A TSHβ Variant with Impaired Immunoreactivity but Intact Biological Activity and Its Clinical Implications
Open accessAbstract
BACKGROUND: Thyrotropin (TSH) deficiency caused by TSHβ gene mutations is a rare form of congenital central hypothyroidism. Nine different TSHβ gene mutations have been reported, all with clinical manifestations. The aim was to identify the genetic cause of undetectable TSH levels in two siblings with clinical euthyroidism. METHODS: Two brothers born to consanguineous Pakistani parents presented with undetectable serum TSH but normal iodothyronine concentrations and no clinical signs of hypothyroidism. Direct sequencing of the TSHβ gene, functional and immunological studies, protein homology modeling, and population frequency analysis were performed to characterize the cause of undetectable TSH in this family. RESULTS: Direct sequencing of the TSHβ gene revealed that the two brothers were homozygous for a single nucleotide substitution (c.223A>G) resulting in the replacement of arginine 55 with glycine (R55G). This variant was found in 12 out of 5008 alleles in the 1000 Genomes project (all South Asian). Serum TSH of the two brothers was undetectable in two of five platforms, both produced by Siemens, whereas TSH levels of the heterozygous brother and mother were half compared to the other three platforms (Roche Elecsys, Abbott Architect, and Beckman Coulter DxI). The falsely low TSH concentration was caused by the monoclonal antibody not recognizing the region containing the variant amino acid. This is supported by the fact that arginine modification--following phenylglyoxal treatment--led to a significant (96%) decrease in the TSH measurement with the Siemens platforms. Predictions based on PolyPhen-2 and in silico modeling revealed no functional impairment of the variant TSH. CONCLUSIONS: A TSHβ variant with impaired immunoreactivity, but not bioactivity, is reported, and its biochemical impact in the homo- and heterozygous state is demonstrated. It is also shown that failure to bind to the monoclonal antibody is a direct consequence of the amino acid substitution.
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TSHβ allelic variants with conserved bioactivity but lost immunoreactivity of circulating TSH can be a confounding condition.
“A peculiar confounding condition may be represented by TSHβ allelic variants with conserved bioactivity but lost immunoreactivity of circulating TSH (44).”
From The diagnosis and management of central hypothyroidism in 2018 (2019) · cites this paper as [44]
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Cites
A hierarchical approach to all‐atom protein loop prediction
Jacobson, M. P., Pincus, D. L., Rapp, C. S., Day, T., Honig, B. H., Shaw, D. E., & Friesner, R. A. (2004) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.10613 · Cited by 2,541 · see citing works
Glycoprotein Hormones: Structure and Function
Pierce, J. G., & Parsons, T. F. (1981) · Annual Review of Biochemistry · doi:10.1146/annurev.bi.50.070181.002341 · Cited by 2,306 · see citing works
On the Role of the Crystal Environment in Determining Protein Side-chain Conformations
Jacobson, M. P., Friesner, R. A., Xiang, Z., & Honig, B. H. (2002) · Journal of Molecular Biology · doi:10.1016/s0022-2836(02)00470-9 · Cited by 1,289 · see citing works
Grossmann, M., Weintraub, B. D., & Szkudlinski, M. W. (1997) · Endocrine Reviews · doi:10.1210/edrv.18.4.0305 · Cited by 155 · see citing works
Hayashizaki, Y., Hiraoka, Y., Endo, Y., Miyai, K., & Matsubara, K. (1989) · The EMBO Journal · doi:10.1002/j.1460-2075.1989.tb08355.x · Cited by 152 · see citing works
A circulating, biologically inactive thyrotropin caused by a mutation in the beta subunit gene.
Medeiros-Neto, G. A., Herodotou, D. T., Rajan, S. S., Kommareddi, S., de Lacerda, L., Sandrini, R., Boguszewski, M. C. D. S., Hollenberg, A. N., Radovick, S., & Wondisford, F. E. (1996) · Journal of Clinical Investigation · doi:10.1172/jci118540 · Cited by 134 · see citing works
Dacou‐Voutetakis, C., Feltquate, D., Drakopoulou, M. I., KOURIDES, I. A., & Dracopoli, N. C. (1990) · PubMed · Cited by 116 · see citing works
Familial Isolated Thyrotropin Deficiency with Cretinism
Miyai, K., Azukizawa, M., & Kumahara, Y. (1971) · New England Journal of Medicine · doi:10.1056/nejm197111042851902 · Cited by 113 · see citing works
HAYASHIZAK, Y., Hiraoka, Y., Tatsumi, K.-I., Hashimoto, T., Furuyama, J.-I., Miyai, K., Nishijo, K., Matsuura, M., Kohno, H., Labbé, A., et al. (1990) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-71-4-792 · Cited by 78 · see citing works
Bonomi, M. (2001) · Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.86.4.1600 · Cited by 71 · see citing works
Doeker, B. M., Pfäffle, R. W., Pohlenz, J., & Andler, W. (1998) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.83.5.4780 · Cited by 56 · see citing works
Congenital Central Isolated Hypothyroidism Caused by a Homozygous Mutation in the TSH-β Subunit Gene
Heinrichs, C., Parma, J., Scherberg, N. H., Delange, F. M., Vliet, G. V., Duprez, L., Bourdoux, P., Bergmann, P., Vassart, G., & Refetoff, S. (2000) · Thyroid · doi:10.1089/thy.2000.10.387 · Cited by 56 · see citing works
Self-citationSevere Congenital Hypothyroidism Due to a Homozygous Mutation of the βTSH Gene
Biebermann, H., Liesenkötter, K., Emeis, M., Obladen, M., & Grüters, A. (1999) · Pediatric Research · doi:10.1203/00006450-199908000-00007 · Cited by 55 · see citing works
Pohlenz, J., Dumitrescu, A. M., Aumann, U., Koch, G., Melchior, R., Prawitt, D., & Refetoff, S. (2002) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.87.1.8154 · Cited by 54 · see citing works
Self-citationBrumm, H., Pfeufer, A., Biebermann, H., Schnabel, D., Deiss, D., & Grüters, A. (2002) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2002-020297 · Cited by 45 · see citing works
Baquedano, M. S., Ciaccio, M., Dujovne, N., Herzovich, V., Longueira, Y., Warman, D. M., Rivarola, M. A., & Belgorosky, A. (2010) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2010-0223 · Cited by 41 · see citing works
Congenital Isolated Central Hypothyroidism Caused by a "Hot Spot" Mutation in the Thyrotropin-β Gene
McDermott, M. T., Haugen, B. R., Black, J. N., Wood, W. M., Gordon, D. F., & Ridgway, E. C. (2002) · Thyroid · doi:10.1089/105072502321085252 · Cited by 35 · see citing works
Domené, H. M., Gruñeiro‐Papendieck, L., Chiesa, A. E., Iorcansky, S., Herzovich, V., Papazian, R., Forclaz, M. V., Prieto, L., Sansó, G., Scaglia, P. A., et al. (2003) · Hormone Research in Paediatrics · doi:10.1159/000075196 · Cited by 33 · see citing works
New Autosomal Recessive Mutation of the TSH-β Subunit Gene Causing Central Isolated Hypothyroidism
Vuissoz, J., Deladoëy, J., Büyükgebiz, A., Cemeroglu, P., Gex, G., Gallati, S., & Mullis, P. E. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.9.7876 · Cited by 33 · see citing works
Partsch, C., Riepe, F. G., Krone, N. P., Sippell, W. G., & Pohlenz, J. (2006) · Experimental and Clinical Endocrinology & Diabetes · doi:10.1055/s-2006-924232 · Cited by 32 · see citing works
Karges, B., LeHeup, B., Schoenle, E., Castro-Correia, C., Fontoura, M., Pfäffle, R., Andler, W., Debatin, K.-M., & Karges, W. (2004) · Hormone Research in Paediatrics · doi:10.1159/000080071 · Cited by 32 · see citing works
Deladoëy, J., Vuissoz, J., Domené, H. M., Malik, N. J., Gruñeiro‐Papendieck, L., Chiesa, A. E., Heinrich, J. J., & Mullis, P. E. (2003) · Thyroid · doi:10.1089/105072503322238818 · Cited by 30 · see citing works
Borck, G., Topaloglu, A. K., Korsch, E., Martiné, U., Wildhardt, G., Mungan, N. Ö., Yüksel, B., Aumann, U., Koch, G., Özer, G., et al. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-0494 · Cited by 30 · see citing works
Self-citationFalsely Undetectable TSH in a Cohort of South Asian Euthyroid Patients
Drees, J. C., Stone, J. A., Reamer, C. R., Arboleda, V. E., Huang, K., Hrynkow, J., Greene, D. N., Petrie, M. S., Hoke, C., Lorey, T. S., et al. (2013) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-2092 · Cited by 27 · see citing works
Ramos, H. E., Labedan, I., Carré, A., Castanet, M., Guemas, I., Tron, E., Madhi, F., Delacourt, C., Maciel, R. M. B., & Polak, M. (2010) · Thyroid · doi:10.1089/thy.2009.0462 · Cited by 27 · see citing works
Sertedaki, A., Papadimitriou, A., Voutetakis, A., Dracopoulou, M., Maniati-Christidi, M., & Dacou‐Voutetakis, C. (2002) · Pediatric Research · doi:10.1203/00006450-200212000-00020 · Cited by 23 · see citing works
Bonomi, M., Proverbio, M. C., Weber, G., Chiumello, G., Beck‐Peccoz, P., & Persani, L. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.4.7411 · Cited by 20 · see citing works
Mori, R., Sawai, T., Kinoshita, E., Baba, T., Matsumoto, T., Yoshimoto, M., Tsuji, Y., Satake, Y., & Sawada, K. B. (1991) · The Japanese Journal of Human Genetics · doi:10.1007/bf01883604 · Cited by 19 · see citing works
Doeker, B. M. (1998) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.83.5.1762 · Cited by 18 · see citing works
Pohlenz, J. (2002) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.87.1.336 · Cited by 16 · see citing works
Novel TSHβ Subunit Gene Mutation Causing Congenital Central Hypothyroidism in a Newborn Male
Morales, A. E., Shi, J. D., Wang, C., She, J., & Muira, A. (2004) · Journal of Pediatric Endocrinology and Metabolism · doi:10.1515/jpem.2004.17.3.355 · Cited by 15 · see citing works
Hypothyroidism in Siblings Due to a Homozygous Mutation of the TSH-β Subunit Gene
Felner, E. I., Dickson, Β. A., & White, P. C. (2004) · Journal of Pediatric Endocrinology and Metabolism · doi:10.1515/jpem.2004.17.4.669 · Cited by 13 · see citing works
Serum Free Thyrotropin subunit in Congenital Isolated Thyrotropin Deficiency.
Miyai, K., Endo, Y., IIJIMA, Y., Kabutomori, O., & Hayashizaki, Y. (1988) · Endocrinologia Japonica · doi:10.1507/endocrj1954.35.517 · Cited by 13 · see citing works
New Autosomal Recessive Mutation of the TSH- Subunit Gene Causing Central Isolated Hypothyroidism
Vuissoz, J.-M. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.86.9.4468 · Cited by 12 · see citing works
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Beck-Peccoz, P., Rodari, G., Giavoli, C., & Lania, A. (2017) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2017.47 · Cited by 140 · see citing works
Recent advances in central congenital hypothyroidism
Schoenmakers, N., Alatzoglou, K. S., Chatterjee, V. K., & Dattani, M. T. (2015) · Journal of Endocrinology · doi:10.1530/joe-15-0341 · Cited by 125 · see citing works
Van Uytfanghe, K., Ehrenkranz, J., Halsall, D., Hoff, K., Loh, T. P., Spencer, C. A., Köhrle, J., & ATA Thyroid Function Tests Writing Group (2023) · Thyroid® · doi:10.1089/thy.2023.0169 · Cited by 100 · see citing works
The diagnosis and management of central hypothyroidism in 2018
Persani, L., Cangiano, B., & Bonomi, M. (2019) · Endocrine Connections · doi:10.1530/ec-18-0515 · Cited by 64 · see citing works
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Persani, L., & Bonomi, M. (2017) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2017.04.003 · Cited by 46 · see citing works
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Tsai, K., & Leung, A. M. (2021) · Endocrine Practice · doi:10.1016/j.eprac.2021.02.002 · Cited by 45 · see citing works
Approach to the Patient With Raised Thyroid Hormones and Nonsuppressed TSH
Moran, C., Schoenmakers, N. A., Halsall, D. J., Oddy, S., Lyons, G., van den Berg, S. A. A., Gurnell, M., & Chatterjee, K. (2023) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgad681 · Cited by 29 · see citing works
Kleinau, G., Kalveram, L., Köhrle, J., Szkudlinski, M. W., Schomburg, L., Biebermann, H., & Grüters‐Kieslich, A. (2016) · Molecular Endocrinology · doi:10.1210/me.2016-1065 · Cited by 12 · see citing works
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Croce, L., Chytiris, S., Coperchini, F., Ferraro, G., Minelli, L., Navarra, A., Magri, F., Chiovato, L., Trimboli, P., & Rotondi, M. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12082934 · Cited by 8 · see citing works
Croce, L., Beneventi, F., Ripepi, F. A., Maggio, I. D., Malovini, A. L., Bellingeri, C., Coperchini, F., Teliti, M., Rotondi, M., Spinillo, A., et al. (2024) · European Thyroid Journal · doi:10.1530/etj-23-0213 · Cited by 5 · see citing works
Ebrhim, R. S., Bruellman, R., Watanabe, Y., Creech, M. K., Abdullah, M. A., Dumitrescu, A. M., Refetoff, S., & Weiss, R. E. (2019) · Hormone Research in Paediatrics · doi:10.1159/000504981 · Cited by 2 · see citing works
Self-citationBorges, M. D. F., Domené, H. M., Scaglia, P. A., Lara, B. H. J., Palhares, H. M. D. C., Santos, A. V. A., Gonçalves, A. L. F., Oliveira, M. M., & de Marqui, A. B. T. (2019) · Revista Paulista de Pediatria · doi:10.1590/1984-0462/;2019;37;4;00017 · Cited by 2 · see citing works
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Rahimkhani, M., Kazemian, K., & Daryasari, R. R. (2020) · Thyroid Research · doi:10.1186/s13044-020-0076-y · Cited by 2 · see citing works
Stoupa, A., Carré, A., Polak, M., & Szinnai, G. (2024) · Elsevier eBooks · doi:10.1016/b978-0-12-812531-1.00013-0 · Cited by 1 · see citing works
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- Authors
- Pappa, T., Johannesen, J., Scherberg, N., Torrent, M., Dumitrescu, A., & Refetoff, S.
- Affiliations
- Department of Medicine, The University of Chicago, Chicago, Illinois.
- Herlev Hospital (DK)
- University of Chicago (US)
- AbbVie (United States) (US)
- Corresponding author
- Refetoff, Samuel
- Venue
- Thyroid
- Publisher
- SAGE Publications
- Published
- 2015-08
- Volume
- 25
- Issue
- 8
- Pages
- 869-876
- ISSN
- 1050-7256 (ISSN-L)
- 1557-9077
- PMC
- PMC4533086
- OpenAlex
- W1615115188
- Cited by
- 19
- References
- 34
- Citations by year
- 2025: 2 · 2024: 2 · 2023: 3 · 2022: 2 · 2021: 1 · 2020: 1 · 2019: 4 · 2017: 2 · 2016: 1 · 2015: 1
- FWCI
- 1.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Thyroid (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (R37-DK 15070, R37DK015070, R01DK015070)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Health Sciences › Medicine › Physiology › Clinical Laboratory Practices and Quality Control
- Keywords
- arginine modification, phenylglyoxal, consanguinity, South Asian populations, heterozygous carriers, homology modeling
- MeSH terms
- Alleles, Antibodies, Monoclonal, Arginine, Child, Preschool, Consanguinity, Female, Glycine, Heterozygote, Homozygote, Humans, Hypothyroidism, Male, Models, Molecular, Mutation, Pakistan, Pedigree, Protein Conformation, Thyroid Function Tests, Thyroxine, Triiodothyronine, Sequence Analysis, DNA, Polymorphism, Single Nucleotide, Thyrotropin, beta Subunit
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