A mutation in a novel ATP-dependent Lon protease gene in a kindred with mild mental retardation
A mutation in a novel ATP-dependent Lon protease gene in a kindred with mild mental retardation
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DOI：
10.1212/01.wnl.0000146196.01316.a2
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发表时间：
2004-11-23
期刊：
影响因子：
9.9
通讯作者：
Rooney, JP
中科院分区：
文献类型：
--
作者：
Higgins, JJ;Pucilowska, J;Rooney, JP
背景资料：识别有助于记忆和学习的遗传因素受到大脑发育复杂性和缺乏合适的轻度认知障碍人类模型的限制。研究方法：以前，在一个大家族中，一种轻度非综合征性精神发育迟滞（智商在50到70之间）的疾病位点被定位在染色体3 p25-pter上的4.2-MB区间。通过单链多态性分析和DNA测序系统地分析候选区域内的基因和转录本的突变。结果如下：一个无义突变导致一个新的基因（cereblon; CRBN）提前终止密码子被鉴定为编码ATP依赖性Lon蛋白酶。预测的蛋白质序列在物种间高度保守，并且它属于选择性降解短寿命多肽并调节线粒体复制和转录的蛋白质家族。含Lon-containing蛋白家族的一个成员在人海马中区域性表达，海马是参与长时程增强和学习的重要神经解剖区域。所描述的CRBN基因中的突变中断了N-豆蔻酰化位点，并消除了C末端的酪蛋白激酶II磷酸化位点。结论：染色体3 p上的一个基因与一个大家族的轻度精神发育迟滞有关。这一发现暗示了记忆和学习中蛋白质的ATP依赖性降解的作用。
Background: Identifying the genetic factors that contribute to memory and learning is limited by the complexity of brain development and the lack of suitable human models for mild disorders of cognition. Methods: Previously, a disease locus was mapped for a mild type of nonsyndromic mental retardation ( IQ between 50 and 70) to a 4.2-MB interval on chromosome 3p25-pter in a large kindred. The genes and transcripts within the candidate region were systematically analyzed for mutations by single-strand polymorphism analysis and DNA sequencing. Results: A nonsense mutation causing a premature stop codon in a novel gene (cereblon; CRBN) was identified that encodes for an ATP-dependent Lon protease. The predicted protein sequence is highly conserved across species, and it belongs to a family of proteins that selectively degrade short-lived polypeptides and regulate mitochondrial replication and transcription. One member of the Lon-containing protein family is regionally expressed in the human hippocampus, an important neuroanatomic region that is involved in long-term potentiation and learning. The mutation in the CRBN gene described interrupts an N-myristoylation site and eliminates a casein kinase II phosphorylation site at the C terminus. Conclusions: A gene on chromosome 3p that is associated with mild mental retardation in a large kindred is reported. This finding implicates a role for the ATP-dependent degradation of proteins in memory and learning.