Your browser doesn't support javascript.
loading
LGR4 deficiency results in delayed puberty through impaired Wnt/ß-catenin signaling.
Mancini, Alessandra; Howard, Sasha R; Marelli, Federica; Cabrera, Claudia P; Barnes, Michael R; Sternberg, Michael Je; Leprovots, Morgane; Hadjidemetriou, Irene; Monti, Elena; David, Alessia; Wehkalampi, Karoliina; Oleari, Roberto; Lettieri, Antonella; Vezzoli, Valeria; Vassart, Gilbert; Cariboni, Anna; Bonomi, Marco; Garcia, Marie Isabelle; Guasti, Leonardo; Dunkel, Leo.
Afiliação
  • Mancini A; Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
  • Howard SR; Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
  • Marelli F; Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
  • Cabrera CP; IRCCS Istituto Auxologico Italiano, Department of Endocrine and Metabolic Diseases and Lab of Endocrine and Metabolic Research, Milan, Italy.
  • Barnes MR; Centre for Translational Bioinformatics, William Harvey Research Institute, and.
  • Sternberg MJ; NIHR Barts Cardiovascular Biomedical Research Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
  • Leprovots M; Centre for Translational Bioinformatics, William Harvey Research Institute, and.
  • Hadjidemetriou I; NIHR Barts Cardiovascular Biomedical Research Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
  • Monti E; Centre for Integrative Systems Biology and Bioinformatics, Department of Life Sciences, Imperial College London, London, United Kingdom.
  • David A; Université Libre de Bruxelles, Bruxelles, Belgium.
  • Wehkalampi K; Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
  • Oleari R; St George's NHS Foundation Trust, London, United Kingdom.
  • Lettieri A; Centre for Integrative Systems Biology and Bioinformatics, Department of Life Sciences, Imperial College London, London, United Kingdom.
  • Vezzoli V; Children's Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
  • Vassart G; Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy.
  • Cariboni A; Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy.
  • Bonomi M; IRCCS Istituto Auxologico Italiano, Department of Endocrine and Metabolic Diseases and Lab of Endocrine and Metabolic Research, Milan, Italy.
  • Garcia MI; Université Libre de Bruxelles, Bruxelles, Belgium.
  • Guasti L; Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy.
  • Dunkel L; Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
JCI Insight ; 5(11)2020 06 04.
Article em En | MEDLINE | ID: mdl-32493844
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/ß-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/ß-catenin signaling pathway activation during GnRH neuron development. In conclusion, our results show that LGR4 deficiency impairs Wnt/ß-catenin signaling with observed defects in GnRH neuron development, resulting in a DP phenotype.
Assuntos
Palavras-chave

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Puberdade Tardia / Receptores Acoplados a Proteínas G / Via de Sinalização Wnt / Neurônios Tipo de estudo: Observational_studies / Prognostic_studies / Risk_factors_studies Limite: Animals / Female / Humans / Male Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Puberdade Tardia / Receptores Acoplados a Proteínas G / Via de Sinalização Wnt / Neurônios Tipo de estudo: Observational_studies / Prognostic_studies / Risk_factors_studies Limite: Animals / Female / Humans / Male Idioma: En Ano de publicação: 2020 Tipo de documento: Article