title: A novel albumin gene mutation (R222I) in familial dysalbuminemic hyperthyroxinemia.
abstract: 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.
authors.affiliation: 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.
authors.forename: Nadia
authors.initials: N
authors.lastname: Schoenmakers
authors.forename: Carla
authors.initials: C
authors.lastname: Moran
authors.forename: Irene
authors.initials: I
authors.lastname: Campi
authors.forename: Maura
authors.initials: M
authors.lastname: Agostini
authors.forename: Olivia
authors.initials: O
authors.lastname: Bacon
authors.forename: Odelia
authors.initials: O
authors.lastname: Rajanayagam
authors.forename: John
authors.initials: J
authors.lastname: Schwabe
authors.forename: Sonia
authors.initials: S
authors.lastname: Bradbury
authors.forename: Timothy
authors.initials: T
authors.lastname: Barrett
authors.forename: Frank
authors.initials: F
authors.lastname: Geoghegan
authors.forename: Maralyn
authors.initials: M
authors.lastname: Druce
authors.forename: Paolo
authors.initials: P
authors.lastname: Beck-Peccoz
authors.forename: Angela
authors.initials: A
authors.lastname: O'Toole
authors.forename: Penelope
authors.initials: P
authors.lastname: Clark
authors.forename: Michelle
authors.initials: M
authors.lastname: Bignell
authors.forename: Greta
authors.initials: G
authors.lastname: Lyons
authors.forename: David
authors.initials: D
authors.lastname: Halsall
authors.forename: Mark
authors.initials: M
authors.lastname: Gurnell
authors.forename: Krishna
authors.initials: K
authors.lastname: Chatterjee
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D001120:Arginine / Q000235:genetics; D002675:Child, Preschool; D005260:Female; D006801:Humans; D050010:Hyperthyroxinemia, Familial Dysalbuminemic / Q000097:blood / Q000235:genetics*; D007532:Isoleucine / Q000235:genetics; D008297:Male; D008958:Models, Molecular; D020125:Mutation, Missense; D011228:Prealbumin / Q000737:chemistry / Q000235:genetics*; D013960:Thyroid Function Tests; D055815:Young Adult
chemical_list: D011228:Prealbumin; D007532:Isoleucine; D001120:Arginine