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, Junior Gil Guerra, Filho Guilherme Guaragna, Gucev Zoran, Arnhold Ivo J P, de Castro Margaret, Moreira Ayrton C, Martinelli Carlos Eduardo, Hirschhorn Joel N, Mendonca Berenice B, Brito Vinicius N, Antonini Sonir R, Kaiser Ursula B, Latronico Ana Claudia
Unidade de Endocrinologia do Desenvolvimento e Laboratório de Hormônios e Genética Molecular/LIM42, Disciplina de Endocrinologia (D.B.M., A.P.A., L.R.M., D.B., P.C., L.F.G.S., M.G.T., I.J.P.A., B.B.M., V.N.B., A.C.L.), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil, 05403-900; Departamento de Puericultura e Pediatria (A.C.S.R., M.C., A.C.M., C.E.M., S.R.A.), Faculdade de Medicina de Ribeirão Preto, da Universidade de São Paulo, Ribeirão Preto, SP, Brasil, 14049900; Division of Endocrinology, Diabetes, and Hypertension (A.P.A., R.S.C., U.B.K.), Brigham and Women's Hospital and Harvard Medical School and Division of Endocrinology, (A.D., J.N.H.) Boston Children's Hospital, Boston, Massachusetts 02115, Program in Medical and Population Genetics Broad Institute (A.D., J.N.H.), Cambridge, Massachusetts 02142; Unidade de Endocrinologia Pediátrica (G.G.J., G.G.F.), Universidade de Campinas, SP, Brasil, 13084-970; and Medical Faculty Skopje (Z.G.), 50 Divizija BB, 1000 Skopje, Macedonia.
J Clin Endocrinol Metab. 2014 Jun;99(6):E1097-103. doi: 10.1210/jc.2013-3126. Epub 2014 Mar 14.
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.
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.
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.
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.
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 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 five of the eight girls with MKRN3 mutations; in all cases, the mutation was inherited on the paternal allele.
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.
Makorin 环指蛋白 3（MKRN3）是位于 15 号染色体长臂上的一个印记基因，其功能丧失突变最近被认为是人类家族性中枢性性早熟（CPP）的一个病因。MKRN3 对促性腺激素释放激素（GnRH）的分泌具有潜在抑制作用。
本研究的目的是调查明显散发型 CPP 患者中 MKRN3 的潜在序列变异以及 15q11 位点的拷贝数和甲基化异常情况。
我们研究了来自三个大学医学中心的 215 名无血缘关系的儿童（207 名女孩和 8 名男孩），他们被诊断为 CPP。除两名患者（213 例）外，所有患者均无性早熟家族史。已鉴定出 MKRN3 变异的患者的一级亲属被纳入遗传分析。
对所有 215 例 CPP 患者进行自动测序以筛查 MKRN3 突变。在 52 例患者的部分重叠队列中进行多重连接依赖探针扩增。
我们在 8 名无血缘关系的 CPP 女孩中鉴定出 5 个 MKRN3 的新型杂合突变。4 个是移码突变，预计编码截短蛋白，1 个是错义突变，计算机分析提示该突变有害。所有 MKRN3 突变患者均具有 CPP 的典型特征，发病年龄中位数为 6 岁。在检测这些异常的患者中未发现 15q11 位点的拷贝数和甲基化异常。在 8 名有 MKRN3 突变的女孩中，有 5 名可以进行分离分析；在所有病例中，突变均从父本等位基因遗传而来。
我们在明显散发型 CPP 儿童中鉴定出新型遗传性 MKRN3 缺陷，支持该肽在抑制生殖轴方面的重要作用。
