Three novel mutations causing complete T4-binding globulin deficiency

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 T4-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(4)-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 beta -strand s5B from the core of the T(4)- binding 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 identified 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.