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A novel albumin gene mutation (R222I) in familial dysalbuminemic hyperthyroxinemia. 2014

Nadia Schoenmakers, and Carla Moran, and Irene Campi, and Maura Agostini, and Olivia Bacon, and Odelia Rajanayagam, and John Schwabe, and Sonia Bradbury, and Timothy Barrett, and Frank Geoghegan, and Maralyn Druce, and Paolo Beck-Peccoz, and Angela O'Toole, and Penelope Clark, and Michelle Bignell, and Greta Lyons, and David Halsall, and Mark Gurnell, and Krishna Chatterjee
University of Cambridge Metabolic Research Laboratories (N.S., C.M., M.A., O.R., G.L., M.G., K.C.), Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; Institute of Endocrine Sciences (I.C., P.B.-P.), University of Milan, 20132 Milan, Italy; Department of Biochemistry (J.S.), University of Leicester, Leicester LE1 7RH, United Kingdom; Departments of Paediatrics (T.B.) and Clinical Chemistry (M.B.), Birmingham Childrens Hospital, Birmingham B15 2TT, United Kingdom; Departments of Endocrinology (M.D.), St Bartholomew's Hospital, London E1 4NS, United Kingdom; Department of Clinical Biochemistry (F.G.), Ealing Hospital, London UB1 3EU, United Kingdom; Department of Clinical Biochemistry (A.O., P.C.), Selly Oak Hospital, Birmingham B29 6JD, United Kingdom; and Department of Clinical Biochemistry (O.B., S.B., D.H.), Addenbrooke's Hospital, Cambridge CB2 2OO, United Kingdom.

BACKGROUND 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. RESULTS Laboratory biochemical assessment, radiolabeled T4 binding studies, and ALB sequencing were undertaken. (125)I-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.

UI MeSH Term Description Entries
D007532 Isoleucine An essential branched-chain aliphatic amino acid found in many proteins. It is an isomer of LEUCINE. It is important in hemoglobin synthesis and regulation of blood sugar and energy levels. Alloisoleucine,Isoleucine, L-Isomer,L-Isoleucine,Isoleucine, L Isomer,L-Isomer Isoleucine
D008297 Male Males
D008958 Models, Molecular Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures. Molecular Models,Model, Molecular,Molecular Model
D011228 Prealbumin A tetrameric protein, molecular weight between 50,000 and 70,000, consisting of 4 equal chains, and migrating on electrophoresis in 3 fractions more mobile than serum albumin. Its concentration ranges from 7 to 33 per cent in the serum, but levels decrease in liver disease. Proalbumin,Transthyretin
D002675 Child, Preschool A child between the ages of 2 and 5. Children, Preschool,Preschool Child,Preschool Children
D005260 Female Females
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000328 Adult A person having attained full growth or maturity. Adults are of 19 through 44 years of age. For a person between 19 and 24 years of age, YOUNG ADULT is available. Adults
D001120 Arginine An essential amino acid that is physiologically active in the L-form. Arginine Hydrochloride,Arginine, L-Isomer,DL-Arginine Acetate, Monohydrate,L-Arginine,Arginine, L Isomer,DL Arginine Acetate, Monohydrate,Hydrochloride, Arginine,L Arginine,L-Isomer Arginine,Monohydrate DL-Arginine Acetate
D013960 Thyroid Function Tests Blood tests used to evaluate the functioning of the thyroid gland. Jostel's TSH Index,Jostel's Thyrotropin Index,Protein-Bound Iodine Test,SPINA-GD,SPINA-GT,Secretory Capacity of the Thyroid Gland,Sum Activity of Peripheral Deiodinases,Thyrotroph Thyroid Hormone Sensitivity Index,Thyroid Gland Function Tests,Function Test, Thyroid,Iodine Test, Protein-Bound,Jostel TSH Index,Jostel Thyrotropin Index,Jostel's TSH Indices,Jostels TSH Index,Jostels Thyrotropin Index,Protein Bound Iodine Test,Protein-Bound Iodine Tests,TSH Index, Jostel's,Test, Protein-Bound Iodine,Test, Thyroid Function,Thyroid Function Test,Thyrotropin Index, Jostel's

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