|Publication Type||Journal Article|
|Year of Publication||2014|
|Authors||Macedo, DB, Abreu, AP, Reis, AC, Montenegro, LR, Dauber, A, Beneduzzi, D, Cukier, P, Silveira, LF, Teles, MG, Carroll, RS, Guerra Junior, G, Guaragna Filho, G, Gucev, Z, Arnhold, IJ, de Castro, M, Moreira, AC, Martinelli CE, J, Hirschhorn, JN, Mendonca, BB, Brito, VN, Antonini, SR, Kaiser, UB, Latronico, AC|
|Journal||The Journal of clinical endocrinology and metabolism|
Context: 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: 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 8 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 frameshift 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 MKRN3 mutations 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 5 of the 8 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.