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Three Novel Mutations Causing Complete T₄-Binding Globulin Deficiency

Departments of Medicine (Si.R., Sa.R.) and Pediatrics (Sa.R.) and the J. P. Kennedy Jr. Mental Retardation Research Center (Sa.R.), The University of Chicago, Chicago, Illinois 60637; and Division of Endocrinology (O.E.J.), Department of Medicine, University of Essen, Essen D-45122, Germany

Address all correspondence and requests for reprints to: Samuel Refetoff, M.D., The University of Chicago, 5841 South Maryland Avenue, Chicago, Illinois 60637. E-mail: refetoff{at}medicine.bsd.uchicago.edu

Abstract

Inherited T₄-binding globulin deficiency is caused by mutations in the T₄-binding globulin gene located on the X chromosome. We describe herein three novel mutations in three different families producing complete T₄-binding globulin deficiency. The proposita of a family from Harwichport is a female with XO Turner’s syndrome who expressed only the mutant T₄-binding globulin allele. Her T₄-binding globulin sequence has a 19-nucleotide deletion in the distal portion of exon 4. This causes a frameshift and a premature stop at codon 384 of the mature protein. Structure analysis with the Swiss PDB-Viewer revealed that this mutation removes ß-strand s5B from the core of the T₄-binding globulin molecule, leading to a severe folding defect that is likely to prevent synthesis and secretion. The propositi of complete T₄-binding globulin deficiency 7 and 8 were 7-month-old and 3-wk-old male infants who were identified because of low serum T₄ levels detected during neonatal screening. Sequencing of complete T₄-binding globulin deficiency 7 revealed a single nucleotide deletion, a G at position 2690 in exon 3. This leads to an alteration of the amino acid sequence starting at codon 283 and a premature stop at codon 301. Complete T₄-binding globulin deficiency 8 also has a deletion of the first nucleotide of exon 4, a G at position 3358. This leads to a frameshift and a premature stop at codon 374. As in the case of complete T₄-binding globulin deficiency J, which has also a nucleotide deletion but downstream (position 3421) and a stop at codon 374, these two T₄-binding globulin mutants undoubtedly have a defect in intracellular transport and therefore fail to be secreted. This explains the lack of T₄-binding globulin in the hemizygous affected subjects.

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