The SERPINA7 gene, also known as thyroxine-binding globulin (TBG), encodes for a glycoprotein that is a major plasma transporter of thyroid hormones, specifically thyroxine (T4) and triiodothyronine (T3). It is a member of the serpin superfamily of proteins, which are characterized by their serine protease inhibitor function. The SERPINA7 gene is located on the X chromosome at position Xq22.3. Mutations in this gene can lead to thyroxine-binding globulin deficiency, a condition where the levels of TBG are reduced or absent, leading to low levels of total T4 and T3 in the blood. This can be mistaken for hypothyroidism, as total T4 and T3 levels are low, but free T4, free T3, and thyroid-stimulating hormone (TSH) levels are normal[1][4][5][6][7].

The SERPINA7 gene has been the subject of several studies aimed at understanding the genetic basis of TBG deficiency and its clinical implications. These studies have identified various mutations in the SERPINA7 gene that lead to TBG deficiency. For example, a frameshift mutation (p.l372ffs * 32) was identified in a patient with partial thyroxine-binding globulin deficiency, which resulted in a decrease in the affinity of TBG for T4[4]. Another study identified a novel missense mutation in exon 4 of the SERPINA7 gene (C.909 (exon 4) g > T) in a patient with partial thyroxine-binding globulin deficiency[5]. Additionally, a novel mutation (p.Phe269Cysfs*18) causing partial TBG deficiency was identified in a patient from Korea[6]. These studies highlight the importance of genetic testing in diagnosing TBG deficiency and avoiding unnecessary treatment.

Furthermore, the SERPINA7 gene has been implicated in the regulation of thyroid function. A genome-wide association study conducted in Australian adolescents found a novel association between a single nucleotide polymorphism (SNP) near the SERPINA7 gene (rs12687280) and free T3 levels[3]. This suggests that the SERPINA7 gene may play a role in the regulation of thyroid function beyond its role as a thyroid hormone transporter.

Another study investigated the role of the unfolded protein response (UPR) in regulating hepatic autophagy. The UPR is a cellular stress response pathway that is activated in response to endoplasmic reticulum (ER) stress. The study found that the spliced X-box binding protein 1 (sXBP1) regulates genes involved in lysosomal function in the liver, including SERPINA7/TBG[2]. This suggests that the SERPINA7 gene may be involved in the UPR and its regulation of hepatic autophagy.

In summary, the SERPINA7 gene plays a critical role in the transport of thyroid hormones and has been implicated in the regulation of thyroid function. Mutations in the SERPINA7 gene can lead to TBG deficiency, which can be mistaken for hypothyroidism. Genetic testing is important in diagnosing TBG deficiency and avoiding unnecessary treatment. Additionally, the SERPINA7 gene has been implicated in the regulation of hepatic autophagy through its involvement in the UPR. Further research is needed to fully understand the role of the SERPINA7 gene in thyroid function and other biological processes.

References:

1. Fang, Yanlan, Chen, Hong, Chen, Qingqing, Wang, Chunlin, Liang, Li. 2021. Compound hemizygous variants in SERPINA7 gene cause thyroxine-binding globulin deficiency. In Molecular genetics & genomic medicine, 9, e1571. doi:10.1002/mgg3.1571. https://pubmed.ncbi.nlm.nih.gov/33554479/

2. Zhang, Zeyuan, Qian, Qingwen, Li, Mark, Cao, Huojun, Yang, Ling. 2020. The unfolded protein response regulates hepatic autophagy by sXBP1-mediated activation of TFEB. In Autophagy, 17, 1841-1855. doi:10.1080/15548627.2020.1788889. https://pubmed.ncbi.nlm.nih.gov/32597296/

3. Nolan, James, Campbell, Purdey J, Brown, Suzanne J, Martin, Nicholas G, Wilson, Scott G. 2021. Genome-wide analysis of thyroid function in Australian adolescents highlights SERPINA7 and NCOA3. In European journal of endocrinology, 185, 743-753. doi:10.1530/EJE-21-0614. https://pubmed.ncbi.nlm.nih.gov/34524976/

4. Cao, Lulu, Lou, Xiaojia, Zhou, Lili, Wu, Yuedan. . The decrease of T3 / T4 is not hypothyroidism - a new mutation of Serpina7 gene results in partial thyroglobulin deficiency. In Die Pharmazie, 76, 428-430. doi:10.1691/ph.2021.1559. https://pubmed.ncbi.nlm.nih.gov/34481533/

5. Liu, Xuefang, Li, Suyan, Xiong, Jingni, Qiu, Youyan, Xia, Bi-Wen. 2023. Partial Thyroid Hormone-Binding Globulin Deficiency: A Case Report and Literature Review. In Diabetes, metabolic syndrome and obesity : targets and therapy, 16, 2225-2232. doi:10.2147/DMSO.S413048. https://pubmed.ncbi.nlm.nih.gov/37525823/

6. Heo, Jung, Kim, Sang-Mi, Ryu, Hyun Jin, Park, Hyung-Doo, Kim, Sun Wook. 2022. Identification of Mutations in the Thyroxine-Binding Globulin (TBG) Gene in Patients with TBG Deficiency in Korea. In Endocrinology and metabolism (Seoul, Korea), 37, 870-878. doi:10.3803/EnM.2022.1591. https://pubmed.ncbi.nlm.nih.gov/36475360/

7. Fang, Y L, Wang, C L, Liang, L. . [Partial thyroxine binding globulin deficiency in test tube infants: report of cases and literature review]. In Zhonghua er ke za zhi = Chinese journal of pediatrics, 54, 428-32. doi:10.3760/cma.j.issn.0578-1310.2016.06.008. https://pubmed.ncbi.nlm.nih.gov/27256229/