Two Novel Mutations of the TSH-β Subunit Gene Underlying Congenital Central Hypothyroidism Undetectable in Neonatal TSH Screening
Open accessAbstract
CONTEXT: Patients with TSH-beta subunit defects and congenital hypothyroidism are missed by TSH-based neonatal screening. OBJECTIVE: Our objective was to report the molecular consequences of a novel splice-junction mutation and a novel missense mutation in the TSH-beta subunit gene found in two patients with congenital central hypothyroidism and conventional treatment-resistant anemia. RESULTS: Patient 1 had a homozygous G to A nucleotide change at the 5' donor splice site of exon/intron 2. This resulted in a silent change at codon 34 of the mature protein. In vitro splicing assays showed that the mutant minigene dramatically affected pre-mRNA processing, causing exon 2 to be completely skipped. The putative product from a new out-of-frame translational start point in exon 3 is expected to yield a nonsense 25-amino-acid peptide. In patient 2, sequence analysis revealed a compound heterozygosis for the already reported 313delT (C105Vfs114X) mutation and for a second novel mutation in exon 3, substituting G for A at cDNA nucleotide position 323, resulting in a C88Y change. This cysteine residue is conserved among all dimeric pituitary and placental glycoprotein hormone-beta subunits. Data from in silico analysis confirmed that the C88Y mutation would affect subunit conformation. Indeed, two different bioinformatics approaches, PolyPhen and SIFT analysis, predicted C88Y to be a damaging substitution. CONCLUSIONS: In isolated TSH deficiency, the exact molecular diagnosis is mandatory for diagnosis of isolated pituitary deficiency, delineation of prognosis, and genetic counseling. Moreover, diagnosis of central hypothyroidism should be considered in the face of severe infant anemia of uncertain etiology.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Central hypothyroidism represents a major false negative result of the reflex TSH strategy, a widely accepted method for screening thyroid function by a first-line TSH measurement.
“Therefore, CeH represents a major false negative result of the 'reflex TSH strategy,' which is a widely accepted method for screening thyroid function by a first-line TSH measurement [4-7].”
From 2018 European Thyroid Association (ETA) Guidelines on the Diagnosis and Management of Central Hypothyroidism (2018) · cites this paper as [7]
Cites
Splicing in action: assessing disease causing sequence changes
Baralle, D., & Baralle, M. (2005) · Journal of Medical Genetics · doi:10.1136/jmg.2004.029538 · Cited by 507 · see citing works
Aebi, M., Hornig, H., & Weissmann, C. (1987) · Cell · doi:10.1016/0092-8674(87)90219-4 · Cited by 209 · 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
Detecting Polymorphisms and Mutations in Candidate Genes
Collins, J. S., & Schwartz, C. E. (2002) · The American Journal of Human Genetics · doi:10.1086/344344 · Cited by 120 · 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
Prevalence and mechanisms of hearing loss in patients with resistance to thyroid hormone
Brücker-Davis, F., Skarulis, M. C., Pikus, A., Ishizawar, D. C., Mastroianni, M. A., Koby, M. B., & Weintraub, B. D. (1996) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.81.8.8768826 · Cited by 105 · 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
Grüters, A., Biebermann, H., & Krude, H. (2003) · Hormone Research in Paediatrics · doi:10.1159/000067841 · Cited by 76 · see citing works
Bonomi, M. (2001) · Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.86.4.1600 · Cited by 71 · see citing works
Sensorineural hearing loss in sporadic congenital hypothyroidism.
Vanderschueren‐Lodeweyckx, M., Debruyne, F., Dooms, L., Eggermont, E., & Eeckels, R. (1983) · Archives of Disease in Childhood · doi:10.1136/adc.58.6.419 · Cited by 69 · 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
Severe 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
Dracopoli, N. C., Rettig, W. J., Whitfield, G. K., et al. (1986) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.83.6.1822 · Cited by 52 · see citing works
Brumm, 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
Antonijevic, N. M., Nesović, M., Trbojević, B., et al. (1999) · PubMed · Cited by 43 · see citing works
Pepe, C. M., Saraco, N. I., Baquedano, M. S., et al. (2007) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2007.02948.x · Cited by 35 · see citing works
Self-citationCongenital 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
Self-citationNew 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
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
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
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
Flagged first, then by citations
Cited by
Sorted by citations
Central Hypothyroidism: Pathogenic, Diagnostic, and Therapeutic Challenges
Persani, L. (2012) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2012-1616 · Cited by 295 · see citing works
Persani, L., Brabant, G., Dattani, M., Bonomi, M., Feldt-Rasmussen, U., Fliers, E., Gruters, A., Maiter, D., Schoenmakers, N., & van Trotsenburg, A. S. P. (2018) · European Thyroid Journal · doi:10.1159/000491388 · Cited by 222 · see citing works
DIAGNOSIS OF ENDOCRINE DISEASE: Congenital hypothyroidism: update and perspectives
Peters, C., van Trotsenburg, A. S. P., & Schoenmakers, N. (2018) · European Journal of Endocrinology · doi:10.1530/eje-18-0383 · Cited by 162 · see citing works
Central hypothyroidism — a neglected thyroid disorder
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
IGSF1 Deficiency: Lessons From an Extensive Case Series and Recommendations for Clinical Management
Joustra, S. D., Heinen, C. A., Schoenmakers, N., Bonomi, M., Ballieux, B. E. P. B., Turgeon, M.-O., Bernard, D. J., Fliers, E., van Trotsenburg, A. S. P., Losekoot, M., et al. (2016) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-3880 · Cited by 91 · see citing works
Thyrotropin Isoforms: Implications for Thyrotropin Analysis and Clinical Practice
Estrada, J. M., Soldin, D., Buckey, T. M., Burman, K. D., & Soldin, O. P. (2014) · Thyroid® · doi:10.1089/thy.2013.0119 · Cited by 64 · see citing works
Pappa, T., Johannesen, J., Scherberg, N., Torrent, M., Dumitrescu, A., & Refetoff, S. (2015) · Thyroid · doi:10.1089/thy.2015.0096 · Cited by 19 · see citing works
- Authors
- Baquedano, M. S., Ciaccio, M., Dujovne, N., Herzovich, V., Longueira, Y., Warman, D. M., Rivarola, M. A., & Belgorosky, A.
- Affiliations
- Garrahan Hospital (AR)
- Corresponding author
- Belgorosky, Alicia
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2010-09
- Volume
- 95
- Issue
- 9
- Pages
- E98-E103
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2110207339
- Cited by
- 41
- References
- 28
- Citations by year
- 2025: 1 · 2024: 2 · 2022: 2 · 2021: 2 · 2020: 1 · 2019: 4 · 2018: 3 · 2017: 3 · 2016: 5 · 2015: 3 · 2014: 4 · 2013: 5 · 2012: 3
- FWCI
- 2.64
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Conicet (publishedVersion, cc-by-nc-sa)
- 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 › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
- Keywords
- splice site mutation, exon skipping, missense mutations, compound heterozygosity, pre-mRNA splicing, molecular diagnosis
- MeSH terms
- Child, Child, Preschool, Congenital Hypothyroidism, False Negative Reactions, Humans, Infant, Newborn, Mutation, Pedigree, Protein Conformation, Neonatal Screening, Amino Acid Substitution, Polymorphism, Single Nucleotide, Thyrotropin, beta Subunit
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
