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Cited by 38Thyroid Disorders and TreatmentsHypothalamic control of reproductive hormonesGenomics and Rare Diseases

Mutations in IRS4 are associated with central hypothyroidism

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Heinen, Charlotte A, de Vries, Emmely M, Alders, Mariëlle, Bikker, Hennie, Zwaveling-Soonawala, Nitash, van den Akker, Erica L T, Bakker, Boudewijn, Hoorweg-Nijman, Gera +5 more·2018·Journal of Medical Genetics
DOI 10.1136/jmedgenet-2017-105113PMC PMC6161650
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Abstract

Background: Four genetic causes of isolated congenital central hypothyroidism (CeH) have been identified, but many cases remain unexplained. We hypothesised the existence of other genetic causes of CeH with a Mendelian inheritance pattern. Methods: We performed exome sequencing in two families with unexplained isolated CeH and subsequently Sanger sequenced unrelated idiopathic CeH cases. We performed clinical and biochemical characterisation of the probands and carriers identified by family screening. We investigated IRS4 mRNA expression in human hypothalamus and pituitary tissue, and measured serum thyroid hormones and Trh and Tshb mRNA expression in hypothalamus and pituitary tissue of Irs4 knockout mice. Results: We found mutations in the insulin receptor substrate 4 (IRS4) gene in two pairs of brothers with CeH (one nonsense, one frameshift). Sequencing of IRS4 in 12 unrelated CeH cases negative for variants in known genes yielded three frameshift mutations (two novel) in three patients and one male sibling. All male carriers (n=8) had CeH with plasma free thyroxine concentrations below the reference interval. MRI of the hypothalamus and pituitary showed no structural abnormalities (n=12). 24-hour thyroid-stimulating hormone (TSH) secretion profiles in two adult male patients showed decreased basal, pulsatile and total TSH secretion. IRS4 mRNA was expressed in human hypothalamic nuclei, including the paraventricular nucleus, and in the pituitary gland. Female knockout mice showed decreased pituitary Tshb mRNA levels but had unchanged serum thyroid hormone concentrations. Conclusions: Mutations in IRS4 are associated with isolated CeH in male carriers. As IRS4 is involved in leptin signalling, the phenotype may be related to disrupted leptin signalling.

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Authors
Heinen, C. A., de Vries, E. M., Alders, M., Bikker, H., Zwaveling-Soonawala, N., van den Akker, E. L. T., Bakker, B., Hoorweg-Nijman, G., Roelfsema, F., Hennekam, R. C., Boelen, A., van Trotsenburg, A. S. P., & Fliers, E.
Affiliations
  • Amsterdam UMC Location University of Amsterdam (NL)
  • Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
  • Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
  • Department of Paediatric Endocrinology, Emma Children’s Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
  • Department of Paediatric Endocrinology, Erasmus MC, Rotterdam, The Netherlands
  • Reinier de Graaf Hospital (NL)
  • St. Antonius Ziekenhuis (NL)
  • Leiden University Medical Center (NL)
ORCID
Venue
Journal of Medical Genetics
Publisher
BMJ
Published
2018-07-30
Volume
55
Issue
10
Pages
693-700
ISSN
  • 0022-2593 (ISSN-L)
  • 1468-6244
DOI
10.1136/jmedgenet-2017-105113
PMC
PMC6161650
OpenAlex
W2885057795
Cited by
38
References
11
Citations by year
2026: 2 · 2025: 4 · 2024: 3 · 2023: 7 · 2022: 6 · 2021: 8 · 2020: 3 · 2019: 4
FWCI
2.98
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Journal of Medical Genetics (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion, cc-by-nc)
  • Leiden Repository (Leiden University) (submittedVersion, cc-by-nc)
  • Pure Amsterdam UMC (submittedVersion, cc-by)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • HighWire Press Open Archive (submittedVersion)
  • Leiden Repository (Leiden University) (submittedVersion)
Funders
AMC Foundation
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
  • Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Keywords
central hypothyroidism, IRS4, genetic mutations, frameshift mutation, leptin signaling, TSH secretion, hypothalamus, pituitary gland, TSH beta, male carriers, Mendelian inheritance
MeSH terms
Adolescent, Adult, Animals, Child, Child, Preschool, Female, Heterozygote, Humans, Hypothalamus, Hypothyroidism, Infant, Male, Middle Aged, Mutation, Pedigree, Pituitary Gland, Thyroxine, Signal Transduction, Leptin, Mice, Insulin Receptor Substrate Proteins, Young Adult

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