| 1 | Biochemistry 2012 Jul 51: 5663-73 |
|---|---|
| PMID | 22738176 |
| 标题 | Structural organization of the nine spectrin repeats of Kalirin. |
| 抽象的 | Sequence analysis suggests thatKALRN，Rho GDP/GTP交换因子遗传与schizophrenia, could contain as many as nine tandem spectrin repeats (SRs). We expressed and purified fragments of Kalirin containing from one to five putative SRs to determine whether they formed nested structures that could endow Kalirin with the flexible rodlike properties characteristic of spectrin and dystrophin. Far-UV circular dichroism studies indicated that Kalirin contains nine SRs. On the basis of thermal denaturation, sensitivity to chemical denaturants, and the solubility of pairs of repeats, the nine SRs of Kalirin form nested structures. Modeling studies confirmed this conclusion and identified an exposed loop in SR5; consistent with the modeling, this loop was extremely labile to proteolytic cleavage. Analysis of a direpeat fragment (SR4:5) encompassing the region of Kalirin known to interact with NOS2, DISC-1, PAM, and Arf6 identified this as the least stable region. Analytical ultracentrifugation indicated that SR1:3, SR4:6, and SR7:9 were monomers and adopted an extended conformation. Gel filtration suggested that ?Kal7, a natural isoform that includes SR5:9, was monomeric and was not more extended than SR5:9. Similarly, the nine SRs of Kal7, which was also monomeric, were not more extended than SR5:9. The rigidity and flexibility of the nine SRs of Kal7, which separate its essential N-terminal Sec14p domain from its catalytic domain, play an essential role in its contribution to the formation and function of dendritic spines. |
| SCZ关键字 | 精神分裂症，精神分裂症 |
| 2 | Schizophr Bull 2012 May 38: 552-60 |
| PMID | 21041834 |
| 标题 | Resequencing and association analysis of the KALRN and EPHB1 genes and their contribution to schizophrenia susceptibility. |
| 抽象的 | Our genome-wide association study ofschizophreniafound association signals at the Kalirin gene (KALRN) and EPH receptor B1 gene (EPHB1) in a Japanese population. The importance of these synaptogenic pathway genes inschizophreniais gaining independent supports. Although there has been growing interest in rare (<1%) missense mutations as potential contributors to the unexplained heritability ofschizophrenia, there are no population-based studies targeting rare (<1%) coding mutations with a larger effect size (eg, OR >1.5) inKALRNor EPHB1. 本研究设计由3个阶段组成。在发现阶段，我们对所有外显子区域进行了重新方程分析KALRNand EPHB1 using a DNA microarray-based method. Seventeen rare (<1%) missense mutations were discovered in the first sample set (320schizophrenicpatients). After the prioritization phase based on frequencies in the second sample set (729 cases and 562 controls), we performed association analyses for each selected mutation using the third sample set (1511 cases and 1517 controls), along with a combined association analysis across all selected mutations. InKALRN, we detected a significant association betweenschizophrenia和P2255T（OR = 2.09，校正P = .048，1尾巴）;合并结合分析（OR = 2.07，校正后的p = .006，1尾巴）得到了支持。我们没有发现EPHB1与schizophrenia. In silico analysis indicated the functional relevance of these rare missense mutations. 我们提供多种的证据rare (<1%) missense mutations inKALRNmay be genetic risk factors forschizophrenia. |
| SCZ关键字 | 精神分裂症，精神分裂症 |
| 3 | Mol. Psychiatry 2012 Jan 17: 1, 99-107 |
| PMID | 21483438 |
| 标题 | Control of interneuron dendritic growth through NRG1/erbB4-mediated kalirin-7 disinhibition. |
| 抽象的 | Neuregulin 1 (NRG1) is a secreted trophic factor that activates the postsynaptic erbB4 receptor tyrosine kinase. Both NRG1 and erbB4 have been repeatedly associated withschizophrenia，但是它们的下游目标没有很好地表征。ERBB4在中间神经元中高度丰富，NRG1介导的ERBB4激活已证明可以调节中间神经元的功能，但是NRG1-ERBB4信号在调节神经元的树突状生长中的作用尚不很好地理解。在这里，我们表明NRG1/ERBB4通过主要的树枝状Rac1-GEF Kalirin促进成熟中间神经元中树突的生长。最近的研究表明KALRNgene withschizophrenia. Our data point to an essential role of phosphorylation in kalirin-7's C terminus as the critical site for these effects. As reduced interneuron dendrite length occurs inschizophrenia, understanding how NRG1-erbB4 signaling modulates interneuron dendritic morphogenesis might shed light on disease-related alterations in cortical circuits. |
| SCZ关键字 | 精神分裂症，精神分裂症 |
| 4 | Schizophr Bull 2012 May 38: 552-60 |
| PMID | 21041834 |
| 标题 | Resequencing and association analysis of the KALRN and EPHB1 genes and their contribution to schizophrenia susceptibility. |
| 抽象的 | Our genome-wide association study ofschizophreniafound association signals at the Kalirin gene (KALRN) and EPH receptor B1 gene (EPHB1) in a Japanese population. The importance of these synaptogenic pathway genes inschizophreniais gaining independent supports. Although there has been growing interest in rare (<1%) missense mutations as potential contributors to the unexplained heritability ofschizophrenia, there are no population-based studies targeting rare (<1%) coding mutations with a larger effect size (eg, OR >1.5) inKALRNor EPHB1. 本研究设计由3个阶段组成。在发现阶段，我们对所有外显子区域进行了重新方程分析KALRNand EPHB1 using a DNA microarray-based method. Seventeen rare (<1%) missense mutations were discovered in the first sample set (320schizophrenicpatients). After the prioritization phase based on frequencies in the second sample set (729 cases and 562 controls), we performed association analyses for each selected mutation using the third sample set (1511 cases and 1517 controls), along with a combined association analysis across all selected mutations. InKALRN, we detected a significant association betweenschizophrenia和P2255T（OR = 2.09，校正P = .048，1尾巴）;合并结合分析（OR = 2.07，校正后的p = .006，1尾巴）得到了支持。我们没有发现EPHB1与schizophrenia. In silico analysis indicated the functional relevance of these rare missense mutations. 我们提供多种的证据rare (<1%) missense mutations inKALRNmay be genetic risk factors forschizophrenia. |
| SCZ关键字 | 精神分裂症，精神分裂症 |
| 5 | Nat Commun 2014 -1 5：4858 |
| PMID | 25224588 |
| 标题 | A sequence variant in human KALRN impairs protein function and coincides with reduced cortical thickness. |
| 抽象的 | Dendritic spine pathology is a key feature of several neuropsychiatric disorders. The Rac1 guanine nucleotide exchange factor kalirin-7 is critical for spine morphogenesis on cortical pyramidal neurons. Here we identify a rare coding variant in theKALRNgene region that encodes the catalytic domain, in aschizophrenia病人和他患有严重抑郁症的兄弟姐妹。D1338N取代显着降低了蛋白质催化Rac1激活的能力。与野生型Kalirin-7相反，Kalirin-7-D1338N未能增加脊柱的大小和密度。两位携带多态性的受试者在上颞沟（STS）中均显示皮质体积减少，该区域与涉及的区域有关schizophrenia. Consistent with this, mice with reduced kalirin expression showed reduced neuropil volume in the rodent homologue of the STS. These data suggest that single amino acid changes in proteins involved in dendritic spine function can have significant effects on the structure and function of the cerebral cortex. |
| SCZ关键字 | 精神分裂症，精神分裂症 |