FRANCISCA DELANIE BULCAO DE MACEDO
Projetos de Pesquisa
Unidades Organizacionais
Instituto Central, Hospital das Clínicas, Faculdade de Medicina - Médico
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina
2 resultados
Resultados de Busca
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- Paternally Inherited DLK1 Deletion Associated With Familial Central Precocious Puberty(2017) 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 ClaudiaContext: 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.
- Central Precocious Puberty That Appears to Be Sporadic Caused by Paternally Inherited Mutations in the Imprinted Gene Makorin Ring Finger 3(2014) MACEDO, Delanie B.; ABREU, Ana Paula; REIS, Ana Claudia S.; MONTENEGRO, Luciana R.; DAUBER, Andrew; BENEDUZZI, Daiane; CUKIER, Priscilla; SILVEIRA, Leticia F. G.; TELES, Milena G.; CARROLL, Rona S.; GUERRA JUNIOR, Gil; GUARAGNA FILHO, Guilherme; GUCEV, Zoran; ARNHOLD, Ivo J. P.; CASTRO, Margaret de; MOREIRA, Ayrton C.; MARTINELLI JR., Carlos Eduardo; HIRSCHHORN, Joel N.; MENDONCA, Berenice B.; BRITO, Vinicius N.; ANTONINI, Sonir R.; KAISER, Ursula B.; LATRONICO, Ana ClaudiaContext: Loss-of-function mutations in makorin ring finger 3 (MKRN3), an imprinted gene located on the long arm of chromosome 15, have been recognized recently as a cause of familial central precocious puberty (CPP) in humans. MKRN3 has a potential inhibitory effect on GnRH secretion. Objectives: The objective of the study was to investigate potential MKRN3 sequence variations as well as copy number and methylation abnormalities of the 15q11 locus in patients with apparently sporadic CPP. Setting and Participants: We studied 215 unrelated children (207 girls and eight boys) from three university medical centers with a diagnosis of CPP. All but two of these patients (213 cases) reported no family history of premature sexual development. First-degree relatives of patients with identified MKRN3 variants were included for genetic analysis. Main Outcome Measures: All 215 CPP patients were screened for MKRN3 mutations by automatic sequencing. Multiplex ligation-dependent probe amplification was performed in a partially overlapping cohort of 52 patients. Results: We identified five novel heterozygous mutations in MKRN3 in eight unrelated girls with CPP. Four were frame shift mutations predicted to encode truncated proteins and one was a missense mutation, which was suggested to be deleterious by in silico analysis. All patients with MKRN3mutations had classical features of CPP with a median age of onset at 6 years. Copy number and methylation abnormalities at the 15q11 locus were not detected in the patients tested for these abnormalities. Segregation analysis was possible in five of the eight girls with MKRN3 mutations; in all cases, the mutation was inherited on the paternal allele. Conclusions: We have identified novel inherited MKRN3 defects in children with apparently sporadic CPP, supporting a fundamental role of this peptide in the suppression of the reproductive axis.