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

BACKGROUNDThyroxine-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 SUMMARYA 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%.CONCLUSIONA 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).

Compound hemizygous variants in SERPINA7 gene cause thyroxine‐binding globulin deficiency

“…The TBG‐poly had been considered as a benign variant in early studies, but our conclusion seems inconsistent with the previous literature (Janssen et al, 1992). The statistical results of the serum TBG levels in the p.L303F hemizygotes were significantly lower than WT individuals ( p = 0.0002) in our subjects, which is consistent with two recent reports (Chen et al, 2020; Dang et al, 2019). The TBG levels of >13 μg/ml has been described as a cutoff between normal and abnormal.…”

“…There were no significant differences between groups in the level of TT4 ( p = 0.664) most likely due to the low sample size of this study (Figure 4c). We pooled SERPINA7 p.L303F variant and/or WT samples along with samples harboring this variant and/or wild type from previous research (Chen et al, 2020; Dang et al, 2019; Mannavola et al, 2006). The TT4 levels of p.L303F group were significantly lower than the WT group ( p = 0.0006; Table , Figure 4d).…”

“…As shown in Figure 4a, the TBG levels of p.L303F group(12.1 ± 0.7983, n = 8)was significantly lower than that of the WT group (21.5 ± 1.831, n = 4) (p = 0.0002). To test the reliability of our results, we first compared our data with that reported in the literature (Chen et al, 2020;Dang et al, 2019;Mannavola et al, 2006). PubMed articles on TBG deficiency as of June 2020 are collected.…”

“…This SNP is often associated with other variants in the SERPINA7 gene, whose role is not yet defined (Bertenshaw et al,;Janssen et al, 2000;Mannavola et al, 2006;Mori et al, 1990;Su et al, 2003). Although p.L303F was previously considered to be a "benign" variant, two recent reports have shown that the serum TBG levels were lower in males with p.L303F variant compared to the normal controls (Chen et al, 2020;Dang et al, 2019). The mean TBG concentration in heterozygous females with TBG-PD is usually higher than half the normal level, and this level is intermediate between those found in affected and unaffected males.…”

Identification of Mutations in the Thyroxine-Binding Globulin (TBG) Gene in Patients with TBG Deficiency in Korea

“…To date, 49 mutations in the SERPINA7 gene have been reported to cause TBG deficiency [10][11][12][13][14]. In Korea, reports of TBG deficiency mainly discuss neonates and pediatric patients, and only a few mutation analyses of the SERPINA7 gene have been conducted.…”