ArticleJCI insight2020
LGR4 deficiency results in delayed puberty through impaired Wnt/β-catenin signaling.
Article in JCI insight, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 61 citations in OpenAlex.
- Recent developments in GPCR signalling in appetite regulation.Bioscience reports · 2026Review
- Deleterious variants in intolerant genes reveal new candidates for self-limited delayed puberty.European journal of endocrinology · 2025Article
- The role of LGR4 in bone metabolism and tumor bone metastasis.Frontiers in endocrinology · 2025Review
- Regulation of RSPO3-LGR4 Signaling: Emerging Role in Inflammation Revealed by Network Analysis.Archives of clinical and biomedical research · 2025Article
- Contributions of Common Genetic Variants to Constitutional Delay of Puberty and Idiopathic Hypogonadotropic Hypogonadism.The Journal of clinical endocrinology and metabolism · 2024Article
- The frequency of known germline LGR4 missense variant in the ethnic groups of West Siberia.Molecular biology reports · 2024Article
- Association of childhood dehydroepiandrosterone sulfate concentration, pubertal development, and DNA methylation at puberty-related genes.European journal of endocrinology · 2024Article
- Step by step analysis on gene datasets of growth phases in hematopoietic stem cells.Biochemistry and biophysics reports · 2024Article
- FAK loss reduces BRAFeLife · 2024Article
- Exome Sequencing: the Search for Mutations Associated with Hereditary Breast and Ovarian Cancers in the Tuvan Ethnic Group (A Pilot Study).Bulletin of experimental biology and medicine · 2024Article
- SEMA6A drives GnRH neuron-dependent puberty onset by tuning median eminence vascular permeability.Nature communications · 2023Article
- LGR4: A New Receptor Member in Endocrine and Metabolic Diseases.Endocrine reviews · 2023Review
- Loss of LGR4/GPR48 causes severe neonatal salt wasting due to disrupted WNT signaling altering adrenal zonation.The Journal of clinical investigation · 2023Article
- Deciphering the Transcriptional Landscape of Human Pluripotent Stem Cell-Derived GnRH Neurons: The Role of Wnt Signaling in Patterning the Neural Fate.Stem cells (Dayton, Ohio) · 2022Article
- The role of the Wnt signalling pathway in the energy metabolism of bone remodelling.Cell proliferation · 2022Review
- Genetics of pubertal delay.Clinical endocrinology · 2022Review
- Genetic architecture of self-limited delayed puberty and congenital hypogonadotropic hypogonadism.Frontiers in endocrinology · 2022Review
- Genetics of pubertal timing.Best practice & research. Clinical endocrinology & metabolism · 2022Review
- LGR4, a G Protein-Coupled Receptor With a Systemic Role: From Development to Metabolic Regulation.Frontiers in endocrinology · 2022Review
- Whole exome sequencing identifies deleterious rare variants in CCDC141 in familial self-limited delayed puberty.NPJ genomic medicine · 2021Article
Corrections and comments
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Authors and funding
20 authors at 7 institutions in 4 countries.
Funding
Abstract
The initiation of puberty is driven by an upsurge in hypothalamic gonadotropin-releasing hormone (GnRH) secretion. In turn, GnRH secretion upsurge depends on the development of a complex GnRH neuroendocrine network during embryonic life. Although delayed puberty (DP) affects up to 2% of the population, is highly heritable, and is associated with adverse health outcomes, the genes underlying DP remain largely unknown. We aimed to discover regulators by whole-exome sequencing of 160 individuals of 67 multigenerational families in our large, accurately phenotyped DP cohort. LGR4 was the only gene remaining after analysis that was significantly enriched for potentially pathogenic, rare variants in 6 probands. Expression analysis identified specific Lgr4 expression at the site of GnRH neuron development. LGR4 mutant proteins showed impaired Wnt/β-catenin signaling, owing to defective protein expression, trafficking, and degradation. Mice deficient in Lgr4 had significantly delayed onset of puberty and fewer GnRH neurons compared with WT, whereas lgr4 knockdown in zebrafish embryos prevented formation and migration of GnRH neurons. Further, genetic lineage tracing showed strong Lgr4-mediated Wnt/β-catenin signaling pathway activation during GnRH neuron development. In conclusion, our results show that LGR4 deficiency impairs Wnt/β-catenin signaling with observed defects in GnRH neuron development, resulting in a DP phenotype.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.