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

Emory University, Atlanta, Georgia, United States
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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    • "(Cahoy et al., 2008; Vidal et al., 2009). We found that JAKMIP1 was differentially expressed in patients with two syndromic forms of ASD, fragile X and (dup)15q11-13 syndrome, and upon RBFOX1 knockdown (Fogel et al., 2012; Nishimura et al., 2007). To date, 11 ASD subjects have been identified with copy-number variants that contain JAKMIP1 (Szatmari et al., 2007; Kaminsky et al., 2011; Poultney et al., 2013; Tzetis et al., 2012). "
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    ABSTRACT: Autism spectrum disorder (ASD) is a heritable, common neurodevelopmental disorder with diverse genetic causes. Several studies have implicated protein synthesis as one among several of its potential convergent mechanisms. We originally identified Janus kinase and microtubule-interacting protein 1 (JAKMIP1) as differentially expressed in patients with distinct syndromic forms of ASD, fragile X syndrome, and 15q duplication syndrome. Here, we provide multiple lines of evidence that JAKMIP1 is a component of polyribosomes and an RNP translational regulatory complex that includes fragile X mental retardation protein, DEAD box helicase 5, and the poly(A) binding protein cytoplasmic 1. JAKMIP1 loss dysregulates neuronal translation during synaptic development, affecting glutamatergic NMDAR signaling, and results in social deficits, stereotyped activity, abnormal postnatal vocalizations, and other autistic-like behaviors in the mouse. These findings define an important and novel role for JAKMIP1 in neural development and further highlight pathways regulating mRNA translation during synaptogenesis in the genesis of neurodevelopmental disorders.
    Full-text · Article · Nov 2015 · Neuron
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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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    ABSTRACT: Autism spectrum disorders (ASD) are clinically heterogeneous and biologically complex. In general it remains unclear, what biological factors lead to changes in the brains of autistic individuals. A considerable number of transcriptome analyses have been performed in attempts to address this question, but their findings lack a clear consensus. As a result, each of these individual studies has not led to any significant advance in understanding the autistic phenotype as a whole. Here, we report a meta-analysis of more than 1000 microarrays across twelve independent studies on expression changes in ASD compared to unaffected individuals, in both blood and brain tissues. We identified a number of known and novel genes that are consistently differentially expressed across three studies of the brain (71 samples in total). A subset of the highly ranked genes is suggestive of effects on mitochondrial function. In blood, consistent changes were more difficult to identify, despite individual studies tending to exhibit larger effects than the brain studies. Our results are the strongest evidence to date of a common transcriptome signature in the brains of individuals with ASD. Autism Res 2015. © 2015 International Society for Autism Research, Wiley Periodicals, Inc. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.
    Full-text · Article · Feb 2015 · Autism Research
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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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    ABSTRACT: Fragile X mental retardation protein (FMRP) is encoded by Fmr1 gene in which mutation is known to cause fragile X syndrome characterized by mental impairment and other psychiatric symptoms similar to autism spectrum disorders. FMRP plays important roles in cellular mRNA biology such as transport, stability, and translation as an RNA-binding protein. In the present study, we identified potential role of FMRP in the neural differentiation, using cortical neural progenitor cells from Sprague-Dawley rat. We newly found NeuroD1, an essential regulator of glutamatergic neuronal differentiation, as a new mRNA target interacting with FMRP in co-immunoprecipitation experiments. We also identified FMRP as a regulator of neuronal differentiation by modulating NeuroD1 expression. Down-regulation of FMRP by siRNA also increased NeuroD1 expression along with increased pre- and post-synaptic development of glutamatergic neuron, as evidenced by Western blot and immunocytochemistry. On the contrary, cells harboring FMRP over-expression construct showed decreased NeuroD1 expression. Treatment of cultured neural precursor cells with a histone deacetylase inhibitor, valproic acid known as an inducer of hyper-glutamatergic neuronal differentiation, down-regulated the expression of FMRP, and induced NeuroD1 expression. Our study suggests that modulation of FMRP expression regulates neuronal differentiation by interaction with its binding target mRNA, and provides an example of the gene and environmental interaction regulating glutamatergic neuronal differentiation.
    Full-text · Article · Dec 2013 · Cellular and Molecular Neurobiology
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