GFRAL genetic variations and circulating GFRAL in hyperemesis gravidarum

Abstract

Hyperemesis gravidarum, the most severe form of nausea and vomiting in pregnancy, is linked to variants in GDF15 and its receptor GFRAL. This study combined exome and targeted sequencing, genotyping, immunoassays, and clinical data to characterize GFRAL sequence variation and circulating soluble GFRAL (sGFRAL) in pregnancy. Rare GFRAL variants were identified in patients with hyperemesis gravidarum and in asymptomatic pregnancies. A common variant was associated with symptoms persisting beyond 27 weeks’ gestation. sGFRAL was frequently detectable in early pregnancy, with dynamic changes across gestation and inverse correlation with weight loss, and subsequently more common in hyperemesis gravidarum. In silico promoter analysis suggested progesterone-dependent repression of GFRAL transcription, concordant with sGFRAL downregulation in controls after week 6. In contrast, women with hyperemesis gravidarum maintained soluble receptor levels. These findings implicate genetic and post-translational regulation of GFRAL in pregnancy sickness and support further evaluation of sGFRAL as a biomarker and mechanistic readout.

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BibTeX RIS

BibTeX

@article{haack2026gfral,
  title = {{GFRAL genetic variations and circulating GFRAL in hyperemesis gravidarum}},
  author = {Beatrice Haack and Zainab H. Neemuchwala and Summer DeVera and Kimber W. MacGibbon and Birgitt Fischer and Florian Höschle and Peter A. Fasching and Andrew Housholder and Eszter Vanky and Manuel A. Friese and Marie Bixo and Louise Stiernman and Emelie Ekwurtzel and Malin Nording and Marie-Therese Vinnars and Jörg Wischhusen and Marlena S. Fejzo},
  journal = {iScience},
  year = {2026},
  month = oct,
  doi = {10.1016/j.isci.2026.117975},
  url = {https://www.cell.com/iscience/fulltext/S2589-0042(26)03358-4},
  note = {CC BY 4.0},
}

RIS

TY  - JOUR
TI  - GFRAL genetic variations and circulating GFRAL in hyperemesis gravidarum
AU  - Beatrice Haack
AU  - Zainab H. Neemuchwala
AU  - Summer DeVera
AU  - Kimber W. MacGibbon
AU  - Birgitt Fischer
AU  - Florian Höschle
AU  - Peter A. Fasching
AU  - Andrew Housholder
AU  - Eszter Vanky
AU  - Manuel A. Friese
AU  - Marie Bixo
AU  - Louise Stiernman
AU  - Emelie Ekwurtzel
AU  - Malin Nording
AU  - Marie-Therese Vinnars
AU  - Jörg Wischhusen
AU  - Marlena S. Fejzo
PY  - 2026
DA  - 2026/10/23
JO  - iScience
DO  - 10.1016/j.isci.2026.117975
UR  - https://www.cell.com/iscience/fulltext/S2589-0042(26)03358-4
AB  - Hyperemesis gravidarum, the most severe form of nausea and vomiting in pregnancy, is linked to variants in GDF15 and its receptor GFRAL. This study combined exome and targeted sequencing, genotyping, immunoassays, and clinical data to characterize GFRAL sequence variation and circulating soluble GFRAL (sGFRAL) in pregnancy. Rare GFRAL variants were identified in patients with hyperemesis gravidarum and in asymptomatic pregnancies. A common variant was associated with symptoms persisting beyond 27 weeks’ gestation. sGFRAL was frequently detectable in early pregnancy, with dynamic changes across gestation and inverse correlation with weight loss, and subsequently more common in hyperemesis gravidarum. In silico promoter analysis suggested progesterone-dependent repression of GFRAL transcription, concordant with sGFRAL downregulation in controls after week 6. In contrast, women with hyperemesis gravidarum maintained soluble receptor levels. These findings implicate genetic and post-translational regulation of GFRAL in pregnancy sickness and support further evaluation of sGFRAL as a biomarker and mechanistic readout.
SN  - 2589-0042
ER  -

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