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

Abstract

Sub‐headingCompound hemizygous variants in SERPINA7 gene.BackgroundThyroxine‐binding globulin (TBG) is encoded by SERPINA7 (OMIM. 314200) which is located on Xq22.3. SERPINA7 variants caused TBG deficiency which does not require treatment, but the decreased thyroxine may be misdiagnosed as hypothyroidism. We discovered some variants of TBG caused by alterations that differ from previously reported.Materials and MethodsIn this study, we enrolled 32 subjects from 10 families and sequenced the SERPINA7 genes of TBG‐deficient subjects. Then, variants were analyzed to assess their effect on TBG expression and secretion. Bioinformatics database, protein structure, and dynamics simulation were used to evaluate the deleterious effects. Finally, we identified 2 novel and 4 known variants, and found 26 of 30 subjects carried the p.L303F. The DynaMut predictions indicated the variants (p.E91K, p.I92T, p.R294C, and p.L303F) exhibited decreased stability.ConclusionAnalyses revealed the p.L303F change the protein stability and flexibility, and it had an impact on the function of TBG, but when coexisted with other variants it might change the conformational structure of the protein and aggravate the damage to the protein. We speculated that the existence of a higher number of variants resulted in lower TBG secretion.

Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications

“…Furthermore, we explained with only few variants a large part of the variation in TT3 (9.5%). This is mainly driven by a common missense variant in the SERPINA7 gene (rs1804495; p.L303F) on chromosome X, which encodes thyroxine-binding globulin (TBG), one of the serum T4 and T3 binding proteins 43 . We successfully replicated previously known loci from the meta-GWAS on reference range thyroid function of the ThyroidOmics Consortium and almost all (98 out of 99) of the genome-wide significant variants identified in a whole range TSH GWAS 24 , 27 .…”

Multi-Trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications

“…Furthermore, we explained with only few variants a large part of the variation in TT3 (9.5%). This is mainly driven by a common missense variant in the SERPINA7 gene (rs1804495; p.L303F) on chromosome X, which encodes thyroxine-binding globulin (TBG), one of the serum T4 and T3 binding proteins 43 . We successfully replicated previously known loci from the meta-GWAS on reference range thyroid function of the ThyroidOmics Consortium and almost all (98 out of 99) of the genome-wide significant variants identified in a whole range TSH GWAS 24,27 .…”

Partial Thyroid Hormone-Binding Globulin Deficiency: A Case Report and Literature Review

“…Results obtained via DynaMut server prediction indicated that the p.E91K, p.I92T and p.L303F variants reduced the protein stability, and that the p.L303F variants had a significant effect on the protein stability. 13 The more mutation sites, the greater the impact of TBG. Fang Yanlan et al 13 concluded that polymorphisms in the Serpina7 gene can cause the disease, especially when multiple SNP sites are present at the same time, which can lead to decreased expression.…”

“… 13 The more mutation sites, the greater the impact of TBG. Fang Yanlan et al 13 concluded that polymorphisms in the Serpina7 gene can cause the disease, especially when multiple SNP sites are present at the same time, which can lead to decreased expression. The more SNPs carried, the lower the TBG and the higher the likelihood of complete TBG.…”