LINKAGE OF FAMILIAL DYSALBUMINEMIC HYPERTHYROXINEMIA TO THE ALBUMIN GENE IN A LARGE AMISH KINDRED

Familial dysalbuminemic hyperthyroxinemia (FDH) is the most common cau se of inherited euthyroid hyperthyroxinemia in Caucasians. Transmitted as an autosomal dominant trait, it is always associated with high ser um total T-4 (TT4) and more rarely with elevated total T-3 (TT3) and/o r rT(3) (TrT(3)) concentrations. Free T-4, by dialysis, and TSH levels are normal, suggesting the presence of a T-4-binding protein abnormal ity. The abnormal serum T-4 carrier shares some physical and immunolog ical properties with albumin, suggesting that it may be albumin itself . Here we show linkage between FDH and the albumin gene in a large Ami sh family of Swiss descent, using as markers a SacI polymorphism in th e coding sequence of the albumin gene and the group-specific component (Gc) gene, located less than 1 centimorgan from the albumin gene. Blo od samples were obtained from 160 members of this kindred, and 22 had FDH identified by the pattern of T-4 binding to serum proteins separat ed by isoelectric focusing. Serum TT4 values were above the normal ran ge in all subjects expressing the FDH phenotype, and TrT(3) levels wer e above the normal range in only one half. TT4 concentrations correlat ed positively with TrT(3) and TT3. All TT3 values were, however, withi n the normal range. Free T-4 and TSH levels were normal, confirming th e euthyroid state in these subjects. FDH was associated with the album in SacI(+)/Gc 1S haplotype, yielding a LOD (logarithm of the odds rati o) score of 5.53, with a recombination frequency of O. These data prov ide strong support that a variant albumin is the cause of FDH in this kindred.