| Title: | Identification and characterization of human GDF15 knockouts |
| Journal: | Nature Metabolism |
| Published: | 26 Sep 2024 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/39327531/ |
| DOI: | https://doi.org/10.1038/s42255-024-01135-3 |
Publication 13438
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Abstract
Growth differentiation factor 15 (GDF15) is a secreted protein that regulates food intake, body weight and stress responses in pre-clinical models1. The physiological function of GDF15 in humans remains unclear. Pharmacologically, GDF15 agonism in humans causes nausea without accompanying weight loss2, and GDF15 antagonism is being tested in clinical trials to treat cachexia and anorexia. Human genetics point to a role for GDF15 in hyperemesis gravidarum, but the safety or impact of complete GDF15 loss, particularly during pregnancy, is unknown3-7. Here we show the absence of an overt phenotype in human GDF15 loss-of-function carriers, including stop gains, frameshifts and the fully inactivating missense variant C211G3. These individuals were identified from 75,018 whole-exome/genome-sequenced participants in the Pakistan Genomic Resource8,9 and recall-by-genotype studies with family-based recruitment of variant carrier probands. We describe 8 homozygous ('knockouts') and 227 heterozygous carriers of loss-of-function alleles, including C211G. GDF15 knockouts range in age from 31 to 75 years, are fertile, have multiple children and show no consistent overt phenotypes, including metabolic dysfunction. Our data support the hypothesis that GDF15 is not required for fertility, healthy pregnancy, foetal development or survival into adulthood. These observations support the safety of therapeutics that block GDF15.</p>
11 Keywords
- Adult
- Aged
- Female
- Growth Differentiation Factor 15
- Homozygote
- Humans
- Loss of Function Mutation
- Male
- Middle Aged
- Phenotype
- Pregnancy
37 Authors
- Allan M. Gurtan
- Shareef Khalid
- Christopher Koch
- Maleeha Zaman Khan
- Lindsey B. Lamarche
- Igor Splawski
- Elizabeth Dolan
- Ana M. Carrion
- Richard Zessis
- Matthew E. Clement
- Zhiping Chen
- Loren D. Lindsley
- Yu-Hsin Chiu
- Ryan S. Streeper
- Daniel P. Denning
- Allison B. Goldfine
- Brian Doyon
- Ali Abbasi
- Jennifer L. Harrow
- Kazuhisa Tsunoyama
- Makoto Asaumi
- Ikuyo Kou
- Alan R. Shuldiner
- Juan L. Rodriguez-Flores
- Asif Rasheed
- Muhammad Jahanzaib
- Muhammad Rehan Mian
- Muhammad Bilal Liaqat
- Syed Shahzaib Raza
- Riffat Sultana
- Anjum Jalal
- Muhammad Hamid Saeed
- Shahid Abbas
- Fazal Rehman Memon
- Mohammad Ishaq
- John E. Dominy
- Danish Saleheen
1 Application
| Application ID | Title |
|---|---|
| 59456 | Using UK Biobank data to support the Novartis drug discovery and development pipeline |
Enabling scientific discoveries that improve human health