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

• Published in: The journal of clinical endocrinology and metabolism Vol. 99; no. 7; pp. E1381 - E1386
• Main Authors: Schoenmakers, Nadia, Moran, Carla, Campi, Irene, Agostini, Maura, Bacon, Olivia, Rajanayagam, Odelia, Schwabe, John, Bradbury, Sonia, Barrett, Timothy, Geoghegan, Frank, Druce, Maralyn, Beck-Peccoz, Paolo, O'Toole, Angela, Clark, Penelope, Bignell, Michelle, Lyons, Greta, Halsall, David, Gurnell, Mark, Chatterjee, Krishna
• Format: Journal Article
• Language: English
• Published: United States Endocrine Society 01-07-2014; Copyright by The Endocrine Society
• Series: Brief Report
• Subjects: Adult; Amino Acid Substitution; Arginine - genetics; Child, Preschool; Female; Humans; Hyperthyroxinemia, Familial Dysalbuminemic - blood; Hyperthyroxinemia, Familial Dysalbuminemic - genetics; Isoleucine - genetics; JCEM Online: Advances in Genetics; Male; Models, Molecular; Mutation, Missense; Prealbumin - chemistry; Prealbumin - genetics; Thyroid Function Tests; Young Adult
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2013-4077

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.