Linkage of familial dysalbuminemic hyperthyroxinemia to the albumin gene in a large Amish kindred.

Abstract

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.

A point mutation in the albumin gene in a Chinese patient with familial dysalbuminemic hyperthyroxinemia

“…These discrepancies are due to the presence of an abnormal serum albumin that exhibits enhanced binding of T 4 , and patients with FDH are clinically euthyroid (7)(8)(9)(10). Although FDH has been widely reported in the medical literature and accounts for the most common cause of genetic euthyroid hyperthyroxinemia in western countries, particularly among hispanics of Puerto Rican origin (11)(12)(13), to our knowledge no case has been reported in individuals of Chinese or African origin. Recently, the molecular basis of FDH has been found to be a substitution of histidine (CAC) and proline (CCC) for arginine (CGC) in codon 218 of the albumin gene in unrelated western families and in a Japanese kindred, respectively (14)(15)(16).…”

Human serum albumin: From bench to bedside

“…FDH is the most common inherited cause of increase in plasma total T 4 (TT 4 ) in the Caucasian population (Croxson et al, 1985), with the highest prevalence in communities of Portuguese or Hispanic origin (De Cosimo et al, 1987;Sunthornthepvarakul et al, 1994;Petersen et al, 1996;Pannain et al, 2000). Indeed, FDH is characterized by an approximate doubling of TT 4 and, to a lesser extent, total reverse T 3 (TrT 3 ) (Weiss et al, 1995). Although subjects with FDH are euthyroid, falsely elevated free T 4 (FT 4 ) values, as measured by standard clinical laboratory techniques (Stockigt et al, 1983), have often led to the erroneous diagnosis of hyperthyroidism, resulting in inappropriate thyroid gland ablative or drug therapy (Croxson et al, 1985;Fleming et al, 1987;Wood et al, 1987;Weiss et al, 1995).…”

“…Indeed, FDH is characterized by an approximate doubling of TT 4 and, to a lesser extent, total reverse T 3 (TrT 3 ) (Weiss et al, 1995). Although subjects with FDH are euthyroid, falsely elevated free T 4 (FT 4 ) values, as measured by standard clinical laboratory techniques (Stockigt et al, 1983), have often led to the erroneous diagnosis of hyperthyroidism, resulting in inappropriate thyroid gland ablative or drug therapy (Croxson et al, 1985;Fleming et al, 1987;Wood et al, 1987;Weiss et al, 1995).…”

“…Although earlier studies based on electrophoretic, chemical, and immunological properties have associated the TT 4 abnormality to a HSA variant (Lee et al, 1979;Stockigt et al, 1981;Silverberg and Premachandra, 1982;Lalloz et al, 1983;Weiss et al, 1995), the precise defect was identified only in 1994 (Petersen et al, 1994;Sunthornthepvarakul et al, 1994). In particular, the missense mutation Arg218His produces a HSA variant (named FDH-2) with 10-to 15-fold higher affinity for T 4 than the wild-type molecule, and a 5-fold increase in affinity for T 3 (Sunthornthepvarakul et al, 1994;Petersen et al, 1996;Petitpas et al, 2003).…”

“…The presence of a further abnormal HSA variant (named FDH-2; Arg218His) with predominantly increased affinity for T 3 was observed in a Japanese patient with Graves' disease, who had undergone subtotal thyroidectomy (Sunthornthepvarakul et al, 1994). Both HSA variants have a lesser increase in affinity for T 3 , although only subjects with the Arg218Pro mutation have consistently high plasma total T 3 (TT 3 ) levels (Weiss et al, 1995;Wada et al, 1997). The structural analysis of Arg218His and Arg218Pro HSA mutants showed that the increased affinity of TT 4 arises because the substitution of the Arg218 residue, which contacts the hormone bound in subdomain IIA, produces localized conformational changes to relax steric restrictions limiting T 4 binding (Petitpas et al, 2003).…”