Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Universidade de São Paulo, São Paulo, Brazil.
Horm Res Paediatr. 2012;78(3):144-50. doi: 10.1159/000342212. Epub 2012 Sep 6.
To investigate LIN28B gene variants in children with idiopathic central precocious puberty (CPP).
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.
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.
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.
研究 LIN28B 基因变异与特发性中枢性性早熟（CPP）儿童的关系。
我们研究了 178 名巴西 CPP 儿童（171 名女孩，16.8%为家族性病例）。一个大型多民族群体（1599 例；多民族队列，MEC）被用作对照。进行了 DNA 分析和生化体外研究。
在一名 5.2 岁发生 CPP 的女孩中发现了一个杂合的 LIN28B 变异，p.H199R。该变异在 310 名巴西对照个体中不存在，但在 MEC 队列的女性中以相同的等位基因频率存在，与初潮年龄无关。功能研究表明，当突变蛋白在外源表达时，能够与前 let-7 微 RNA 结合，并以与野生型 Lin28B 蛋白相同的程度抑制 let-7 表达。在 CPP 患者和对照中还发现了其他罕见的 LIN28B 变异（p.P173P、c.198+32_33delCT、g.9575731A>C 和 c.-11C>T）。因此，没有发现功能突变。
体外研究表明，在一名 CPP 女孩中发现的罕见 LIN28B p.H199R 变异不影响 Lin28B 在调节 let-7 表达中的功能。尽管 LIN28B SNP 与正常青春期时间有关，但该基因的罕见变异似乎并不常见于 CPP 的分子发病机制中。
