Pedrosa Erika, Stefanescu Radu, Margolis Benjamin, Petruolo Oriana, Lo Yungtai, Nolan Karen, Novak Tomas, Stopkova Pavla, Lachman Herbert M
Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, New York 10461, United States.
Schizophr Res. 2008 Jul;102(1-3):210-9. doi: 10.1016/j.schres.2008.04.013. Epub 2008 May 27.
Cadherins and protocadherins are cell adhesion proteins that play an important role in neuronal migration, differentiation and synaptogenesis, properties that make them targets to consider in schizophrenia (SZ) and bipolar disorder (BD) pathogenesis. Consequently, allelic variation occurring in protocadherin and cadherin encoding genes that map to regions of the genome targeted in SZ and BD linkage studies are particularly strong candidates to consider. One such set of candidate genes is the 5q31-linked PCDH family, which consists of more than 50 exons encoding three related, though distinct family members--alpha, beta, and gamma--which can generate thousands of different protocadherin proteins through alternative promoter usage and cis-alternative splicing. In this study, we focused on a SNP, rs31745, which is located in a putative PCDHalpha enhancer mapped by ChIP-chip using antibodies to covalently modified histone H3. A striking increase in homozygotes for the minor allele at this locus was detected in patients with BD. Molecular analysis revealed that the SNP causes allele-specific changes in binding to a brain protein. The findings suggest that the 5q31-linked PCDH locus should be more thoroughly considered as a disease-susceptibility locus in psychiatric disorders.
钙黏蛋白和原钙黏蛋白是细胞黏附蛋白，在神经元迁移、分化和突触形成过程中发挥重要作用，这些特性使它们成为精神分裂症（SZ）和双相情感障碍（BD）发病机制研究中值得考虑的靶点。因此，原钙黏蛋白和钙黏蛋白编码基因中发生的等位基因变异，若映射到SZ和BD连锁研究中所针对的基因组区域，就特别值得考虑作为候选基因。其中一组候选基因是5q31连锁的原钙黏蛋白（PCDH）家族，该家族由50多个外显子组成，编码三个相关但不同的家族成员——α、β和γ——通过不同启动子的使用和顺式可变剪接，它们可以产生数千种不同的原钙黏蛋白。在本研究中，我们聚焦于一个单核苷酸多态性（SNP），rs31745，它位于通过染色质免疫沉淀芯片（ChIP-chip）使用针对共价修饰组蛋白H3的抗体所定位的一个假定的PCDHα增强子中。在BD患者中检测到该位点的次要等位基因纯合子显著增加。分子分析表明，该SNP导致与一种脑蛋白结合的等位基因特异性变化。这些发现表明，5q31连锁的PCDH基因座应更全面地被视为精神疾病的疾病易感基因座。
