Gene expression profiling differentiates autism case–controls and phenotypic variants of autism spectrum disorders: evidence for circadian rhythm dysfunction in severe autism

Abstract

Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by delayed/abnormal language development, deficits in social interaction, repetitive behaviors and restricted interests. The heterogeneity in clinical presentation of ASD, likely due to different etiologies, complicates genetic/biological analyses of these disorders. DNA microarray analyses were conducted on 116 lymphoblastoid cell lines (LCL) from individuals with idiopathic autism who are divided into three phenotypic subgroups according to severity scores from the commonly used Autism Diagnostic Interview-Revised questionnaire and age-matched, nonautistic controls. Statistical analyses of gene expression data from control LCL against that of LCL from ASD probands identify genes for which expression levels are either quantitatively or qualitatively associated with phenotypic severity. Comparison of the significant differentially expressed genes from each subgroup relative to the control group reveals differentially expressed genes unique to each subgroup as well as genes in common across subgroups. Among the findings unique to the most severely affected ASD group are 15 genes that regulate circadian rhythm, which has been shown to have multiple effects on neurological as well as metabolic functions commonly dysregulated in autism. Among the genes common to all three subgroups of ASD are 20 novel genes mostly in putative noncoding regions, which appear to associate with androgen sensitivity and which may underlie the strong 4:1 bias toward affected males.

Abnormal Cell Properties and Down-Regulated FAK-Src Complex Signaling in B Lymphoblasts of Autistic Subjects

“…One of them reported reduced integrin ␤1 expression in autistic samples using a microarray approach, which supports our findings. [37][38][39][40][41] FAK and Src family members are the major proteins localized to FAs, which are sites of cell attachment to the ECM. Reelin has exerted a proteolytic activity on ECM proteins through the activation of integrin ␤1.…”

Subphenotype-Dependent Disease Markers for Diagnosis and Personalized Treatment of Autism Spectrum Disorders

“…The odds ratio for the SNP rs7725785 at the intron boundary of HTR4 is 1.44 for the severe ASD phenotype while the odds ratio is ∼0.7 for both the mild and moderate phenotypes. This geneticallydefined difference in susceptibility is corroborated by separate studies involving gene expression profiling of lymphoblastoid cell lines (LCL) from these three ASD subtypes in which the expression of HTR4 was downregulated in the language-impaired group, but not in the mild or moderate subgroups [17]. This corroboration suggests a functional connection between this intronic SNP and gene expression, and provides independent support for the differential subtype-dependent involvement of HTR4 in ASD.…”

“…To test the hypothesis that these ASD behavioral subphenotypes represented distinct biological phenotypes, we conducted large-scale gene expression analyses on lymphoblastoid cell lines (LCL) derived from individuals in 3 of the 4 defined ASD phenotypes: the severely language-impaired, the mild, and the "savant" subtypes [17]. The resulting gene expression profiles -2012-0916) differentiated the individuals with ASD from controls while distinguishing each ASD subtype from the others, thus associating a "biological phenotype" with a specific behavioral or symptomatic phenotype.…”

Melatonin as an Interventional Novel Candidate for the Individual with Autistic Fragile X Syndrome in Human

“…Sleep disorder is common in patients with neurological diseases [83][84][85]. Melatonin modulating the sleep pattern and the circadian rhythms is associated with development of ASD [86,87].…”