A Novel Albumin Gene Mutation (R222I) in Familial Dysalbuminemic Hyperthyroxinemia

Abstract

Context:Familial dysalbuminemic hyperthyroxinemia, characterized by abnormal circulating albumin with increased T4 affinity, causes artefactual elevation of free T4 concentrations in euthyroid individuals.Objective:Four unrelated index cases with discordant thyroid function tests in different assay platforms were investigated.Design and Results:Laboratory biochemical assessment, radiolabeled T4 binding studies, and ALB sequencing were undertaken. 125I-T4 binding to both serum and albumin in affected individuals was markedly increased, comparable with known familial dysalbuminemic hyperthyroxinemia cases. Sequencing showed heterozygosity for a novel ALB mutation (arginine to isoleucine at codon 222, R222I) in all four cases and segregation of the genetic defect with abnormal biochemical phenotype in one family. Molecular modeling indicates that arginine 222 is located within a high-affinity T4 binding site in albumin, with substitution by isoleucine, which has a smaller side chain predicted to reduce steric hindrance, thereby facilitating T4 and rT3 binding. When tested in current immunoassays, serum free T4 values from R222I heterozygotes were more measurably abnormal in one-step vs two-step assay architectures. Total rT3 measurements were also abnormally elevated.Conclusions:A novel mutation (R222I) in the ALB gene mediates dominantly inherited dysalbuminemic hyperthyroxinemia. Susceptibility of current free T4 immunoassays to interference by this mutant albumin suggests likely future identification of individuals with this variant binding protein.

Inherited defects of thyroxine-binding proteins

“…This mutant HSA has a remarkably high TrT 3 level but relatively modest increase in TT 4 , similar to that in HSA R218H (44) (Table 4). HSA L66P has only high serum TT 3 .…”

“…Similarly, in-silico analysis predicts that the side chains of arginines 218 and 222 must undergo a marked displacement to accommodate T 4 . Their substitution with histidine or proline at position 218 and isoleucine at position 222 results in a conformational adjustment forming a more favorable binding pocket for T 4 (44). …”

A case of familial dysalbuminemic hyperthyroxinemia (FDH) in Japan: FDH as a possible differential diagnosis of syndrome of inappropriate secretion of thyroid-stimulating hormone (SITSH)

“…FT 4 measurements tend to be higher in the one-step platform than in the two-step platform, and this pattern resembled the differential of susceptibility of such assays with R218H FDH sera [8]. Reverse T 3 concentrations were 40-to 70-fold elevated when compared with the normal upper limit [9]. Characteristics of the described mutations are summarized in Table 1.…”

Familial dysalbuminaemic hyperthyroxinaemia: a rapid and novel mass spectrometry approach to diagnosis

“…Familial dysalbuminaemic hyperthyroxinaemia (FDH) is an important cause of discordant thyroid function test (TFT) results. It is due to an inherited (autosomal dominant) albumin variant exhibiting increased thyroxine (T4) binding [1][2][3] and affects an estimated 1 in 10,000 (but may be more common in certain ethnic groups such as Hispanics). 2,3 Despite the abnormal binding protein, FDH patients are euthyroid, and therefore treatment is unwarranted.…”