Three Novel Mutations Causing Complete T4-Binding Globulin Deficiency

Sirimon Reutrakul, Onno E. Janssen, Samuel Refetoff
2001 Journal of Clinical Endocrinology and Metabolism  
Inherited T 4 -binding globulin deficiency is caused by mutations in the T 4 -binding globulin gene located on the X chromosome. We describe herein three novel mutations in three different families producing complete T 4 -binding globulin deficiency. The proposita of a family from Harwichport is a female with XO Turner's syndrome who expressed only the mutant T 4 -binding globulin allele. Her T 4binding globulin sequence has a 19-nucleotide deletion in the distal portion of exon 4. This causes
more » ... frameshift and a premature stop at codon 384 of the mature protein. Structure analysis with the Swiss PDB-Viewer revealed that this mutation removes ␤-strand s5B from the core of the T 4binding globulin molecule, leading to a severe folding defect that is likely to prevent synthesis and secretion. The propositi of complete T 4 -binding globulin deficiency 7 and 8 were 7-month-old and 3-wk-old male infants who were iden-tified because of low serum T 4 levels detected during neonatal screening. Sequencing of complete T 4 -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 T 4 -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 T 4 -binding globulin deficiency J, which has also a nucleotide deletion but downstream (position 3421) and a stop at codon 374, these two T 4 -binding globulin mutants undoubtedly have a defect in intracellular transport and therefore fail to be secreted. This explains the lack of T 4 -binding globulin in the hemizygous affected subjects. (J Clin Endocrinol Metab 86: 5039 -5044, 2001)
doi:10.1210/jcem.86.10.7916 pmid:11600582 fatcat:b46u5nuntbdulm4ao7ywjec4fu