De Novo GMNN Mutations Cause Autosomal-Dominant Primordial Dwarfism Associated with Meier-Gorlin Syndrome
De Novo GMNN Mutations Cause Autosomal-Dominant Primordial Dwarfism Associated with Meier-Gorlin Syndrome
复制标题
DOI：
10.1016/j.ajhg.2015.11.006
复制
发表时间：
2015-12-01
影响因子：
9.8
通讯作者：
Yang, Yaping
中科院分区：
文献类型：
--
作者：
Burrage, Lindsay C.;Charng, Wu-Lin;Yang, Yaping
Meier-Gorlin综合征（MGS）是一种遗传异质性原始侏儒综合征，已知由编码复制前复合蛋白的五个基因之一的双等位基因功能丧失突变引起：ORC 1，ORC 4，ORC 6，CDT 1和CDC 6。这些基因中的突变导致DNA复制起始起点的破坏。迄今为止，只有常染色体隐性遗传模式已被描述在个人与这种疾病，与分子病因建立在约四分之三的情况下。在这里，我们报告了三个主题与MGS和从头杂合突变的5'端GMNN，编码DNA复制抑制剂geminin。我们在外显子2（第一编码外显子）中鉴定了两个截短突变，c.16A>T（p.Lys6*）和c.35_38delTCAA（p.Ile12Lysfs*4），以及一个错义突变，c.50A>G（p.Lys17Arg），其影响外显子2的倒数第二个核苷酸和可能的RNA剪接。Geminin存在于细胞周期的S、G2和M期，并在中期-后期转换期间被后期促进复合物（APC）降解，所述后期促进复合物（APC）识别Geminin蛋白5'端附近的破坏盒序列。鉴定的所有三个GMNN突变都改变了位于破坏盒内的蛋白质残基Met 28的5'位点。我们目前的数据支持功能获得机制，其中GMNN突变导致蛋白质缺乏破坏盒，因此增加了蛋白质的稳定性和长期抑制复制，导致常染色体显性MGS。
Meier-Gorlin syndrome (MGS) is a genetically heterogeneous primordial dwarfism syndrome known to be caused by biallelic loss-of-function mutations in one of five genes encoding pre-replication complex proteins: ORC1, ORC4, ORC6, CDT1, and CDC6. Mutations in these genes cause disruption of the origin of DNA replication initiation. To date, only an autosomal-recessive inheritance pattern has been described in individuals with this disorder, with a molecular etiology established in about three-fourths of cases. Here, we report three subjects with MGS and de novo heterozygous mutations in the 5' end of GMNN, encoding the DNA replication inhibitor geminin. We identified two truncating mutations in exon 2 (the 1 st coding exon), c.16A>T (p.Lys6*) and c.35_38delTCAA (p.Ile12Lysfs*4), and one missense mutation, c.50A>G (p.Lys17Arg), affecting the second-to-last nucleotide of exon 2 and possibly RNA splicing. Geminin is present during the S, G2, and M phases of the cell cycle and is degraded during the metaphase-anaphase transition by the anaphase-promoting complex (APC), which recognizes the destruction box sequence near the 5' end of the geminin protein. All three GMNN mutations identified alter sites 5' to residue Met28 of the protein, which is located within the destruction box. We present data supporting a gain-of-function mechanism, in which the GMNN mutations result in proteins lacking the destruction box and hence increased protein stability and prolonged inhibition of replication leading to autosomal-dominant MGS.