title: Partial deficiency of thyroxine-binding globulin-Allentown is due to a mutation in the signal peptide.
abstract: We present an unusual variant of T(4)-binding globulin (TBG) found in a family from Allentown, Pennsylvania (TBG-AT). The heterozygous proposita presented serum total T(4) and TBG levels ranging from low to normal. TBG gene sequencing revealed a C-to-T substitution in codon -2 (CAC to TAC) leading to the substitution of the normal histidine by a tyrosine within the signal peptide. No mutation within the mature peptide was found. Allele-specific PCR confirmed the H(-2)Y mutation in the propositas mother and son. T(4)-binding analysis of TBG in serum from the proposita and son showed normal affinity but reduced capacity when compared with the unaffected father. Heat stability and isoelectric focusing of TBG-AT were normal. In vitro expression of a recombinant TBG-AT in Xenopus oocytes revealed a diminished secretory efficiency and confirmed the normal binding affinity and heat stability of the small amount of secreted TBG-AT. This study has defined impaired cotranslational processing as a hitherto unrecognized cause of hereditary TBG deficiency.
authors.affiliation: Department of Medicine, University of Essen, 45122 Essen, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Fingerhut
authors.forename: Sirimon
authors.initials: S
authors.lastname: Reutrakul
authors.forename: Sebastian D
authors.initials: SD
authors.lastname: Knuedeler
authors.forename: Lars C
authors.initials: LC
authors.lastname: Moeller
authors.forename: Carol
authors.initials: C
authors.lastname: Greenlee
authors.forename: Samuel
authors.initials: S
authors.lastname: Refetoff
authors.forename: Onno E
authors.initials: OE
authors.lastname: Janssen
mesh_terms: D000293:Adolescent; D019943:Amino Acid Substitution; D000818:Animals; D005260:Female; D006639:Histidine / Q000235:genetics; D006801:Humans; D008661:Metabolism, Inborn Errors / Q000235:genetics; D009154:Mutation; D009865:Oocytes / Q000378:metabolism; D010375:Pedigree; D021382:Protein Sorting Signals / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013960:Thyroid Function Tests; D013961:Thyroid Gland / Q000502:physiology; D013975:Thyroxine-Binding Proteins / Q000172:deficiency* / Q000235:genetics*; D014443:Tyrosine / Q000235:genetics; D014981:Xenopus / Q000378:metabolism
chemical_list: D021382:Protein Sorting Signals; D012333:RNA, Messenger; D011994:Recombinant Proteins; D013975:Thyroxine-Binding Proteins; C486983:tyroxine-binding globulin-Allentown, human; D014443:Tyrosine; D006639:Histidine