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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.\n                    <jats:italic>LGR4<\/jats:italic>\n                    was the only gene remaining after analysis that was significantly enriched for potentially pathogenic, rare variants in 6 probands. Expression analysis identified specific\n                    <jats:italic>Lgr4<\/jats:italic>\n                    expression at the site of GnRH neuron development. LGR4 mutant proteins showed impaired Wnt\/\u03b2-catenin signaling, owing to defective protein expression, trafficking, and degradation. Mice deficient in\n                    <jats:italic>Lgr4<\/jats:italic>\n                    had significantly delayed onset of puberty and fewer GnRH neurons compared with WT, whereas\n                    <jats:italic>lgr4<\/jats:italic>\n                    knockdown in zebrafish embryos prevented formation and migration of GnRH neurons. Further, genetic lineage tracing showed strong Lgr4-mediated Wnt\/\u03b2-catenin signaling pathway activation during GnRH neuron development. In conclusion, our results show that\n                    <jats:italic>LGR4<\/jats:italic>\n                    deficiency impairs Wnt\/\u03b2-catenin signaling with observed defects in GnRH neuron development, resulting in a DP phenotype.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.133434","type":"journal-article","created":{"date-parts":[[2020,6,9]],"date-time":"2020-06-09T08:24:50Z","timestamp":1591691090000},"source":"Crossref","is-referenced-by-count":44,"title":["LGR4 deficiency results in delayed puberty through impaired Wnt\/\u03b2-catenin signaling"],"prefix":"10.1172","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3047-1589","authenticated-orcid":true,"given":"Alessandra","family":"Mancini","sequence":"first","affiliation":[{"name":"Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United 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