A Novel Thyrotropin-Releasing Hormone Receptor Missense Mutation (P81R) in Central Congenital Hypothyroidism
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CONTEXT: Isolated central congenital hypothyroidism (CCH) is rare and evades diagnosis on TSH-based congenital hypothyroidism (CH) screening programs in the United Kingdom. Accordingly, genetic ascertainment facilitates diagnosis and treatment of familial cases. Recognized causes include TSH β subunit (TSHB) and Ig superfamily member 1 (IGSF1) mutations, with only two previous reports of biallelic, highly disruptive mutations in the TRH receptor (TRHR) gene. CASE DESCRIPTION: A female infant presenting with prolonged neonatal jaundice was found to have isolated CCH, with TSH of 2.2 mU/L (Reference range, 0.4-3.5) and free T4 of 7.9 pmol/L (0.61 ng/dL) (Reference range, 10.7-21.8 pmol/L). Because TSHB or IGSF1 mutations are usually associated with profound or X-linked CCH, TRHR was sequenced, and a homozygous mutation (p.P81R) was identified, substituting arginine for a highly conserved proline residue in transmembrane helix 2. Functional studies demonstrated normal cell membrane expression and localization of the mutant TRHR; however, its ability to bind radio-labelled TRH and signal via Gqα was markedly impaired, likely due to structural distortion of transmembrane helix 2. CONCLUSIONS: Two previously reported biallelic, highly disruptive (nonsense; R17*, in-frame deletion and single amino acid substitution; p.[S115-T117del; A118T]) TRHR mutations have been associated with CCH; however, we describe the first deleterious, missense TRHR defect associated with this phenotype. Importantly, the location of the mutated amino acid (proline 81) highlights the functional importance of the second transmembrane helix in mediating hormone binding and receptor activation. Future identification of other naturally occurring TRHR mutations will likely offer important insights into the molecular basis of ligand binding and activation of TRHR, which are still poorly understood.
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The diagnosis in 3 of 4 probands with biallelic TRHR mutations was made during childhood because of delayed growth accompanied by lethargy and fatigue or by overweight.
“The diagnosis in 3 of 4 probands with biallelic TRHR mutations was made during childhood because of delayed growth accompanied by lethargy and fatigue or by overweight.”
From 2018 European Thyroid Association (ETA) Guidelines on the Diagnosis and Management of Central Hypothyroidism (2018) · cites this paper as [29]
The Discussion reports growth retardation in two previously described children with biallelic TRHR mutations. The Results (Clinical and biochemical features; page unavailable) say this paper’s patient was diagnosed after presenting with neonatal jaundice and had grown normally; the paper does not establish that three of four were diagnosed because of delayed growth accompanied by lethargy, fatigue, or overweight. (LLM, conf=0.87)
Experimental — accuracy not yet measuredEven complete TRH resistance does not cause severe neonatal hypothyroidism.
“Though prolonged neonatal jaundice was reported in 1 female, even complete TRH resistance does not cause severe neonatal hypothyroidism.”
From 2018 European Thyroid Association (ETA) Guidelines on the Diagnosis and Management of Central Hypothyroidism (2018) · cites this paper as [29]
Defective TRH action due to biallelic mutations in the TRHR gene has, to date, been described in few families.
“Defective TRH action due to biallelic mutations in the TRHR gene has, to date, been described in few families [11, 28-30].”
From 2018 European Thyroid Association (ETA) Guidelines on the Diagnosis and Management of Central Hypothyroidism (2018) · cites this paper as [29]
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Cites
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- Authors
- Koulouri, O., Nicholas, A. K., Schoenmakers, E., Mokrosinski, J., Lane, F., Cole, T., Kirk, J., Farooqi, I. S., Chatterjee, V. K., Gurnell, M., & Schoenmakers, N.
- Affiliations
- University of Cambridge (GB)
- Corresponding author
- Schoenmakers, N.
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2016-03
- Volume
- 101
- Issue
- 3
- Pages
- 847-851
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC4803180
- OpenAlex
- W2230134529
- Cited by
- 32
- References
- 10
- Citations by year
- 2025: 2 · 2024: 1 · 2023: 3 · 2022: 4 · 2019: 5 · 2018: 7 · 2017: 6 · 2016: 4
- FWCI
- 7.36
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion, other-oa)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Funders
- Wellcome Trust (095564/Z/11/Z, 095564, 100585/Z/12/Z, 098497/Z/12/Z)
- National Institute for Health and Care Research (NF-SI-0508-10198, NF-SI-0514-10176)
- Evelyn Trust
- Medical Research Council
- 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 › Growth Hormone and Insulin-like Growth Factors
- Keywords
- thyrotropin-releasing hormone receptor, missense mutations, transmembrane helix 2, TSH receptor signaling, Gαq, neonatal jaundice, TSH screening, IGSF1, TSH beta subunit, ligand-receptor interactions
- MeSH terms
- Congenital Hypothyroidism, Female, Humans, Infant, Newborn, Receptors, Thyrotropin-Releasing Hormone, Mutation, Missense, HEK293 Cells
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