Central Precocious Puberty That Appears to Be Sporadic Caused by Paternally Inherited Mutations in the Imprinted Gene Makorin Ring Finger 3
Central Precocious Puberty That Appears to Be Sporadic Caused by Paternally Inherited Mutations in the Imprinted Gene Makorin Ring Finger 3
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DOI：
10.1210/jc.2013-3126
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发表时间：
2014-06-01
影响因子：
5.8
通讯作者：
Latronico, Ana Claudia
中科院分区：
文献类型：
--
作者：
Macedo, Delanie B.;Abreu, Ana Paula;Latronico, Ana Claudia
内容：Makorin无名指3（MKRN3）是位于15号染色体长臂上的印记基因，其功能缺失突变最近被认为是人类家族性中枢性早熟（CPP）的原因。MKRN3有一个潜在的抑制作用GnRH secretory.Objectives：本研究的目的是调查潜在的MKRN3序列变异以及拷贝数和甲基化异常的15q11位点的患者明显散发CPP.Setting和参与者：我们研究了215无关的儿童（207名女孩和8名男孩）从三所大学的医疗中心诊断为CPP。除2例患者（213例）外，所有患者均无性早熟家族史。MKRN3变异患者的一级亲属被纳入进行遗传分析。主要结果测量：所有215例CPP患者通过自动测序筛查MKRN3突变。多重连接依赖的探针扩增进行了部分重叠的队列52 patients.Results：我们确定了5个新的杂合突变MKRN3在8个无关的女孩与CPP。四个是预测编码截短蛋白的移码突变，一个是错义突变，通过计算机模拟分析表明是有害的。所有MKRN 3突变患者均具有典型的CPP特征，中位发病年龄为6岁。在检测这些异常的患者中未检测到15q11位点的拷贝数和甲基化异常。分离分析是可能的，在五个8个女孩与MKRN3突变，在所有情况下，突变是遗传的父亲allele.Conclusions：我们已经确定了新的遗传MKRN3缺陷的儿童明显散发CPP，支持这种肽在抑制生殖轴的基本作用。
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: 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.