Partial Deficiency of Thyroxine-Binding Globulin-Allentown Is Due to a Mutation in the Signal Peptide

We present an unusual variant of T4-binding globulin (TBG) found in a family from Allentown, Pennsylvania (TBG-AT). The heterozygous proposita presented serum total T4 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 th...

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Bibliographic Details
Published in:	The journal of clinical endocrinology and metabolism Vol. 89; no. 5; pp. 2477 - 2483
Main Authors:	Fingerhut, Anja, Reutrakul, Sirimon, Knuedeler, Sebastian D., Moeller, Lars C., Greenlee, Carol, Refetoff, Samuel, Janssen, Onno E.
Format:	Journal Article
Language:	English
Published:	Bethesda, MD Endocrine Society 01-05-2004 Copyright by The Endocrine Society
Subjects:	Adolescent Amino Acid Substitution Animals Biological and medical sciences Endocrinopathies Feeding. Feeding behavior Female Fundamental and applied biological sciences. Psychology Histidine - genetics Humans Medical sciences Metabolism, Inborn Errors - genetics Mutation Oocytes - metabolism Pedigree Protein Sorting Signals - genetics Recombinant Proteins - metabolism RNA, Messenger - metabolism Thyroid Function Tests Thyroid Gland - physiology Thyroxine-Binding Proteins - deficiency Thyroxine-Binding Proteins - genetics Tyrosine - genetics Vertebrates: anatomy and physiology, studies on body, several organs or systems Vertebrates: endocrinology Xenopus - metabolism Signal transduction Signal Nutrition Partial Peptides Deficiency Thyroxine binding globulin Metabolic diseases Mutation Endocrinology
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Summary:	We present an unusual variant of T4-binding globulin (TBG) found in a family from Allentown, Pennsylvania (TBG-AT). The heterozygous proposita presented serum total T4 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. T4-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.
Bibliography:	ObjectType-Case Study-3 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-4 content type line 23 ObjectType-Report-2
ISSN:	0021-972X 1945-7197
DOI:	10.1210/jc.2003-031613