Metabolism, 1995Co-Authors: Roy E Weiss, Thongkum Sunthornthepvarakul, Piamsook Angkeow, Deborah Marcusbagley, Nancy J Cox, Chester A Alper, Samuel RefetoffAbstract:Familial Dysalbuminemic Hyperthyroxinemia (FDH) is the most common cause of inherited euthyroid Hyperthyroxinemia in Caucasians. Transmitted as an autosomal dominant trait, it is always associated with high serum total T4 (TT4) and more rarely with elevated total T3 (TT3) and/or rT3 (TrT3) concentrations. Free T4, by dialysis, and TSH levels are normal, suggesting the presence of a T4-binding protein abnormality. The abnormal serum T4 carrier shares some physical and immunological properties with albumin, suggesting that it may be albumin itself. Here we show linkage between FDH and the albumin gene in a large Amish family of Swiss descent, using as markers a SacI polymorphism in the coding sequence of the albumin gene and the group-specific component (Gc) gene, located less than 1 centimorgan from the albumin gene. Blood samples were obtained from 160 members of this kindred, and 22 had FDH identified by the pattern of T4 binding to serum proteins separated by isoelectric focusing. Serum TT4 values were above the normal range in all subjects expressing the FDH phenotype, and TrT3 levels were above the normal range in only one half. TT4 concentrations correlated positively with TrT3 and TT3. All TT3 values were, however, within the normal range. Free T4 and TSH levels were normal, confirming the euthyroid state in these subjects. FDH was associated with the albumin SacI(+)/Gc 1S haplotype, yielding a LOD (logarithm of the odds ratio) score of 5.53, with a recombination frequency of 0. These data provide strong support that a variant albumin is the cause of FDH in this kindred.
Charles E Petersen - One of the best experts on this subject based on the ideXlab platform.
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structural basis of albumin thyroxine interactions and Familial Dysalbuminemic Hyperthyroxinemia
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Isabelle Petitpas, Charles E Petersen, Chungeun Ha, A A Bhattacharya, Patricia A. Zunszain, J Ghuman, Nadhipuram V. Bhagavan, Stephen CurryAbstract:Human serum albumin (HSA) is the major protein component of blood plasma and serves as a transporter for thyroxine and other hydrophobic compounds such as fatty acids and bilirubin. We report here a structural characterization of HSA–thyroxine interactions. Using crystallographic analyses we have identified four binding sites for thyroxine on HSA distributed in subdomains IIA, IIIA, and IIIB. Mutation of residue R218 within subdomain IIA greatly enhances the affinity for thyroxine and causes the elevated serum thyroxine levels associated with Familial Dysalbuminemic Hyperthyroxinemia (FDH). Structural analysis of two FDH mutants of HSA (R218H and R218P) shows that this effect arises because substitution of R218, which contacts the hormone bound in subdomain IIA, produces localized conformational changes to relax steric restrictions on thyroxine binding at this site. We have also found that, although fatty acid binding competes with thyroxine at all four sites, it induces conformational changes that create a fifth hormone-binding site in the cleft between domains I and III, at least 9 A from R218. These structural observations are consistent with binding data showing that HSA retains a high-affinity site for thyroxine in the presence of excess fatty acid that is insensitive to FDH mutations.
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Familial Dysalbuminemic Hyperthyroxinemia may result in altered warfarin pharmacokinetics
Chemico-Biological Interactions, 2000Co-Authors: Charles E Petersen, Krishna Harohalli, David S Park, Nadhipuram V. BhagavanAbstract:Abstract Two distinct genotypes that result in the amino acid substitutions R218P and R218H in subdomain 2A of human serum albumin (HSA) have been identified as the cause of Familial Dysalbuminemic Hyperthyroxinemia (FDH). These substitutions increase the affinity of subdomain 2A for thyroxine by approximately 10-fold elevating plasma thyroxine levels in affected individuals. While many studies have examined the binding of thyroxine to FDH HSA, the binding of FDH HSA to drugs has not been widely investigated. The widely administered drug warfarin was selected as a model compound to study FDH HSA/drug interactions since it binds to subdomain 2A and its pharmacokinetics are dramatically influenced by HSA binding. Using two independent methods, fluorescence spectroscopy and equilibrium dialysis with radioactive warfarin, the binding of recombinant R218P, R218H, R218M and wild type HSA to warfarin was measured. Both methods showed an approximately 5-fold decrease in the affinity of R218P, R218H and R218M HSA for warfarin relative to wild type HSA. The K d values determined by fluorescence spectroscopy for wild type, R218H, R218P and R218M HSA binding to warfarin were 1.35, 5.38, 5.61, and 8.34 μM, respectively. The values determined by equilibrium dialysis were 5.36, 29.5, 14.5, and 23.4 μM, respectively. Based on the above findings one would expect the free serum warfarin concentration in homozygous R218P and R218H FDH patients to be elevated about 5-fold, resulting in about a 5-fold reduction in the serum half-life of the drug.
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structural investigations of a new Familial Dysalbuminemic Hyperthyroxinemia genotype
Clinical Chemistry, 1999Co-Authors: Charles E Petersen, Osamu Isozaki, Krishna Harohalli, David S Park, Jimmy B Feix, Nadhipuram V. BhagavanAbstract:Background: In a previous study, we found that the amino acid substitution R218H in human serum albumin (HSA) was the cause of Familial Dysalbuminemic Hyperthyroxinemia (FDH) in several Caucasian patients. Subsequently the substitution R218P was shown to be the cause of FDH in several members of a Japanese family. This study attempts to resolve discrepancies in the only other study of R218P HSA and identifies two new Japanese R218P FDH patients unrelated to those described previously. Methods and Results: Recombinant R218H, R218P, and wild-type HSA were synthesized in yeast, and the affinities of these HSA species for l- and d-thyroxine were determined using fluorescence spectroscopy. The dissociation constants for the binding of wild-type, R218P, and R218H HSA to l-thyroxine were 1.44 × 10−6, 2.64 × 10−7, and 2.49 × 10−7 mol/L, respectively. The circular dichroism spectra of thyroxine bound to R218H and R218P HSA were markedly different, indicating that the structure of the thyroxine/HSA complex is different for either protein. Conclusions: The K d values for l-thyroxine bound to R218P and R218H HSA determined in this study were similar. The extremely high serum total-thyroxine concentrations reported previously for R218P FDH patients (10-fold higher than those reported for R218H FDH patients) are not consistent with the K d values determined in this study. Possible explanations for these discrepancies are discussed.
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mutations in a specific human serum albumin thyroxine binding site define the structural basis of Familial Dysalbuminemic Hyperthyroxinemia
Journal of Biological Chemistry, 1996Co-Authors: Charles E Petersen, David M Jameson, Nadhipuram V. BhagavanAbstract: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. Site-directed 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.