Genome-wide expression profiling of lymphoblastoid cell lines distinguishes different forms of autism and reveals shared pathways

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.
Human Molecular Genetics (Impact Factor: 6.39). 08/2007; 16(14):1682-98. DOI: 10.1093/hmg/ddm116
Source: PubMed


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.

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    • "The hypothesis is that molecular commonalities might be revealed across individuals , helping to explain the autistic phenotype regardless of their genetic background or specific causal variants underlying their autism. In agreement with this, two previous studies reported some convergence in the transcriptomes of independent ASD cohorts [Nishimura et al., 2007; Voineagu et al., 2011]. Nishimura et al. [2007] studied ASD individuals with either maternally derived 15q duplications, or fragile–X mutations (FMR1-FM). "
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    • "Although no report has yet suggested that NeuroD1 strongly binds to FMRP (Brown et al. 2001; Miyashiro et al. 2003; Darnell et al. 2011), the binding of FMRP to RNA targets is more complex than originally speculated. Actually, several mRNA and protein targets such as JAKMIP1, GPR155, and CYFIP2 (Nishimura et al. 2007; Hoeffer et al. 2012) were not included in the original list of the binding partner RNAs for FMRP (Brown et al. 2001; Miyashiro et al. 2003). For example, CYFIP2 mRNA contains no structural motif recognized by FMRP, but still, it was identified as a mRNP (messenger ribonucleoprotein) associated with FMRP (Darnell et al. 2011). "
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    • "For analysis, we collected 2,159 pathways that included modified Gene Ontology (GO) terms [44], Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways [45,46], Reactome pathways [47], and Biocarta pathways ( from the Molecular Signatures Database (MSigDb) version 3.0 [48], two genesets consisting of differentially expressed genes for autism-linked syndromes i.e., Fragile X mental retardation and 15q duplication based on the data of Nishimura and colleagues [19], and two sets of de novo mutation-containing genes from two recent exome sequencing studies [49,50] (see Methods). "
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