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1.
Horm Res Paediatr ; 78(3): 144-50, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22964795

RESUMO

AIM: To investigate LIN28B gene variants in children with idiopathic central precocious puberty (CPP). PATIENTS AND METHODS: We studied 178 Brazilian children with CPP (171 girls, 16.8% familial cases). A large multiethnic group (1,599 subjects; Multiethnic Cohort, MEC) was used as control. DNA analysis and biochemical in vitro studies were performed. RESULTS: A heterozygous LIN28B variant, p.H199R, was identified in a girl who developed CPP at 5.2 years. This variant was absent in 310 Brazilian control individuals, but it was found in the same allele frequency in women from the MEC cohort, independent of the age of menarche. Functional studies revealed that when ectopically expressed in cells, the mutant protein was capable of binding pre-let-7 microRNA and inhibiting let-7 expression to the same extent as wild-type Lin28B protein. Other rare LIN28B variants (p.P173P, c.198+ 32_33delCT, g.9575731A>C and c.-11C>T) were identified in CPP patients and controls. Therefore, no functional mutation was identified. CONCLUSION: In vitro studies revealed that the rare LIN28B p.H199R variant identified in a girl with CPP does not affect the Lin28B function in the regulation of let-7 expression. Although LIN28B SNPs were associated with normal pubertal timing, rare variations in this gene do not seem to be commonly involved in the molecular pathogenesis of CPP.


Assuntos
Proteínas de Ligação a DNA/genética , Mutação de Sentido Incorreto , Puberdade Precoce/genética , Adolescente , Adulto , Substituição de Aminoácidos , Criança , Pré-Escolar , Estudos de Coortes , Proteínas de Ligação a DNA/biossíntese , Feminino , Regulação da Expressão Gênica/genética , Células HEK293 , Células HeLa , Humanos , Lactente , Recém-Nascido , Masculino , MicroRNAs/biossíntese , MicroRNAs/genética , Puberdade Precoce/metabolismo , Proteínas de Ligação a RNA
2.
Eur J Endocrinol ; 165(1): 145-50, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21543378

RESUMO

CONTEXT: Necdin activates GNRH gene expression and is fundamental for the development, migration, and axonal extension of murine GNRH neurons. In humans, necdin plays a potential role in the hypogonadotropic hypogonadism phenotype in patients with Prader-Willi syndrome. AIM: To investigate necdin gene (NDN) variants in patients with isolated hypogonadotropic hypogonadism (IHH). PATIENTS AND METHODS: We studied 160 Brazilian patients with IHH, which includes 92 with Kallmann syndrome and 68 with normosmic IHH. Genomic DNA was extracted and the single NDN exon was amplified and sequenced. To measure GNRH transcriptional activity, luciferase reporter plasmids containing GNRH regulatory regions were transiently transfected into GT1-7 cells in the presence and absence of overexpressed wild-type or mutant necdin. RESULTS: A heterozygous variant of necdin, p.V318A, was identified in a 23-year-old male with Kallmann syndrome. The p.V318A was also present in affected aunt and his father and was absent in 100 Brazilian control subjects. Previous FGFR1 gene analysis revealed a missense mutation (p.P366L) in this family. Functional studies revealed a minor difference in the activation of GNRH transcription by mutant protein compared with wild type in that a significant impairment of the necdin protein activity threshold was observed. CONCLUSION: A rare variant of necdin (p.V318A) was described in a family with Kallmann syndrome associated with a FGFR1 mutation. Familial segregation and in vitro analysis suggested that this non-synonymous variant did not have a direct causative role in the hypogonadism phenotype. NDN mutations are not a frequent cause of congenital IHH.


Assuntos
Hipogonadismo/genética , Síndrome de Prader-Willi/genética , Animais , Sequência de Bases , Brasil , Análise Mutacional de DNA , Feminino , Humanos , Hipogonadismo/congênito , Síndrome de Kallmann/genética , Masculino , Camundongos , Proteínas do Tecido Nervoso , Proteínas Nucleares , Linhagem , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética
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