Disruption of the neuronal PAS3 gene in a family affected with schizophrenia
Disruption of the neuronal PAS3 gene in a family affected with schizophrenia
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DOI：
10.1136/jmg.40.5.325
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发表时间：
2003-05-01
影响因子：
4
通讯作者：
Cox, DW
中科院分区：
文献类型：
--
作者：
Kamnasaran, D;Muir, WJ;Cox, DW
精神分裂症及其亚型是一种复杂的大脑疾病的一部分，有多种假设的病因。有证据表明，这种常见疾病具有遗传异质性，涉及多个基因座。在这份报告中，我们描述了一对患有精神分裂症的母女，他们是t(9；14)(q34；q13)染色体的携带者。通过对分离自淋巴母细胞系的Flow排序的异常染色体作图，两个受试者都被发现在标记D14S730和D14S70之间存在易位断点连接，在染色体14q13上有683kb的间隔。通过对EST的基因组序列进行注释以及进行RACE和cDNA文库筛选，发现该区间包含神经性PAS3基因(NPAS3)。NPAS3基因的特征在于基因组结构、人类表达谱和蛋白质细胞定位，以了解基因功能。易位断点连接位于NPAS3的第三内含子内，导致编码电位的破坏。BHLH和PAS结构域从编码蛋白的其余部分被破坏的事实表明，该蛋白的DNA结合和二聚功能被破坏。受影响更严重的女儿(先证者)在NPAS3的第二内含子上有额外的微缺失。在染色体9q34上，D9S752和D9S972之间存在易位断裂点连接，未发现基因突变。我们认为NPAS3的单倍性不足是导致该家庭精神疾病的原因之一。
Schizophrenia and its subtypes are part of a complex brain disorder with multiple postulated aetiologies. There is evidence that this common disease is genetically heterogeneous, with many loci involved. In this report, we describe a mother and daughter affected with schizophrenia, who are carriers of a t(9;14)(q34;q13) chromosome. By mapping on flow sorted aberrant chromosomes isolated from lymphoblast cell lines, both subjects were found to have a translocation breakpoint junction between the markers D14S730 and D14S70, a 683 kb interval on chromosome 14q13. This interval was found to contain the neuronal PAS3 gene (NPAS3), by annotating the genomic sequence for ESTs and performing RACE and cDNA library screenings. The NPAS3 gene was characterised with respect to the genomic structure, human expression profile, and protein cellular localisation to gain insight into gene function. The translocation breakpoint junction lies within the third intron of NPAS3, resulting in the disruption of the coding potential. The fact that the bHLH and PAS domains are disrupted from the remaining parts of the encoded protein suggests that the DNA binding and dimerisation functions of this protein are destroyed. The daughter (proband), who is more severely affected, has an additional microdeletion in the second intron of NPAS3. On chromosome 9q34, the translocation breakpoint junction was defined between D9S752 and D9S972 and no genes were found to be disrupted. We propose that haploinsufficiency of NPAS3 contributes to the cause of mental illness in this family.