2. Academic Validation
  3. Mutations in IRS4 are associated with central hypothyroidism

Mutations in IRS4 are associated with central hypothyroidism

  • J Med Genet. 2018 Oct;55(10):693-700. doi: 10.1136/jmedgenet-2017-105113.
Charlotte A Heinen 1 2,  Emmely M de Vries 1,  Mariëlle Alders 3,  Hennie Bikker 3,  Nitash Zwaveling-Soonawala 2,  Erica L T van den Akker 4,  Boudewijn Bakker 5,  Gera Hoorweg-Nijman 6,  Ferdinand Roelfsema 7,  Raoul C Hennekam 8,  Anita Boelen 1,  A S Paul van Trotsenburg 2,  Eric Fliers 1
Affiliations

Affiliations

  • 1 Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
  • 2 Department of Paediatric Endocrinology, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
  • 3 Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
  • 4 Department of Paediatric Endocrinology, Erasmus MC, Rotterdam, The Netherlands.
  • 5 Department of Paediatrics, Reinier de Graaf Hospital, Delft, The Netherlands.
  • 6 Department of Paediatrics, St. Antonius Hospital, Nieuwegein, The Netherlands.
  • 7 Department of Endocrinology and Metabolism, Leiden University Medical Center, Leiden, The Netherlands.
  • 8 Department of Paediatrics, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
PMID: 30061370 DOI: 10.1136/jmedgenet-2017-105113
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.

Keywords

HPT Axis; IRS4; central hypothyroidism; leptin.

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