Structural investigations of a new familial dysalbuminemic hyperthyroxinemia genotype

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 su bstitution R218P was shown to be the cause of FDH in several members of a J apanese family. This study attempts to resolve discrepancies in the only ot her study of R218P HSA and identifies two new Japanese R21.8 FDH patients u nrelated to those described previously. Methods and Results: Recombinant R218H, R218P, and wild-type HSA were synth esized in yeast, and the affinities of these HSA species for L- and D-thyro xine were determined using fluorescence spectroscopy, The dissociation cons tants for the binding of wild-type, R218P, and R218H HSA to L-thyroxine wer e 1.44 x 10(-6) 2.64 x 10(-7), and 2.49 x 10(-7) mol/L, respectively. The c ircular dichroism spectra of thyroxine bound to R218H and R218P HSA were ma rkedly different, indicating that the structure of the thyroxine/HSA comple x is different for either protein. Conclusions: The K-d values for L-thyroxine bound to R218P and R218H HSA de termined in this study were similar, The extremely high serum total-thyroxi ne concentrations reported previously for R218P FDH patients (1.0-fold high er than those reported for R218H FDH patients) are not consistent with the K-d values determined in this study. Possible explanations for these discre pancies are discussed, (C) 1999 American Association for Clinical Chemistry .