Genome-wide expression profiling of lymphoblastoid cell lines distinguishes different forms of autism and reveals shared pathways †
Abstract
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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DOCK4 mRNA levels are decreased in blood-derived lymphoblastoid cells of two populations of ASD patients.
“Moreover, evidence has shown decreased mRNA levels of DOCK4 in blood derived lymphoblastoid cells of two populations of ASD patients (Supplementary Figure 1) 28.”
From Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function. (2021) · cites this paper as [28]
Genome-wide expression profiling of patients with duplication of 15q11-q13 has demonstrated upregulated Cyfip1 mRNA in those with autism spectrum disorder.
“Furthermore, genome-wide expression profiling of patients with duplication of 15q11–q13 has specifically demonstrated upregulated Cyfip1 mRNA in those that suffer from ASD.10”
From The autism and schizophrenia associated gene CYFIP1 is critical for the maintenance of dendritic complexity and the stabilization of mature spines (2014) · cites this paper as [10]
Altered levels of CYFIP1 are associated with several neurological disorders including SCZ and ASD.
“Altered levels of CYFIP1 are associated with several neurological disorders including SCZ and ASD.4,5,10”
From The autism and schizophrenia associated gene CYFIP1 is critical for the maintenance of dendritic complexity and the stabilization of mature spines (2014) · cites this paper as [10]
CYFIP1 has been implicated in autism.
“CYFIP1 has been implicated in autism107,108.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [107]
Dysregulation or mutations of FMRP-interacting proteins such as CYFIP1, eIF4E, and a subset of FMRP mRNA targets may contribute to the autism spectrum disorder phenotype observed in fragile X syndrome.
“Recent evidence indicates that dysregulation and or mutations of FMRP-interacting proteins, such as the cytoplasmic FMRP-interacting protein 1 (CYFIP1) (52-55), eukaryotic initiation factor 4 (eIF4E) (56,57), and a subset of FMRP mRNA targets (58), may contribute to the ASD phenotype observed in FXS.”
From Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics (2012) · cites this paper as [53]
Maternal duplications of the 15q11-13 locus lead to increased expression of UBE3A and epigenetic silencing of the paternal antisense transcript, UBE3A-ATS.
“Maternal duplications of the 15q11–13 locus lead to increased expression of UBE3A and epigenetic silencing of the paternal antisense transcript, UBE3A-ATS121–124.”
From Rhythms of life: circadian disruption and brain disorders across the lifespan (2019) · cites this paper as [124]
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References 74 · Cited by 276
- Authors
- Nishimura, Y., Martin, C. L., Vazquez-Lopez, A., Spence, S. J., Alvarez-Retuerto, A. I., Sigman, M., Steindler, C., Pellegrini, S., Schanen, N. C., Warren, S. T., & Geschwind, D. H.
- Affiliations
- University of California, Los Angeles (US)
- Emory University (US)
- Institut Pasteur (FR)
- Alfred I. duPont Hospital for Children (US)
- Corresponding author
- Geschwind, Daniel H.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2007-05-21
- Volume
- 16
- Issue
- 14
- Pages
- 1682-1698
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2146036559
- Cited by
- 276
- References
- 74
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 12 · 2023: 5 · 2022: 8 · 2021: 8 · 2020: 8 · 2019: 12 · 2018: 9 · 2017: 12 · 2016: 10 · 2015: 20 · 2014: 20 · 2013: 20 · 2012: 22
- FWCI
- 12.90
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- National Institute of Mental Health (MH 64547, R01MH064547)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U91-HD35470, HD020S21)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Keywords
- autism spectrum disorder, FMR1 gene, lymphoblastoid cell lines, gene expression profiling, CYFIP1, genetic etiology of autism, blood-derived biomarkers
- MeSH terms
- Animals, Autistic Disorder, Fragile X Syndrome, Gene Expression Regulation, Humans, Lymphocytes, Cluster Analysis, RNA-Binding Proteins, Genome, Mice, Knockout, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Adaptor Proteins, Signal Transducing, Mice, Fragile X Mental Retardation Protein, Fragile X Messenger Ribonucleoprotein 1
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