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Haigis AC, Vergauwen L, LaLone CA, Villeneuve DL, O'Brien JM, Knapen D. Cross-species applicability of an adverse outcome pathway network for thyroid hormone system disruption. Toxicol Sci 2023; 195:1-27. [PMID: 37405877 DOI: 10.1093/toxsci/kfad063] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/07/2023] Open
Abstract
Thyroid hormone system disrupting compounds are considered potential threats for human and environmental health. Multiple adverse outcome pathways (AOPs) for thyroid hormone system disruption (THSD) are being developed in different taxa. Combining these AOPs results in a cross-species AOP network for THSD which may provide an evidence-based foundation for extrapolating THSD data across vertebrate species and bridging the gap between human and environmental health. This review aimed to advance the description of the taxonomic domain of applicability (tDOA) in the network to improve its utility for cross-species extrapolation. We focused on the molecular initiating events (MIEs) and adverse outcomes (AOs) and evaluated both their plausible domain of applicability (taxa they are likely applicable to) and empirical domain of applicability (where evidence for applicability to various taxa exists) in a THSD context. The evaluation showed that all MIEs in the AOP network are applicable to mammals. With some exceptions, there was evidence of structural conservation across vertebrate taxa and especially for fish and amphibians, and to a lesser extent for birds, empirical evidence was found. Current evidence supports the applicability of impaired neurodevelopment, neurosensory development (eg, vision) and reproduction across vertebrate taxa. The results of this tDOA evaluation are summarized in a conceptual AOP network that helps prioritize (parts of) AOPs for a more detailed evaluation. In conclusion, this review advances the tDOA description of an existing THSD AOP network and serves as a catalog summarizing plausible and empirical evidence on which future cross-species AOP development and tDOA assessment could build.
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Affiliation(s)
- Ann-Cathrin Haigis
- Zebrafishlab, Veterinary Physiology and Biochemistry, Department of Veterinary Sciences, University of Antwerp, 2610 Wilrijk, Belgium
| | - Lucia Vergauwen
- Zebrafishlab, Veterinary Physiology and Biochemistry, Department of Veterinary Sciences, University of Antwerp, 2610 Wilrijk, Belgium
| | - Carlie A LaLone
- Great Lakes Toxicology and Ecology Division, United States Environmental Protection Agency, Duluth, Minnesota 55804, USA
| | - Daniel L Villeneuve
- Great Lakes Toxicology and Ecology Division, United States Environmental Protection Agency, Duluth, Minnesota 55804, USA
| | - Jason M O'Brien
- Ecotoxicology and Wildlife Health Division, Environment and Climate Change Canada, Carleton University, Ottawa, Ontario K1S 5B6, Canada
| | - Dries Knapen
- Zebrafishlab, Veterinary Physiology and Biochemistry, Department of Veterinary Sciences, University of Antwerp, 2610 Wilrijk, Belgium
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Fang Y, Chen H, Chen Q, Wang C, Liang L. Compound hemizygous variants in SERPINA7 gene cause thyroxine-binding globulin deficiency. Mol Genet Genomic Med 2021; 9:e1571. [PMID: 33554479 PMCID: PMC8077092 DOI: 10.1002/mgg3.1571] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 09/17/2020] [Accepted: 10/29/2020] [Indexed: 11/30/2022] Open
Abstract
Sub‐heading Compound hemizygous variants in SERPINA7 gene. Background Thyroxine‐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 Methods In 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. Conclusion Analyses 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.
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Affiliation(s)
- Yanlan Fang
- Pediatric Department, The 1st Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Hong Chen
- Pediatric Department, The 1st Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Qingqing Chen
- Pediatric Department, The 1st Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Chunlin Wang
- Pediatric Department, The 1st Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Li Liang
- Pediatric Department, The 1st Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
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Chen LD, Lu HJ, Gan YL, Pang SW, Zheng Q, Ye DM, Huang XY, Qi HN, Xu WB, Wen XZ, Li LH, Li L. Partial thyroxine-binding globulin deficiency in a family with coding region mutations in the TBG gene. J Endocrinol Invest 2020; 43:1703-1710. [PMID: 32266677 DOI: 10.1007/s40618-020-01245-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Accepted: 03/30/2020] [Indexed: 12/20/2022]
Abstract
PURPOSE T4-binding globulin (TBG) is the main thyroid hormone (TH) transporter present in human serum. Inherited thyroxine-binding globulin (TBG) deficiency is caused by mutations in the TBG (SERPINA7) gene, which is located on the X chromosome. This study was performed to report and evaluate coding region mutations in TBG gene for partial thyroxine-binding globulin deficiency. METHODS A pedigree spanning four generations is described in this study. The proband is a female with partial TBG deficiency. All members of this pedigree underwent thyroid function tests, while Sanger sequencing was used to identify the TBG gene mutations. Bioinformatics databases were used to evaluate the deleterious effects of the mutation(s). Two hundred and seven unrelated individuals were used to evaluate the thyroid function of individuals with different TBG mutations. A one-way ANOVA was used to analyze the impact of the TBG mutations on thyroid function. RESULTS TBG gene sequencing results revealed that the proband had a novel mutation in codon 27 leading to alanine to valine substitution (p.A27V). This mutation was associated with lower serum T4 levels (p < 0.0001) when compared to the groups that did not carry the mutation. The previously reported p.L283F mutation was also found in the proband. The hemizygous p.L283F individuals presenting with lower T4 serum and TBG levels (p < 0.001) when compared to wildtype males and females. Both mutations were deleterious upon SIFT and PolyPhen-2 evaluation. CONCLUSION Associated with partial thyroxine-binding globulin deficiency, this study reports a novel p.A27V mutation in the TBG gene.
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Affiliation(s)
- L-D Chen
- Department of Laboratory Medicine, General Hospital of Southern Theater Command of PLA, Guangzhou, 510010, Guangdong, China
| | - H-J Lu
- Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Shatai Road 1023, Guangzhou, 510515, Guangdong, China
| | - Y-L Gan
- Department of Laboratory Medicine, General Hospital of Southern Theater Command of PLA, Guangzhou, 510010, Guangdong, China
| | - S-W Pang
- Zhengzhou Yihe Hospital, Zhengzhou, 450000, Henan, China
| | - Q Zheng
- Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Shatai Road 1023, Guangzhou, 510515, Guangdong, China
| | - D-M Ye
- Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Shatai Road 1023, Guangzhou, 510515, Guangdong, China
| | - X-Y Huang
- Department of Laboratory Medicine, General Hospital of Southern Theater Command of PLA, Guangzhou, 510010, Guangdong, China
| | - H-N Qi
- Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Shatai Road 1023, Guangzhou, 510515, Guangdong, China
| | - W-B Xu
- Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Shatai Road 1023, Guangzhou, 510515, Guangdong, China
| | - X-Z Wen
- Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Shatai Road 1023, Guangzhou, 510515, Guangdong, China
| | - L-H Li
- Department of Laboratory Medicine, General Hospital of Southern Theater Command of PLA, Guangzhou, 510010, Guangdong, China.
| | - L Li
- Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Shatai Road 1023, Guangzhou, 510515, Guangdong, China.
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Dang PP, Xiao WW, Shan ZY, Xi Y, Wang RR, Yu XH, Teng WP, Teng XC. 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. World J Clin Cases 2019; 7:3887-3894. [PMID: 31799319 PMCID: PMC6887617 DOI: 10.12998/wjcc.v7.i22.3887] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 10/17/2019] [Accepted: 10/29/2019] [Indexed: 02/05/2023] Open
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).
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Affiliation(s)
- Ping-Ping Dang
- Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Wei-Wei Xiao
- Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Zhong-Yan Shan
- Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Yue Xi
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Jinzhou Medical University, Jinzhou 121000, Liaoning Province, China
| | - Ran-Ran Wang
- Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Xiao-Hui Yu
- Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Wei-Ping Teng
- Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Xiao-Chun Teng
- Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
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Junarta J, Jha V, Banerjee D. Insight into the impact of vitamin D on cardiovascular outcomes in chronic kidney disease. Nephrology (Carlton) 2019; 24:781-790. [DOI: 10.1111/nep.13569] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/21/2019] [Indexed: 02/06/2023]
Affiliation(s)
- Joey Junarta
- Renal and Transplantation UnitSt George's University Hospital NHS Foundation Trust London UK
- Cardiology Clinical Academic GroupMolecular and Clinical Sciences Research Institute, St George's University of London London UK
| | - Vivekanand Jha
- The George Institute of Global Health Oxford UK
- University of Oxford Oxford UK
| | - Debasish Banerjee
- Renal and Transplantation UnitSt George's University Hospital NHS Foundation Trust London UK
- Cardiology Clinical Academic GroupMolecular and Clinical Sciences Research Institute, St George's University of London London UK
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Schweizer U, Towell H, Vit A, Rodriguez-Ruiz A, Steegborn C. Structural aspects of thyroid hormone binding to proteins and competitive interactions with natural and synthetic compounds. Mol Cell Endocrinol 2017; 458:57-67. [PMID: 28131741 DOI: 10.1016/j.mce.2017.01.026] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2016] [Revised: 01/11/2017] [Accepted: 01/17/2017] [Indexed: 12/25/2022]
Abstract
Thyroid hormones and their metabolites constitute a vast class of related iodothyronine compounds that contribute to the regulation of metabolic activity and cell differentiation. They are in turn transported, transformed and recognized as signaling molecules through binding to a variety of proteins from a wide range of evolutionary unrelated protein families, which renders these proteins and their iodothyronine binding sites an example for extensive convergent evolution. In this review, we will briefly summarize what is known about iodothyronine binding sites in proteins, the modes of protein/iodothyronine interaction, and the ligand conformations. We will then discuss physiological and synthetic compounds, including popular drugs and food components, that can interfere with iodothyronine binding and recognition by these proteins. The discussion also includes compounds persisting in the environment and acting as endocrine disrupting chemicals.
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Affiliation(s)
- Ulrich Schweizer
- Institut für Biochemie und Molekularbiologie, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany.
| | - Holly Towell
- Lehrstuhl für Biochemie, Universität Bayreuth, Bayreuth, Germany
| | - Allegra Vit
- Lehrstuhl für Biochemie, Universität Bayreuth, Bayreuth, Germany
| | - Alfonso Rodriguez-Ruiz
- Institut für Biochemie und Molekularbiologie, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
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Korevaar TIM, Chaker L, Medici M, de Rijke YB, Jaddoe VWV, Steegers EAP, Tiemeier H, Visser TJ, Peeters RP. Maternal total T4 during the first half of pregnancy: physiologic aspects and the risk of adverse outcomes in comparison with free T4. Clin Endocrinol (Oxf) 2016; 85:757-763. [PMID: 27187054 DOI: 10.1111/cen.13106] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2016] [Revised: 05/10/2016] [Accepted: 05/12/2016] [Indexed: 11/27/2022]
Abstract
AIM We aimed to investigate TT4 physiological aspects and associations with clinical end-points. BACKGROUND Total T4 (TT4) has been suggested as a marker for maternal thyroid function during pregnancy because as compared to FT4 (i) TT4 measurement is not affected by binding protein interference, (ii) TT4 is considered to be more stable from the second trimester onwards, and (iii) TT4 better reflects changes in the hypothalamic-pituitary-thyroid axis. However, this is based on data from small studies, and, more importantly, it is unknown whether TT4 is associated with adverse pregnancy or child outcomes. METHODS We selected 5647 mother-child pairs from a large population-based prospective cohort with data on maternal TSH, FT4 and TT4 during early pregnancy (median 13·2 weeks, 95% range 9·8-17·6). We used multivariable (non)linear and logistic regression models to study the association of maternal TT4 with pre-eclampsia, premature delivery, birthweight and offspring IQ and compare the results with previously obtained results for FT4. RESULTS The change of mean TT4 levels was 27·5% compared to 20·2% for FT4. There was a log-linear association of TT4 and FT4 with TSH, but the explained variability of TSH was much lower for TT4 than for FT4 (R-squared TT4: 2·5% vs 8·0% for FT4). In contrast to FT4, there was no independent association of maternal TT4 with pre-eclampsia, premature delivery, birthweight or offspring IQ. CONCLUSION Maternal TT4 levels are highly variable in the first half of pregnancy and are poorly related to maternal TSH. This study shows that maternal TT4 levels are either not associated, or not better associated as compared to FT4, with adverse pregnancy or child outcomes. This suggests that the maternal TT4 is inferior to FT4 in the assessment of maternal thyroid function during the first half of pregnancy.
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Affiliation(s)
- Tim I M Korevaar
- The Generation R Study Group, Rotterdam, The Netherlands.
- Department of Internal Medicine, Erasmus University Medical Center and/or Sophia Children's Hospital, Rotterdam, The Netherlands.
- Rotterdam Thyroid Center, Erasmus Medical Center, Rotterdam, The Netherlands.
| | - Layal Chaker
- Department of Internal Medicine, Erasmus University Medical Center and/or Sophia Children's Hospital, Rotterdam, The Netherlands
- Rotterdam Thyroid Center, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Marco Medici
- The Generation R Study Group, Rotterdam, The Netherlands
- Department of Internal Medicine, Erasmus University Medical Center and/or Sophia Children's Hospital, Rotterdam, The Netherlands
- Rotterdam Thyroid Center, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Yolanda B de Rijke
- Department of Internal Medicine, Erasmus University Medical Center and/or Sophia Children's Hospital, Rotterdam, The Netherlands
- Department of Clinical Chemistry, Erasmus University Medical Center and/or Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Vincent W V Jaddoe
- The Generation R Study Group, Rotterdam, The Netherlands
- Department of Pediatrics, Erasmus University Medical Center and/or Sophia Children's Hospital, Rotterdam, The Netherlands
- Department of Epidemiology, Erasmus University Medical Center and/or Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Eric A P Steegers
- Department of Obstetrics and Gynaecology, Erasmus University Medical Center and/or Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Henning Tiemeier
- Department of Epidemiology, Erasmus University Medical Center and/or Sophia Children's Hospital, Rotterdam, The Netherlands
- Department of Child and Adolescent Psychiatry, Erasmus University Medical Center and/or Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Theo J Visser
- Department of Internal Medicine, Erasmus University Medical Center and/or Sophia Children's Hospital, Rotterdam, The Netherlands
- Rotterdam Thyroid Center, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Robin P Peeters
- The Generation R Study Group, Rotterdam, The Netherlands
- Department of Internal Medicine, Erasmus University Medical Center and/or Sophia Children's Hospital, Rotterdam, The Netherlands
- Rotterdam Thyroid Center, Erasmus Medical Center, Rotterdam, The Netherlands
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Soheilipour F, Fazilaty H, Jesmi F, Gahl WA, Behnam B. First report of inherited thyroxine-binding globulin deficiency in Iran caused by a known de novo mutation in SERPINA7. Mol Genet Metab Rep 2016; 8:13-6. [PMID: 27331012 PMCID: PMC4909823 DOI: 10.1016/j.ymgmr.2016.06.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2016] [Revised: 06/06/2016] [Accepted: 06/06/2016] [Indexed: 02/08/2023] Open
Abstract
Background Thyroxine-binding globulin (TBG) is the main transporter of thyroid hormones in human serum, encoded by the gene TBG (SERPINA7), located in long arm of X-chromosome (Xq21-q22). Deficiency of SERPINA7 (serum protease inhibitor, clade A [alpha-1 antiproteinase, antitrypsin], member 7) leads to inherited TBG deficiency. Several mutations have been reported in the coding and noncoding regions of SERPINA7 in association with TGB deficiency. Methods Automated chemiluminescence immunoassays were used to determine TSH, free and total T4 and T3 (fT4, TT4, TT3) and TBG. Direct DNA sequencing identified the mutation in SERPINA7. Results We present a 3 and 4/12 year old boy, born premature, who was mismanaged as hypothyroidism before referral to our center, and was diagnosed with TBG deficiency at our center with a hemizygous substitution in exon 1, position c.347T > A, leading to replacement of isoleucine for arginine in position 96 (considering the first 20 amino acid signal peptide). Conclusion This known mutation, reported as the first SERPINA7 mutation in Iran, emphasizes the point that endocrinologists should pay more attention to inherited TBG to prevent unnecessary treatment.
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Affiliation(s)
- Fahimeh Soheilipour
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, Tehran, Iran
| | - Hassan Fazilaty
- Department of Medical Genetics and Molecular Biology, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Fatemeh Jesmi
- Minimally Invasive Surgery Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - William A Gahl
- NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, MD, USA; Office of the Clinical Director, NHGRI, National Institutes of Health, Bethesda, MD, USA
| | - Babak Behnam
- Department of Medical Genetics and Molecular Biology, Iran University of Medical Sciences (IUMS), Tehran, Iran; NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, MD, USA; Office of the Clinical Director, NHGRI, National Institutes of Health, Bethesda, MD, USA
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9
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Moeller LC, Appiagyei-Dankah Y, Köhler B, Biebermann H, Janssen OE, Führer D. Two Novel Mutations in the Serpina7 Gene Are Associated with Complete Deficiency of Thyroxine-Binding Globulin. Eur Thyroid J 2015; 4:108-12. [PMID: 26601081 PMCID: PMC4640287 DOI: 10.1159/000381093] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2014] [Revised: 02/17/2015] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Thyroxine-binding globulin (TBG) is the main transport protein for T4 in blood. Until now, 22 mutations leading to complete TBG deficiency (TBG-CD) have been reported. OBJECTIVE We report two mutations associated with TBG-CD found in patients from Andrews, S.C., USA (TBG-CD-Andrews), and Berlin, Germany (TBG-CD-Berlin). METHODS Automated chemiluminescence immunoassays were used for the determination of TSH, free and total T4 and T3 (fT4, TT4, TT3) and TBG. Direct DNA sequencing was used to identify the TBG mutations in the propositi. RESULTS TBG-CD-Andrews was found in a 1-month-old boy who was euthyroid with normal TSH and fT4, but reduced TT4, indicating TBG deficiency. TBG was not detectable, confirming TBG-CD. No mutation in the coding region and the promoter of the TBG gene was found, but a single nucleotide substitution in intron 1 disrupts the donor splice site of exon 0 (IVS1+2T>C). Another mutation was found in an 11-year-old boy. He was also euthyroid with normal fT4 and TSH. However, TT4 and TT3 were low, suggesting TBG-CD. Sequencing revealed a 79-nucleotide deletion, ranging from intron 3 into exon 3. CONCLUSION We report two novel mutations of the TBG gene associated with TBG-CD. Whereas most TBG-CDs are caused by small deletions, in TBG-CD-Andrews the disruption of a donor splice site was detected, whilst in TBG-CD-Berlin the largest deletion in the Serpina7 gene to date was found.
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Affiliation(s)
- Lars C. Moeller
- Department of Endocrinology and Metabolism, University of Duisburg-Essen, Essen, Germany
- *PD Dr. med. Lars Moeller, Department of Endocrinology and Metabolism, University of Duisburg-Essen, Hufelandstrasse 55, DE-45147 Essen (Germany), E-Mail
| | | | - Birgit Köhler
- Institut für Experimentelle Pädiatrische Endokrinologie, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Heike Biebermann
- Institut für Experimentelle Pädiatrische Endokrinologie, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Onno E. Janssen
- Department of Endocrinology and Metabolism, University of Duisburg-Essen, Essen, Germany
| | - Dagmar Führer
- Department of Endocrinology and Metabolism, University of Duisburg-Essen, Essen, Germany
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Abstract
Rare diseases are usually defined as entities affecting less than 1 person per 2,000. About 7,000 different rare entities are distinguished and, among them, rare diseases of the thyroid gland. Although not frequent, they can be found in the everyday practice of endocrinologists and should be considered in differential diagnosis. Rare non-neoplastic thyroid diseases will be discussed. Congenital hypothyroidism's frequency is relatively high and its early treatment is of vital importance for neonatal psychomotor development; CH is caused primarily by thyroid dysgenesis (85%) or dyshormonogenesis (10-15%), although secondary defects - hypothalamic and pituitary - can also be found; up to 40% of cases diagnosed on neonatal screening are transient. Inherited abnormalities of thyroid hormone binding proteins (TBG, TBP and albumin) include alterations in their concentration or affinity for iodothyronines, this leads to laboratory test abnormalities, although usually with normal free hormones and clinical euthyroidism. Thyroid hormone resistance is most commonly found in THRB gene mutations and more rarely in THRA mutations; in some cases both genes are unchanged (non-TR RTH). Recently the term 'reduced sensitivity to thyroid hormones' was introduced, which encompass not only iodothyronine receptor defects but also their defective transmembrane transport or metabolism. Rare causes of hyperthyroidism are: activating mutations in TSHR or GNAS genes, pituitary adenomas, differentiated thyroid cancer or gestational trophoblastic disease; congenital hyperthyroidism cases are also seen, although less frequently than CH. Like other organs and tissues, the thyroid can be affected by different inflammatory and infectious processes, including tuberculosis and sarcoidosis. In most of the rare thyroid diseases genetic factors play a key role, many of them can be classified as monogenic disorders. Although there are still some limitations, progress has been made in our understanding of rare thyroid diseases etiopathogenesis, and, thanks to these studies, also in our understanding of how normal thyroid gland functions.
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Affiliation(s)
- Katarzyna Lacka
- Department of Endocrinology, Metabolism and Internal Medicine, University of Medical Sciences, Poznan, Poland
| | - Adam Maciejewski
- Department of Endocrinology, Metabolism and Internal Medicine, University of Medical Sciences, Poznan, Poland
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11
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Powe CE, Evans MK, Wenger J, Zonderman AB, Berg AH, Nalls M, Tamez H, Zhang D, Bhan I, Karumanchi SA, Powe NR, Thadhani R. Vitamin D-binding protein and vitamin D status of black Americans and white Americans. N Engl J Med 2013; 369:1991-2000. [PMID: 24256378 PMCID: PMC4030388 DOI: 10.1056/nejmoa1306357] [Citation(s) in RCA: 796] [Impact Index Per Article: 66.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Low levels of total 25-hydroxyvitamin D are common among black Americans. Vitamin D-binding protein has not been considered in the assessment of vitamin D deficiency. METHODS In the Healthy Aging in Neighborhoods of Diversity across the Life Span cohort of blacks and whites (2085 participants), we measured levels of total 25-hydroxyvitamin D, vitamin D-binding protein, and parathyroid hormone as well as bone mineral density (BMD). We genotyped study participants for two common polymorphisms in the vitamin D-binding protein gene (rs7041 and rs4588). We estimated levels of bioavailable 25-hydroxyvitamin D in homozygous participants. RESULTS Mean (±SE) levels of both total 25-hydroxyvitamin D and vitamin D-binding protein were lower in blacks than in whites (total 25-hydroxyvitamin D, 15.6±0.2 ng per milliliter vs. 25.8±0.4 ng per milliliter, P<0.001; vitamin D-binding protein, 168±3 μg per milliliter vs. 337±5 μg per milliliter, P<0.001). Genetic polymorphisms independently appeared to explain 79.4% and 9.9% of the variation in levels of vitamin D-binding protein and total 25-hydroxyvitamin D, respectively. BMD was higher in blacks than in whites (1.05±0.01 g per square centimeter vs. 0.94±0.01 g per square centimeter, P<0.001). Levels of parathyroid hormone increased with decreasing levels of total or bioavailable 25-hydroxyvitamin D (P<0.001 for both relationships), yet within each quintile of parathyroid hormone concentration, blacks had significantly lower levels of total 25-hydroxyvitamin D than whites. Among homozygous participants, blacks and whites had similar levels of bioavailable 25-hydroxyvitamin D overall (2.9±0.1 ng per milliliter and 3.1±0.1 ng per milliliter, respectively; P=0.71) and within quintiles of parathyroid hormone concentration. CONCLUSIONS Community-dwelling black Americans, as compared with whites, had low levels of total 25-hydroxyvitamin D and vitamin D-binding protein, resulting in similar concentrations of estimated bioavailable 25-hydroxyvitamin D. Racial differences in the prevalence of common genetic polymorphisms provide a likely explanation for this observation. (Funded by the National Institute on Aging and others.).
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Affiliation(s)
- Camille E Powe
- From the Department of Medicine, Brigham and Women's Hospital (C.E.P.), Division of Nephrology, Massachusetts General Hospital (J.W., H.T., I.B., R.T.), Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School (A.H.B.), Division of Nephrology, Beth Israel Deaconess Medical Center (D.Z., S.A.K.), and Howard Hughes Medical Institute (D.Z., S.A.K.) - all in Boston; the Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore (M.K.E., A.B.Z.); the Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD (M.N.); and the Department of Medicine, San Francisco General Hospital and University of California, San Francisco, San Francisco (N.R.P.)
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12
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Lacka K, Nizankowska T, Ogrodowicz A, Lacki JK. A novel mutation (del 1711 G) in the TBG gene as a cause of complete TBG deficiency. Thyroid 2007; 17:1143-6. [PMID: 17887925 DOI: 10.1089/thy.2007.0023] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
OBJECTIVE Inherited thyroxine-binding globulin (TBG) deficiency is caused by mutations in the TBG gene (locus: Xq22.2), which result in defective synthesis or changes in the physical properties or biological function of a protein. DESIGN We report a novel mutation of the TBG gene causing a complete TBG deficiency in three brothers of Polish origin. DNA was extracted from all of the family members and subjected to sequence analysis. We analyzed the family with a heterozygous mother, a normal father, their three hemizygous affected sons, and their two normal sons. MAIN OUTCOME Our studies revealed a novel mutation, a single nucleotide deletion (guanine) at position 1711, codon 201 (Asp) in exon 2 (GAC --> AC). This mutation led to a frame shift and premature termination at codon 206, causing a short TBG protein of 205 amino acids (AA) compared to 395 AA of the normal TBG. This new TBG-CD variant was found in the mother and her three affected sons. CONCLUSION This is a new variant of TBG-CD (TBG-CD-PL Poland) containing 205 AA.
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Affiliation(s)
- Katarzyna Lacka
- Department of Endocrinology, University of Medical Sciences, Przybyszewski Str. 49, Poznan, Poland.
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13
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Mannavola D, Vannucchi G, Fugazzola L, Cirello V, Campi I, Radetti G, Persani L, Refetoff S, Beck-Peccoz P. TBG deficiency: description of two novel mutations associated with complete TBG deficiency and review of the literature. J Mol Med (Berl) 2006; 84:864-71. [PMID: 16947003 DOI: 10.1007/s00109-006-0078-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2005] [Accepted: 05/02/2006] [Indexed: 12/23/2022]
Abstract
Thyroxine-binding globulin (TBG) is the main thyroid hormone transport protein in serum. Inherited TBG defects lead to a complete (TBG-CD) or a partial (TBG-PD) deficiency and have a diagenic transmission, being clinically fully expressed only in hemizygous males and in homozygous females. In the present study, seven patients from two unrelated families with TBG-CD were studied and two novel TBG mutations were documented. In particular, a T insertion at the 5' donor splice site of exon 0, between nucleotides 2 and 3 at the beginning of intron 1 (g.IVS1+2_3insT) was found in one family and was named TBG-Milano. The other novel mutation is a T deletion at nucleotide 214 of exon 1, which leads to a frameshift at codon 50 with a premature stop codon at position 51 (c.214delT, P50fsX51) and was named TBG-Nikita. According to the X-linked transmission of the defect, females harboring the mutation showed a reduction in TBG levels with normal TSH and total thyroid hormone values at the lower limit of normal. Males harboring either TBG-Milano or TBG-Nikita, showed normal TSH values and low levels of total thyroid hormones and lacked TBG. In conclusion, we report two novel mutations of the TBG gene associated with a complete TBG defect. The first mutation lies at the 5' donor splice site of exon 0 and probably alters the start of translation, while the second is a single nucleotide deletion and leads to a premature stop codon.
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Affiliation(s)
- Deborah Mannavola
- Institute of Endocrine Sciences, University of Milan, Pad. Granelli Via F. Sforza, 35, Milan, 20122, Italy
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14
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Moeller LC, Fingerhut A, Lahner H, Grasberger H, Weimer B, Happ J, Mann K, Janssen OE. C-terminal amino acid alteration rather than late termination causes complete deficiency of thyroxine-binding globulin CD-NeuIsenburg. J Clin Endocrinol Metab 2006; 91:3215-8. [PMID: 16735497 DOI: 10.1210/jc.2005-2261] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
CONTEXT T(4)-binding globulin (TBG) is the main transport protein for T(4) in blood and a member of the superfamily of serine proteinase inhibitors. So far, 14 mutations leading to familial complete TBG deficiency have been reported. Eleven of these are caused by mutations leading to truncation of the molecule, and three are caused by single amino acid substitutions. OBJECTIVE We report and study the complete deficiency TBG variant found in a patient from NeuIsenburg, Germany (TBG-CDNI). METHODS Direct DNA sequencing was used to identify the TBG-CDNI mutation in the propositus, which was confirmed by allele-specific amplification. Site-directed mutagenesis and expression in Xenopus oocytes was used to study the secretion defect of TBG-CDNI and several variants by Western blot and T(4)-binding assay. RESULTS The deletion of two nucleotides in codon 384 (1211_1212delTC) causes a frameshift altering the last 11 residues, introduces a new glycosylation site, and elongates the molecule by seven new amino acids. In contrast to normal TBG, TBG-CDNI was not secreted by Xenopus oocytes. Elongation of normal TBG by seven alanines did not affect its secretion or binding properties. On the other hand, neither disruption of its new glycosylation site nor termination of TBG-CDNI at the normal length repaired its secretion defect. CONCLUSIONS In this first late termination variant of complete TBG deficiency, alteration of beta-strand 5B, located in the core of the molecule, rather than elongation of the molecule or introduction of a new glycosylation site, suffices to disrupt secretion of TBG-CDNI.
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Affiliation(s)
- Lars C Moeller
- Division of Endocrinology, Department of Medicine, University Hospital of Essen Medical School, Hufelandstrasse 55, 45122 Essen, Germany
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15
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Yue P, Moult J. Identification and analysis of deleterious human SNPs. J Mol Biol 2005; 356:1263-74. [PMID: 16412461 DOI: 10.1016/j.jmb.2005.12.025] [Citation(s) in RCA: 204] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2005] [Revised: 12/04/2005] [Accepted: 12/08/2005] [Indexed: 11/23/2022]
Abstract
We have developed two methods of identifying which non-synonomous single base changes have a deleterious effect on protein function in vivo. One method, described elsewhere, analyzes the effect of the resulting amino acid change on protein stability, utilizing structural information. The other method, introduced here, makes use of the conservation and type of residues observed at a base change position within a protein family. A machine learning technique, the support vector machine, is trained on single amino acid changes that cause monogenic disease, with a control set of amino acid changes fixed between species. Both methods are used to identify deleterious single nucleotide polymorphisms (SNPs) in the human population. After carefully controlling for errors, we find that approximately one quarter of known non-synonymous SNPs are deleterious by these criteria, providing a set of possible contributors to human complex disease traits.
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Affiliation(s)
- Peng Yue
- Center for Advanced Research in Biotechnology, University of Maryland Biotechnology Institute, Rockville MD 20850, USA
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16
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Abstract
To date, various genetic defects impairing the biosynthesis of thyroid hormone have been identified. These congenital heterogeneous disorders result from mutations of genes involved in many steps of thyroid hormone synthesis, storage, secretion, delivery, or utilization. In contrast to thyroid dyshormonogenesis, the elucidation of the underlying etiology of most cases of thyroid dysgenesis is much less understood. It is suggested that genetic factors might play a role in some cases of thyroid dysgenesis and the best candidate genes involved are those encoding transcription factors known to play a role in the embryonic development of the thyroid gland. Moreover, discordance for thyroid dysgenesis is the rule for monozygotic twins as recently reported and this may result from epigenetic phenomena, early somatic mutations, or postzygotic events. In the final part of this review the molecular defects involved in proteins that transport thyroid hormone in the circulation are described: thyroxine-binding globulin (TBG), transtiretin and albumin, that may be associated with altered thyroid function tests and other pathologic conditions such as amyloidotic polyneuropathy.
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Affiliation(s)
- Meyer Knobel
- Thyroid Unit, Division of Endocrinology, University of Sao Paulo Medical School, Sao Paulo, Brazil
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17
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Su CC, Wu YC, Chiu CY, Won JGS, Jap TS. Two novel mutations in the gene encoding thyroxine-binding globulin (TBG) as a cause of complete TBG deficiency in Taiwan. Clin Endocrinol (Oxf) 2003; 58:409-14. [PMID: 12641622 DOI: 10.1046/j.1365-2265.2003.01730.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
OBJECTIVE Thyroxine-binding globulin (TBG) encoded by the TBG gene on chromosome Xq22 is the major transport protein, carrying approximately 75% of circulating T4. Inherited defects in TBG are associated with three phenotypes based on the level of TBG in serum of affected hemizygous males: complete TBG deficiency (TBG-CD), partial TBG deficiency (TBG-PD) and TBG excess (TBG-E). In this study, we report two unrelated Han Chinese males with complete TBG deficiency who carry different mutations in the TBG gene. PATIENTS Two index cases of Han males who were diagnosed as having TBG deficiency on the basis of undetectable serum TBG and an additional 75 (50 males and 25 females) normal Han Chinese. MEASUREMENT Serum thyroid hormones were measured by chemiluminescent immunoassay, thyroid autoantibodies by an agglutination test, and TSH receptor antibody and TBG by radioimmunoassay. Genomic DNA extraction, polymerase chain reaction (PCR) and DNA sequence analysis of the TBG gene were performed with standard methods. RESULTS One index case had one missense mutation in his copy of the gene, a G --> A transition in codon 52 that results in the replacement of serine by asparagine, and a known polymorphism in codon 283 (TTG --> TTt) that results in the replacement of leucine by phenylalanine. The allelic frequency of TBG-Poly allele in 75 normal Han Chinese (100 chromosomes) was 31%. A second index case was hemizygous for a nonsense mutation in codon 280 of exon 3 (TGG --> TGa). This mutation, located in the C-terminal of TBG, predicts a markedly truncated protein. CONCLUSIONS This is the first report of complete thyroxine-binding globulin deficiency (TBG-CDT1 and TBG-CDT2) due to TBG gene mutations in Taiwan.
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Affiliation(s)
- Ching-Chieh Su
- Division of Endocrinology and Metabolism, Department of Medicine, Veterans General Hospital, Taipei, Taiwan, ROC
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18
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Abstract
Choroid plexus has the highest concentration of transthyretin (TTR) mRNA in the body, 4.4 microg TTR mRNA/g wet weight tissue, compared with 0.39 microg in the liver. The proportion of TTR to total protein synthesis in choroid plexus is 12%. All newly synthesized TTR is secreted towards the ventricles. Net transfer of T4 occurs only towards the ventricle and depends on ongoing protein synthesis. Thyroxine-binding globulin (TBG), TTR and albumin form a "buffering" system for plasma [T4] because of their overlapping affinities and on/off rates for L-thyroxine (T4)-binding. The individual components of this network determining T4 distribution are functionally highly redundant. Absence of TBG (humans), or TTR (mice), or albumin (humans, rats) is not associated with hypothyroidism. Natural selection is based on small, inheritable alterations improving function. The study of these alterations can identify function. TTR genes were cloned and sequenced for a large number of vertebrate species. Systematic, stepwise changes during evolution occurred only in the N-terminal region, which became shorter and more hydrophilic. Simultaneously, a change in function occurred: TTR affinities for T4 are higher in mammals than in reptiles and birds. L-triiodothyronine (T3) affinities show the opposite trend. This favors site-specific regulation of thyroid hormones by tissue-specific deiodinases in the brain.
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Affiliation(s)
- Gerhard Schreiber
- Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia.
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Prapunpoj P, Richardson SJ, Schreiber G. Crocodile transthyretin: structure, function, and evolution. Am J Physiol Regul Integr Comp Physiol 2002; 283:R885-96. [PMID: 12228058 DOI: 10.1152/ajpregu.00042.2002] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Structure and function were studied for Crocodylus porosus transthyretin (crocTTR), an important intermediate in TTR evolution. The cDNA for crocTTR mRNA was cloned and sequenced and the amino acid sequence of crocTTR was deduced. In contrast to mammalian TTRs, but similar to avian and lizard TTRs, the subunit of crocTTR had a long and hydrophobic NH(2)-terminal region. Different from the situation in mammals, triiodothyronine (T(3)) was bound by crocTTR with higher affinity than thyroxine (T(4)). Recombinant crocTTR and a chimeric construct, with the NH(2)-terminal region of crocTTR being replaced by that of Xenopus laevis TTR, were synthesized in the yeast Pichia pastoris. Analysis of the affinity of the chimeric TTRs showed that the NH(2)-terminal region modulates T(4) and T(3) binding characteristics of TTR. The structural differences of the NH(2)-terminal regions of reptilian and amphibian TTRs were caused by a shift in splice sites at the 5' end of exon 2. The comparison of crocodile and other vertebrate TTRs shows that TTR evolution is an example for positive Darwinian evolution and identifies its molecular mechanism.
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Affiliation(s)
- Porntip Prapunpoj
- Department of Biochemistry, Faculty of Science, Prince of Songkla University, Hat-Yai, Songkhla 90112, Thailand.
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Miura Y, Hershkovitz E, Inagaki A, Parvari R, Oiso Y, Phillip M. A novel mutation causing complete thyroxine-binding globulin deficiency (TBG-CD-Negev) among the Bedouins in southern Israel. J Clin Endocrinol Metab 2000; 85:3687-9. [PMID: 11061524 DOI: 10.1210/jcem.85.10.6899] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
T4-binding globulin (TBG) is the major thyroid hormone transport protein in human serum. Inherited TBG abnormalities do not usually alter the metabolic status and are transmitted in X-linked inheritance. A high prevalence of complete TBG deficiency (TBG-CD) has been reported among the Bedouin population in the Negev (southern Israel). In this study we report a novel single mutation causing complete TBG deficiency due to a deletion of the last base of codon 38 (exon 1), which led to a frame shift resulting in a premature stop at codon 51 and a presumed truncated peptide of 50 residues. This new variant of TBG (TBG-CD-Negev) was found among all of the patients studied. We conclude that a single mutation may account for TBG deficiency among the Bedouins in the Negev. This report is the first to describe a mutation in a population with an unusually high prevalence of TBG-CD.
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Affiliation(s)
- Y Miura
- First Department of Internal Medicine, Nagoya University School of Medicine, Japan
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21
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Carvalho GA, Weiss RE, Refetoff S. Complete thyroxine-binding globulin (TBG) deficiency produced by a mutation in acceptor splice site causing frameshift and early termination of translation (TBG-Kankakee). J Clin Endocrinol Metab 1998; 83:3604-8. [PMID: 9768672 DOI: 10.1210/jcem.83.10.5208] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Fourteen T4-binding globulin (TBG) variants have been identified at the gene level. They are all located in the coding region of the gene and 6 produce complete deficiency of TBG (TBG-CD). We now describe the first mutation in a noncoding region producing TBG-CD. The proband was treated for over 20 yr with L-T4 because of fatigue associated with a low concentration of serum total T4. Fifteen family members were studied showing low total T4 inherited as an X chromosome-linked trait, and affected males had undetectable TBG in serum. Sequencing of the entire coding region and promoter of the TBG gene revealed no abnormality. However, an A to G transition was found in the acceptor splice junction of intron II that produced a new HaeIII restriction site cosegregating with the TBG-CD phenotype. Sequencing exon 1 to exon 3 of TBG complementary DNA reverse transcribed from messenger RNA of skin fibroblasts from an affected male, confirmed a shift in the ag acceptor splice site. This results in the insertion of a G in exon 2 and causes a frameshift and a premature stop at codon 195. This early termination of translation predicts a truncated TBG lacking 201 amino acids.
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Affiliation(s)
- G A Carvalho
- Department of Medicine, The University of Chicago, Illinois 60637, USA
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22
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Carvalho GA, Weiss RE, Vladutiu AO, Refetoff S. Complete deficiency of thyroxine-binding globulin (TBG-CD Buffalo) caused by a new nonsense mutation in the thyroxine-binding globulin gene. Thyroid 1998; 8:161-5. [PMID: 9510125 DOI: 10.1089/thy.1998.8.161] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Complete deficiency of thyroxine-binding globulin (TBG-CD) is defined as undetectable TBG in the serum of affected hemizygous subjects. Four distinct mutations have been identified in the TBG gene that cause this phenotype: TBG-CDJ (Japan), TBG-CD6, TBG-CD5, and TBG-CD Yonago. We report a new mutation producing TBG-CD phenotype. Five family members were studied, including two affected males with undetectable TBG in serum and two obligatory heterozygote females with borderline low values. Sequencing of the exons encoding the mature protein, adjacent introns and the promoter region, revealed differences in two nucleotides compared to the common type TBG, both located in exon 3: TGG (Trp) TAG (Stop) at codon 280 and TTG (Leu) TTT (Phe) at codon 283. The former mutation was not previously described and the latter is a polymorphic variant. Genotyping revealed that the two affected males had the mutant and polymorphic allele and their obligatory heterozygous mothers have each a common type and a mutant allele associated with the polymorphic variant. The mutant TBG Trp280Stop causes premature termination of translation that results in the production of a truncated protein that lacks 116 carboxyl terminal amino acids. The latter is believed to be responsible for the TBG-CD either because the aberrant protein is not secreted or because of reduced abundance of its mRNA.
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Affiliation(s)
- G A Carvalho
- Department of Medicine, The University of Chicago, Illinois 60637, USA
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Langsteger W. Clinical aspects and diagnosis of thyroid hormone transport protein anomalies. CURRENT TOPICS IN PATHOLOGY. ERGEBNISSE DER PATHOLOGIE 1997; 91:129-61. [PMID: 9018920 DOI: 10.1007/978-3-642-60531-4_10] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Affiliation(s)
- W Langsteger
- Department of Internal Medicine, Hospital Barmherzige Brüder, Graz, Austria
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Janssen OE, Chen B, Büttner C, Refetoff S, Scriba PC. Molecular and structural characterization of the heat-resistant thyroxine-binding globulin-Chicago. J Biol Chem 1995; 270:28234-8. [PMID: 7499319 DOI: 10.1074/jbc.270.47.28234] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Thyroxine-binding globulin (TBG) is the main transport protein for thyroxine (T4) in blood. It shares considerable sequence homology with alpha 1-antitrypsin (AT) and other members of the serine proteinase inhibitor (serpin) superfamily of proteins. The crystallographic structure of AT has been determined and was found to represent the archetype of the serpins. This model has been used for structure-function correlations of TBG. Sequence analysis of the heat-resistant variant TBG-Chicago (TBG-CH) revealed a substitution of the normal tyrosine 309 with phenylalanine. For further analysis, vectors containing the coding regions of normal TBG (TBG-N) and TBG-CH were constructed, transcribed in vitro, and expressed in Xenopus oocytes. Both TBGs were secreted into the culture medium and could not be distinguished by gel electrophoresis. Scatchard analysis of T4 binding to TBG-N and -CH revealed no significant differences in binding affinity. The rate of heat denaturation of TBGs was determined by measurement of residual T4 binding capacity after incubation at 60 degrees C for various periods of time. The half-life values of denaturation of TBG-N and -CH were 7 and 132 min, respectively. The tyrosine 309 to phenylalanine substitution of TBG-CH involves a highly conserved phenylalanine residue of the serpins. The respective phenylalanine 312 of AT ties the alpha-helix hI1 to the molecule, thus stabilizing the tertiary structure. A substitution with tyrosine would disrupt this interaction. Accordingly, stabilization of the TBG molecule by replacement of tyrosine with phenylalanine in position 309 causes the increased heat stability of TBG-CH.
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Affiliation(s)
- O E Janssen
- Department of Medicine, Klinikum Innenstadt, Ludwig-Maximilians-University, Munich, Federal Republic of Germany
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Mori Y, Miura Y, Oiso Y, Hisao S, Takazumi K. Precise localization of the human thyroxine-binding globulin gene to chromosome Xq22.2 by fluorescence in situ hybridization. Hum Genet 1995; 96:481-2. [PMID: 7557975 DOI: 10.1007/bf00191811] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
The human thyroxine-binding globulin (TBG) gene has been localized to X chromosome (Xq22.2) by in situ hybridization using a biotinylated gDNA probe. This is consistent with previous mapping of the TBG gene to chromosome Xq21-q22.
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Affiliation(s)
- Y Mori
- 4th Dpt. of Internal Medicine, Aichi Medical University, Japan
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Takeda K, Iyota K, Mori Y, Tamura Y, Suehiro T, Kubo Y, Refetoff S, Hashimoto K. Gene screening in Japanese families with complete deficiency of thyroxine-binding globulin demonstrates that a nucleotide deletion at codon 352 may be a race specific mutation. Clin Endocrinol (Oxf) 1994; 40:221-6. [PMID: 8137521 DOI: 10.1111/j.1365-2265.1994.tb02472.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
OBJECTIVE Thyroxine-binding globulin (TBG) is a serum protein that transports 75% of circulating thyroxine. Eleven naturally occurring mutations in the human TBG gene have been identified, ten of which alter the properties of the molecule. Three of these mutations produce complete deficiency of TBG (TBG-CD) and four are associated with a second mutation in codon 283 (TBG-poly) which is polymorphic in some ethnic groups but, when present alone, does not alter the properties of the TBG molecule. In this communication we investigate whether two unrelated Japanese families with TBG-CD harboured the TBG-CDJ mutation in codon 352 associated with TBG-CD in families residing in more distant locations of the Japanese Islands. In addition we examined the possible association with TBG-poly and its incidence in the Japanese population. DESIGN Mutant alleles were identified by amplification of genomic DNAs by the polymerase chain reaction, using allele-specific oligonucleotide primers. PATIENTS Eight family members and 25 normal subjects. MEASUREMENTS Serum free thyroxine and TBG concentration were measured by a conventional radioimmunoassay and a more sensitive enzyme immunoassay. Genomic DNAs were extracted from white blood cells and specific mutations at codons 352 and 283 were identified by allele-specific amplification. RESULTS Three males and three females, whose serum TBG levels were decreased, had mutations at codon 352 as hemizygous and heterozygous, respectively. This mutation was not present in the DNA of any of the related or unrelated subjects with normal TBG concentration. The presence of TBG-poly was demonstrated in only one heterozygous family member and in six out of 30 alleles (20%) in normal unrelated subjects. The frequency of this TBG polymorphism in the Japanese is similar to that of 16% reported in French Canadians. CONCLUSIONS We conclude that TBG-CDJ might be a prevalent cause of complete deficiency of thyroxine-binding globulin in the Japanese and that TBG-poly probably appeared before the divergence of human races.
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Affiliation(s)
- K Takeda
- 2nd Department of Internal Medicine, Kochi Medical School, Nankoku, Japan
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Affiliation(s)
- L Bartalena
- Istituto di Endocrinologia, Università di Pisa, Italy
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Bertenshaw R, Sarne D, Tornari J, Weinberg M, Refetoff S. Sequencing of the variant thyroxine-binding globulin (TBG)-San Diego reveals two nucleotide substitutions. BIOCHIMICA ET BIOPHYSICA ACTA 1992; 1139:307-10. [PMID: 1515456 DOI: 10.1016/0925-4439(92)90105-v] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Thyroxine-binding globulin (TBG) is a liver glycoprotein that transports thyroid hormone in serum. In 1989, a variant TBG was reported with reduced binding affinity for thyroxine (T4) and triiodothyronine (T3) which results in low serum T4 and T3 levels. This variant, TBG-San Diego (TBG-SD), also displays reduced heat stability but has a normal isoelectric focusing pattern. We now report the sequence of the entire coding region of TBG-San Diego. It reveals two nucleotide substitutions: one located in exon 1 which results in the replacement of the normal Ser-23 (TCA) with threonine (ACA) and the other, located in exon 3, changes the normal codon 283 of TTG (leucine) with that of TTT, (phenylalanine). Allele specific amplification was used to search for both nucleotide substitutions in four affected members of the family. Results confirmed the co-segregation of these nucleotide substitutions with the TBG-SD phenotype. The substitution in codon 283 has been previously described and exists as a polymorphism in some ethnic groups or in combination with other TBG variants with different physical characteristics. Thus, it appears that the replacement of Ser-23 with threonine is responsible for the observed alterations in physical properties of TBG-San Diego.
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Affiliation(s)
- R Bertenshaw
- Department of Medicine, University of Chicago 60637-1470
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29
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In vitro expression of thyroxine-binding globulin (TBG) variants. Impaired secretion of TBGPRO-227 but not TBGPRO-113. J Biol Chem 1992. [DOI: 10.1016/s0021-9258(19)49669-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
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Janssen OE, Bertenshaw R, Takeda K, Weiss R, Refetoff S. Molecular basis of inherited thyroxine-binding globulin defects. Trends Endocrinol Metab 1992; 3:49-53. [PMID: 18407078 DOI: 10.1016/1043-2760(92)90043-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Thyroxine-binding globulin (TBG) is a liver glycoprotein that transports thyroid hormones in serum. Inherited TBG defects appear as partial or complete deficiency and TBG excess. Sequencing of the TBG gene located on the X-chromosome has revealed nucleotide substitutions in partial TBG deficiency, and substitutions or deletions in complete deficiency variants. Whereas the deduced changes of the primary structure of the protein have been sufficient to explain the observed alterations of properties in some of the TBG variants, this has not been the case in other inherited TBG defects studied at the gene level. Further analysis of these and other variants may provide helpful information on glycoprotein synthesis and processing and on protein-hormone interaction.
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Affiliation(s)
- O E Janssen
- Department of Medicine, University of Chicago, Chicago, IL 60637, USA
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31
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Abstract
Variations in major thyroid hormone transport proteins may be inherited or acquired and may be associated with changes in serum concentration of the proteins or their affinity for thyroid hormones. These variations most frequently involve thyroxine-binding globulin (TBG), but changes in transthyretin and albumin are also observed. The consequent alteration of thyroid hormone-binding capacity in serum is associated with variations in total thyroid hormone concentration. Increased serum total thyroid hormone levels are found in subjects with TBG excess, familial dysalbuminemic hyperthyroxinemia, and transthyretin-associated hyperthyroxinemia. Conversely, diminished serum thyroid hormone values are observed in subjects with TBG deficiency, and decreased concentration or affinity of transthyretin and albumin is not associated with variations in serum concentrations of thyroid hormones. The transport protein-associated variations in serum total thyroid hormone concentrations do not reflect a change in thyroid status. Euthyroidism can be easily established in subjects with transport protein abnormalities by the normal free thyroid hormone and TSH concentrations. It is, however, crucial to select methods for free thyroid hormone measurement that are not affected by abnormalities of transport proteins. Some assays, such as the analog method, often provide artifactual and misleading results, which may lead to inappropriate and even detrimental treatments. The evolutionary advantage of TBG (and albumin) in terms of thyroid homeostasis still remains to be elucidated.
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Affiliation(s)
- L Bartalena
- Genetics and Biochemistry Branch, NIDDK, NIH, Bethesda, Maryland
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Li P, Janssen OE, Takeda K, Bertenshaw RH, Refetoff S. Complete thyroxine-binding globulin (TBG) deficiency caused by a single nucleotide deletion in the TBG gene. Metabolism 1991; 40:1231-4. [PMID: 1943753 DOI: 10.1016/0026-0495(91)90221-h] [Citation(s) in RCA: 25] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Thyroxine-binding globulin (TBG) is the major thyroid hormone transport protein. Several inherited TBG variants resulting in partial and complete TBG deficiency have been shown to be caused by one or two nucleotide replacements in the coding regions of the TBG gene. Each manifests as a different change in the physical properties and/or biological function of the mature TBG protein. We now report sequencing of the entire coding region and exon-intron junctions of a TBG allele of a subject with inherited complete TBG deficiency, previously classified as TBG-CD6. A single nucleotide deletion was found in the codon for amino acid 165 of the normal TBG molecule. The shift in the reading frame due to this nucleotide deletion results in downstream encoding of two different amino acids followed by an early stop codon. This results in a mature protein of only 167 residues, as compared with the normal 395. Nine members of the TBG-CD6 family were tested for the presence of this mutation by allele-specific amplification. Seven of them were found to be carriers of the defect, with five hemizygous subjects manifesting complete TBG deficiency. The mutant allele correlated with the results of TBG analysis in serum. This defect was not present in affected subjects of any of seven unrelated families with complete TBG deficiency tested.
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Affiliation(s)
- P Li
- Departments of Medicine and Pediatrics, University of Chicago, IL 60637
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Nørby S, Lestienne P, Nelson I, Rosenberg T. Mutation detection in Leber's hereditary optic neuropathy by PCR with allele-specific priming. Biochem Biophys Res Commun 1991; 175:631-6. [PMID: 2018507 DOI: 10.1016/0006-291x(91)91612-g] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
An assay was designed that allows detection, by PCR alone, of the mutation of base pair no. 11,778 in human mitochondrial DNA, causing Leber's hereditary optic neuropathy. This was obtained by using a 20-mer primer with the mutation-specific base in the 3'-position, plus a deliberately introduced C/C-mismatch at base no. four from the 3'-end. The latter mismatch was necessary, and sufficient, to prevent amplification of the normal allele.
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Affiliation(s)
- S Nørby
- Institute of Forensic Genetics, University of Copenhagen, Denmark
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Waltz MR, Pullman TN, Takeda K, Sobieszczyk P, Refetoff S. Molecular basis for the properties of the thyroxine-binding globulin-slow variant in American blacks. J Endocrinol Invest 1990; 13:343-9. [PMID: 2115061 DOI: 10.1007/bf03349576] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Thyroxine-binding globulin-slow (TBG-S), a variant found in 4-12% of Black and Pacific Island populations, is inherited as an X-chromosome linked trait. This variant is detected on isoelectric focusing by the characteristic cathodal shift of all its isoforms, suggesting that the difference resides in the core protein. In addition, TBG-S is slightly more thermolabile, which explains why subjects expressing TBG-S have on the average lower serum TBG, and thus reduced T4, concentrations. We now report the molecular basis for this TBG variant, deduced from sequencing the TBG-S gene of an American Black man. Sequencing of the four coding regions and all intron/exon junctions revealed a single nucleotide substitution in the codon for amino acid 171 of the mature protein. The resulting change of the codon GAC to AAC results in replacement of the normal aspartic acid by asparagine. Since the negative charge provided by the aspartic acid is lost when replaced by the neutral asparagine, this substitution seems responsible for the cathodal shift on isoelectric focusing and slower electrophoretic mobility of TBG-S. An identical nucleotide substitution was identified in an unrelated American Black man expressing TBG-S. Whether the TBG-S phenotype observed in populations from the Pacific Islands is caused by the same mutation remains to be determined.
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Affiliation(s)
- M R Waltz
- Department of Medicine, University of Chicago, IL 60637
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