Central Congenital Hypothyroidism Caused by a Novel Mutation, C47W, in the Cysteine Knot Region of TSHβ
- 8 January 2020
- journal article
- research article
- Published by S. Karger AG in Hormone Research in Paediatrics
- Vol. 92 (6), 390-394
- https://doi.org/10.1159/000504981
Abstract
Background: Isolated central congenital hypothyroidism (ICCH) is a rare form (1:50,000 newborns) of congenital hypothyroidism, which can present with growth and neuropsychological retardation. Unlike the more common primary CH (1:1,500–1:4,000), which presents on newborn screening with elevated serum thyroid-stimulating hormone (TSH) and low thyroxine (T4) and triiodothyronine (T3), ICCH presents with low TSH and low thyroid hormone levels. ICCH, therefore, may be missed in most newborn screens that are based only on elevated TSH. Most cases of ICCH have been associated with mutations in the TSHβ gene. Patient: We present a consanguineous Sudanese family where the proband was diagnosed with “atypical” CH (serum TSH was low, not high). Intervention and Outcome: The propositus underwent whole-exome sequencing, and the C47W TSHβ mutation was identified. Sanger sequencing confirmed the proband to be homozygous for C47W, and both parents were heterozygous for the same mutation. The mutation was predicted by several in silico methods to have a deleterious effect (SIFT 0.0, Damaging; Polyphen2_HDIV 0.973, probably damaging; MutationTaster 1, disease causing; and CADD 3.17, 16.62). C47W affects the first cysteine of the cysteine knot of the TSHβ subunit. The cysteine knot region of TSHβ is highly conserved across species and is critical for binding to the TSH receptor. Only two other mutations were previously reported along the cysteine knot and showed consistently low or undetectable serum TSH and low T4 and T3 levels. Other TSHβ gene mutations causing ICCH have been reported in the “seatbelt” region, necessary for TSHβ dimerization with the alpha subunit. Conclusions: Identification of a mutation in the TSHβ gene reinforces the importance of identifying ICCH that can occur in the absence of elevated serum TSH and demonstrates the functional significance of the TSHβ cysteine knot.Keywords
This publication has 22 references indexed in Scilit:
- Two Novel Mutations of the TSH-β Subunit Gene Underlying Congenital Central Hypothyroidism Undetectable in Neonatal TSH ScreeningJournal of Clinical Endocrinology & Metabolism, 2010
- MutationTaster evaluates disease-causing potential of sequence alterationsNature Methods, 2010
- Congenital hypothyroidismOrphanet Journal of Rare Diseases, 2010
- A method and server for predicting damaging missense mutationsNature Methods, 2010
- Comparative structure analyses of cystine knot-containing molecules with eight aminoacyl ring including glycoprotein hormones (GPH) alpha and beta subunits and GPH-related A2 (GPA2) and B5 (GPB5) moleculesReproductive Biology and Endocrinology, 2009
- Central hypothyroidismPituitary, 2008
- Hypothyroidism in Siblings Due to a Homozygous Mutation of the TSH-β Subunit GeneJournal of Pediatric Endocrinology and Metabolism, 2004
- SIFT: predicting amino acid changes that affect protein functionNucleic Acids Research, 2003
- Low TSH Congenital Hypothyroidism: Identification of a Novel Mutation of the TSH ß-Subunit Gene in One Sporadic Case (C85R) and of Mutation Q49stop in Two Siblings with Congenital HypothyroidismPediatric Research, 2002
- Low TSH Congenital Hypothyroidism: Identification of a Novel Mutation of the TSH beta-Subunit Gene in One Sporadic Case (C85R) and of Mutation Q49stop in Two Siblings with Congenital HypothyroidismPediatric Research, 2002