A novel albumin gene mutation (R222I) in familial dysalbuminemic hyperthyroxinemia

Context: Familial dysalbuminemic hyperthyroxinemia, characterized by abnormal circulating albuminwith 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 T 4 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

Resistance to thyroid hormone caused by a mutation in thyroid hormone receptor (TR)alpha 1 and TR alpha 2: clinical, biochemical, and genetic analyses of three related patients

Background The thyroid hormone receptor alpha gene (THRA) transcript is alternatively spliced to generate either thyroid hormone receptor (TR)alpha 1 or a non-hormone-binding variant protein, TR alpha 2, the function of which is unknown. Here, we describe the first patients identified with a mutation in THRA that affects both TR alpha 1 and TR alpha 2, and compare them with patients who have resistance to thyroid hormone owing to a mutation affecting only TR alpha 1, to delineate the relative roles of TR alpha 1 and TR alpha 2. Methods We did clinical, biochemical, and genetic analyses of an index case and her two sons. We assessed physical and radiological features, thyroid function, physiological and biochemical markers of thyroid hormone action, and THRA sequence. Findings The patients presented in childhood with growth failure, developmental delay, and constipation, which improved after treatment with thyroxine, despite normal concentrations of circulating thyroid hormones. They had similar clinical (macrocephaly, broad faces, skin tags, motor dyspraxia, slow speech), biochemical (subnormal ratio of free thyroxine: free tri-iodothyronine [T-3], low concentration of total reverse T-3, high concentration of creatine kinase, mild anaemia), and radiological (thickened calvarium) features to patients with TR alpha 1-mediated resistance to thyroid hormone, although our patients had a heterozygous mis-sense mutation (Ala263Val) in both TR alpha 1 and TR alpha 2 proteins. The Ala263Val mutant TR alpha 1 inhibited the transcriptional function of normal receptor in a dominant-negative fashion. By contrast, function of Ala263Val mutant TR alpha 2 matched its normal counterpart. In vitro, high concentrations of T-3 restored transcriptional activity of Ala263Val mutant TR alpha 1, and reversed the dominant-negative inhibition of its normal counterpart. High concentrations of T-3 restored expression of thyroid hormone-responsive target genes in patient-derived blood cells. Interpretation TR alpha 1 seems to be the principal functional product of the THRA gene. Thyroxine treatment alleviates hormone resistance in patients with mutations affecting this gene, possibly ameliorating the phenotype. These findings will help the diagnosis and treatment of other patients with resistance to thyroid hormone resulting from mutations in THRA