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Structural Investigations of a New Familial Dysalbuminemic Hyperthyroxinemia Genotype

¹ Department of Biochemistry and Biophysics, University of Hawaii, 1960 East-West Rd., Honolulu, HI 96822.

² Biophysics Research Institute, Medical College of Wisconsin, 8701 Watertown Plank Rd., P.O. Box 26509, Milwaukee, WI 53226.

³ Department of Medicine, Institute of Clinical Endocrinology, Tokyo Women's Medical College, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162, Japan.
^a Author for correspondence. Fax 808-956-9498; e-mail bhagavan{at}jabsom.biomed.hawaii.edu

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 x 10^-6, 2.64 x 10^-7, and 2.49 x 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.© 1999 American Association for Clinical Chemistry

The following articles in journals at HighWire Press have cited this article:

				I. Petitpas, C. E. Petersen, C.-E. Ha, A. A. Bhattacharya, P. A. Zunszain, J. Ghuman, N. V. Bhagavan, and S. Curry Structural basis of albumin-thyroxine interactions and familial dysalbuminemic hyperthyroxinemia PNAS, May 27, 2003; 100(11): 6440 - 6445. [Abstract] [Full Text] [PDF]

				S. Pannain, M. Feldman, U. Eiholzer, R. E. Weiss, N. H. Scherberg, and S. Refetoff Familial Dysalbuminemic Hyperthyroxinemia in a Swiss Family Caused by a Mutant Albumin (R218P) Shows an Apparent Discrepancy between Serum Concentration and Affinity for Thyroxine J. Clin. Endocrinol. Metab., August 1, 2000; 85(8): 2786 - 2792. [Abstract] [Full Text]