Andrew Dauber1, Marina Cunha-Silva2, Delanie B Macedo2, Vinicius N Brito2, Ana Paula Abreu3, Stephanie A Roberts4, Luciana R Montenegro2, Melissa Andrew1, Andrew Kirby5, Matthew T Weirauch6, Guillaume Labilloy7, Danielle S Bessa2, Rona S Carroll3, Dakota C Jacobs8, Patrick E Chappell8, Berenice B Mendonca2, David Haig9, Ursula B Kaiser3, Ana Claudia Latronico2. 1. Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229. 2. Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-093, Brazil. 3. Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115. 4. Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts 02115. 5. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114. 6. Center for Autoimmune Genomics and Etiology, Division of Biomedical Informatics and Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229. 7. Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229. 8. Department of Biological Sciences, College of Veterinary Medicine, Oregon State University, Corvallis, Oregon 97331. 9. Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, Massachusetts 02138.
Abstract
Context: Central precocious puberty (CPP) results from premature activation of the hypothalamic-pituitary-gonadal axis. Few genetic causes of CPP have been identified, with the most common being mutations in the paternally expressed imprinted gene MKRN3. Objective: To identify the genetic etiology of CPP in a large multigenerational family. Design: Linkage analysis followed by whole-genome sequencing was performed in a family with five female members with nonsyndromic CPP. Detailed phenotyping was performed at the time of initial diagnosis and long-term follow-up, and circulating levels of Delta-like 1 homolog (DLK1) were measured in affected individuals. Expression of DLK1 was measured in mouse hypothalamus and in kisspeptin-secreting neuronal cell lines in vitro. Setting: Endocrine clinic of an academic medical center. Patients: Patients with familial CPP were studied. Results: A complex defect of DLK1 (∼14-kb deletion and 269-bp duplication) was identified in this family. This deletion included the 5' untranslated region and the first exon of DLK1, including the translational start site. Only family members who inherited the defect from their father have precocious puberty, consistent with the known imprinting of DLK1. The patients did not demonstrate additional features of the imprinted disorder Temple syndrome except for increased fat mass. Serum DLK1 levels were undetectable in all affected individuals. Dlk1 was expressed in mouse hypothalamus and in kisspeptin neuron-derived cell lines. Conclusion: We identified a genomic defect in DLK1 associated with isolated familial CPP. MKRN3 and DLK1 are both paternally expressed imprinted genes. These findings suggest a role of genomic imprinting in regulating the timing of human puberty.
Context: Central precocious puberty (CPP) results from premature activation of the hypothalamic-pituitary-gonadal axis. Few genetic causes of CPP have been identified, with the most common being mutations in the paternally expressed imprinted gene MKRN3. Objective: To identify the genetic etiology of CPP in a large multigenerational family. Design: Linkage analysis followed by whole-genome sequencing was performed in a family with five female members with nonsyndromic CPP. Detailed phenotyping was performed at the time of initial diagnosis and long-term follow-up, and circulating levels of Delta-like 1 homolog (DLK1) were measured in affected individuals. Expression of DLK1 was measured in mousehypothalamus and in kisspeptin-secreting neuronal cell lines in vitro. Setting: Endocrine clinic of an academic medical center. Patients: Patients with familial CPP were studied. Results: A complex defect of DLK1 (∼14-kb deletion and 269-bp duplication) was identified in this family. This deletion included the 5' untranslated region and the first exon of DLK1, including the translational start site. Only family members who inherited the defect from their father have precocious puberty, consistent with the known imprinting of DLK1. The patients did not demonstrate additional features of the imprinted disorder Temple syndrome except for increased fat mass. Serum DLK1 levels were undetectable in all affected individuals. Dlk1 was expressed in mousehypothalamus and in kisspeptin neuron-derived cell lines. Conclusion: We identified a genomic defect in DLK1 associated with isolated familial CPP. MKRN3 and DLK1 are both paternally expressed imprinted genes. These findings suggest a role of genomic imprinting in regulating the timing of human puberty.
Authors: L G Silveira; S D Noel; A P Silveira-Neto; A P Abreu; V N Brito; M G Santos; S D C Bianco; W Kuohung; S Xu; M Gryngarten; M E Escobar; I J P Arnhold; B B Mendonca; U B Kaiser; A C Latronico Journal: J Clin Endocrinol Metab Date: 2010-03-17 Impact factor: 5.958
Authors: Ana Paula Abreu; Andrew Dauber; Delanie B Macedo; Sekoni D Noel; Vinicius N Brito; John C Gill; Priscilla Cukier; Iain R Thompson; Victor M Navarro; Priscila C Gagliardi; Tânia Rodrigues; Cristiane Kochi; Carlos Alberto Longui; Dominique Beckers; Francis de Zegher; Luciana R Montenegro; Berenice B Mendonca; Rona S Carroll; Joel N Hirschhorn; Ana Claudia Latronico; Ursula B Kaiser Journal: N Engl J Med Date: 2013-06-05 Impact factor: 91.245
Authors: Paolo Giacobini; Vincent Prevot; Charlotte Vanacker; Sara Trova; Sonal Shruti; Filippo Casoni; Andrea Messina; Sophie Croizier; Samuel Malone; Gaetan Ternier; Naresh Kumar Hanchate; S Rasika; Sebastien G Bouret; Philippe Ciofi Journal: EMBO J Date: 2020-08-05 Impact factor: 11.598