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Genotype-phenotype correlations
Original article
Mutations in IRS4 are associated with central hypothyroidism
  1. Charlotte A Heinen1,2,
  2. Emmely M de Vries1,
  3. Mariëlle Alders3,
  4. Hennie Bikker3,
  5. Nitash Zwaveling-Soonawala2,
  6. Erica L T van den Akker4,
  7. Boudewijn Bakker5,
  8. Gera Hoorweg-Nijman6,
  9. Ferdinand Roelfsema7,
  10. Raoul C Hennekam8,
  11. Anita Boelen1,
  12. A S Paul van Trotsenburg2,
  13. Eric Fliers1
  1. 1 Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
  2. 2 Department of Paediatric Endocrinology, Emma Children’s Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
  3. 3 Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
  4. 4 Department of Paediatric Endocrinology, Erasmus MC, Rotterdam, The Netherlands
  5. 5 Department of Paediatrics, Reinier de Graaf Hospital, Delft, The Netherlands
  6. 6 Department of Paediatrics, St. Antonius Hospital, Nieuwegein, The Netherlands
  7. 7 Department of Endocrinology and Metabolism, Leiden University Medical Center, Leiden, The Netherlands
  8. 8 Department of Paediatrics, Emma Children’s Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
  1. Correspondence to Dr. A S Paul van Trotsenburg, Department of Paediatric Endocrinology, Academic Medical Center, Emma Children’s Hospital, University of Amsterdam, Amsterdam, The Netherlands; a.s.vantrotsenburg{at}amc.uva.nl

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.

  • IRS4
  • central hypothyroidism
  • leptin
  • HPT Axis

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/jmedgenet-2017-105113

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    Footnotes

    • Senior authors AB, ASPvT and EF contributed  equally.

    • Contributors CAH coordinated the study. CAH, RCH, AB, ASPvT and EF designed the study. EMdV, NZ-S, ELTvdA, BB, GH-N and ASPvT provided patient care and collected data. MA and HB performed genetic analysis. FR performed statistical analysis. CAH, RCH, AB, ASPvT and EF interpreted the results and wrote the manuscript. All authors critically reviewed the report. No writing assistance was provided. CAH, AB, ASPvT and EF had full access to all of the data in the study and take responsibility for the integrity of the data. All authors revised the manuscript critically and approved the final version for publication.

    • Funding This work was financially supported by an AMC Foundation grant.

    • Competing interests None declared.

    • Patient consent Obtained.

    • Ethics approval The Medical Ethics Committee of the Academic Medical Center, Amsterdam, approved the study protocol (NL52353.018.15).

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Correction notice This article has been corrected since it was published Online First. A statement about equal contribution has been added to the first page.