Nishimura Yuhei, Martin Christa L, Vazquez-Lopez Araceli, Spence Sarah J, Alvarez-Retuerto Ana Isabel, Sigman Marian, Steindler Corinna, Pellegrini Sandra, Schanen N Carolyn, Warren Stephen T, Geschwind Daniel H
Center for Autism Research and Treatment, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
Hum Mol Genet. 2007 Jul 15;16(14):1682-98. doi: 10.1093/hmg/ddm116. Epub 2007 May 21.
Autism is a heterogeneous condition that is likely to result from the combined effects of multiple genetic factors interacting with environmental factors. Given its complexity, the study of autism associated with Mendelian single gene disorders or known chromosomal etiologies provides an important perspective. We used microarray analysis to compare the mRNA expression profile in lymphoblastoid cells from males with autism due to a fragile X mutation (FMR1-FM), or a 15q11-q13 duplication (dup(15q)), and non-autistic controls. Gene expression profiles clearly distinguished autism from controls and separated individuals with autism based on their genetic etiology. We identified 68 genes that were dysregulated in common between autism with FMR1-FM and dup(15q). We also identified a potential molecular link between FMR1-FM and dup(15q), the cytoplasmic FMR1 interacting protein 1 (CYFIP1), which was up-regulated in dup(15q) patients. We were able to confirm this link in vitro by showing common regulation of two other dysregulated genes, JAKMIP1 and GPR155, downstream of FMR1 or CYFIP1. We also confirmed the reduction of the Jakmip1 protein in Fmr1 knock-out mice, demonstrating in vivo relevance. Finally, we showed independent confirmation of roles for JAKMIP1 and GPR155 in autism spectrum disorders (ASDs) by showing their differential expression in male sib pairs discordant for idiopathic ASD. These results provide evidence that blood derived lymphoblastoid cells gene expression is likely to be useful for identifying etiological subsets of autism and exploring its pathophysiology.
自闭症是一种异质性疾病，可能由多种遗传因素与环境因素相互作用的综合影响所致。鉴于其复杂性，对与孟德尔单基因疾病或已知染色体病因相关的自闭症研究提供了一个重要视角。我们使用微阵列分析比较了因脆性X突变（FMR1-FM）或15q11-q13重复（dup(15q)）导致自闭症的男性以及非自闭症对照者的淋巴母细胞中的mRNA表达谱。基因表达谱能够清晰地区分自闭症患者与对照者，并根据遗传病因将自闭症个体区分开来。我们鉴定出68个在FMR1-FM自闭症和dup(15q)自闭症中共同失调的基因。我们还发现了FMR1-FM和dup(15q)之间的一个潜在分子联系，即细胞质FMR1相互作用蛋白1（CYFIP1），它在dup(15q)患者中上调。我们通过显示FMR1或CYFIP1下游另外两个失调基因JAKMIP1和GPR155的共同调控，在体外证实了这种联系。我们还证实了Fmr1基因敲除小鼠中Jakmip1蛋白的减少，证明了其在体内的相关性。最后，我们通过显示JAKMIP1和GPR155在特发性自闭症不一致的男性同胞对中的差异表达，独立证实了它们在自闭症谱系障碍（ASD）中的作用。这些结果提供了证据，表明血液来源的淋巴母细胞基因表达可能有助于识别自闭症的病因亚组并探索其病理生理学。
