Novel frameshift mutation causes early termination of the thyroxine-binding globulin protein and complete thyroxine-binding globulin deficiency in a Chinese family: A case report

Abstract

Background: Thyroxine-binding globulin (TBG; the gene product of SERPINA7) is the main transporter of thyroid hormones in humans. Mutations in the TBG gene may lead to inherited TBG deficiency. There have been 28 reported mutations that associate with complete TBG deficiency (TBG-CD). Here we identified a novel frameshift mutation causing early termination of the TBG protein and TBG-CD in a Chinese family.

Case summary: A 46-year-old Chinese man was referred to our hospital with normal free thyroxine, free triiodothyronine, thyrotropin, but lower total thyroxine and total triiodothyronine, and undetectable serum TBG, indicative of TBG-CD. Blood samples were obtained from the patient's family members and thyroid function and serum TBG were evaluated. Genomic DNA from peripheral blood was sequenced to detect possible TBG mutation(s). Quantitative PCR high-resolution melting curve analysis was used to screen TBG-Poly (L283F) among 117 Chinese men. A novel mutation of TBG (p.Phe135Alafs*21), a 19-nucleotide insertion in exon 1, was identified, which resulted in a truncated TBG protein product and caused TBG-CD. The other mutation, identified in the proband's father, is a known polymorphism, TBG-Poly (L283F). The frequency of the TBG-Poly allele among 117 unrelated Han Chinese men from northeast China was 21.37%.

Conclusion: A novel mutation in the TBG gene associated with the TBG-CD phenotype was identified in a Chinese family. Additionally, it was found that 21.37% of Chinese males had TBG-Poly (L283F).

Keywords: Case report; Complete thyroxine-binding globulin deficiency; Gene polymorphism; Partial thyroxine-binding globulin deficiency; Thyroxine-binding globulin.

Figure 1

Pedigree showing the genotype and thyroid function test results of the proband’s family. The results of thyroid function tests are aligned below each individual. Abnormal values are indicated in bold. Low values are marked with a downward arrow, and undetectable values are marked in red.

Figure 2

Schematic diagram of the DNA sequence for a portion of exons 1 and 3 of the TBG gene. The exons 1–4 region of the TBG gene and intron-exon boundaries were sequenced. For the variant names, the GenBank reference sequences NM_000354.5 and NP_000345.2 are used. Nucleotide numbering reflects cDNA numbering, with +1 corresponding to the A of the ATG translation initiation codon in the reference sequence, according to HGVS guidelines (http://varnomen.hgvs.org/). The initiation codon is codon 1. Panel A displays a portion of exon 1 of the TBG gene showing the location of the insertional mutation. The upper part of the schematic diagram is the normal DNA sequence for this portion of exon 1. The middle and lower parts of the schematic diagram indicate the abnormal sequences of a portion of exon 1 of the TBG gene in two hemizygous sons (III-2 and III-3) and the heterozygous mother (II-1), respectively. A 19-nucleotide sequence was inserted between cDNA positions 381 and 382 (c.381_382insTTGCAGATAGGAAATG CCC) in exon 1. This mutation changes the phenylalanine at codon 135 to alanine and then encodes 19 amino acids, followed by an early termination codon at position 155, leading to premature termination of the thyroxine-binding globulin protein. The arrow indicates the start point of this mutation. The insertion sequence is located between the dotted lines. Panel B shows a schematic of a single nucleotide mutation in exon 3 of the TBG gene. A single nucleotide mutation (TTG→TTT) at codon 909 was identified in the proband’s father (II-2), but not in the other family members.