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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Paternally Inherited DLK1 Deletion Associated With Familial Central Precocious Puberty

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Dauber, Andrew ; Cunha-Silva, Marina ; Macedo, Delanie B. ; Brito, Vinicius N. ; Abreu, Ana Paula ; Roberts, Stephanie A. ; Montenegro, Luciana R. ; Andrew, Melissa ; Kirby, Andrew ; Weirauch, Matthew T. ; Labilloy, Guillaume ; Bessa, Danielle S. ; Carroll, Rona S. ; Jacobs, Dakota C. ; Chappell, Patrick E. ; Mendonca, Berenice B. ; Haig, David ; Kaiser, Ursula B. ; Latronico, Ana Claudia
Total Authors: 19
Document type: Journal article
Source: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; v. 102, n. 5, p. 1557-1567, MAY 1 2017.
Web of Science Citations: 31

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 (similar to 14-kb deletion and 269-bp duplication) was identified in this family. This deletion included the 50 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. (AU)

FAPESP's process: 13/03236-5 - New approaches and methodologies in molecular-genetic studies of growth and pubertal development disorders
Grantee:Alexander Augusto de Lima Jorge
Support type: Research Projects - Thematic Grants
FAPESP's process: 13/06391-1 - New perspectives of the genetic study of idiopathic central precocious puberty
Grantee:Francisca Delanie Bulcão de Macêdo
Support type: Scholarships in Brazil - Doctorate (Direct)