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 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.


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.
Petersen
C E
CE
Department of Biochemistry and Biophysics, University of Hawaii, 1960 East-West Rd., Honolulu, HI 96822, USA.
Ha
C E
CE
Harohalli
K
K
Park
D S
DS
Feix
J B
JB
Isozaki
O
O
Bhagavan
N V
NV
D019943:Amino Acid Substitution; D002942:Circular Dichroism; D006801:Humans; D006981:Hyperthyroxinemia / Q000097:blood / Q000235:genetics*; D010843:Pichia / Q000378:metabolism; D011485:Protein Binding; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D012709:Serum Albumin / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D013974:Thyroxine / Q000097:blood
D011994:Recombinant Proteins; D012709:Serum Albumin; D013974:Thyroxine