Gene Expression Profiling of Lymphoblasts from Autistic and Nonaffected Sib Pairs: Altered Pathways in Neuronal Development and Steroid Biosynthesis

Department of Biochemistry and Molecular Biology, The George Washington University Medical Center, Washington, DC, USA.
PLoS ONE (Impact Factor: 3.23). 02/2009; 4(6):e5775. DOI: 10.1371/journal.pone.0005775
Source: PubMed


Despite the identification of numerous autism susceptibility genes, the pathobiology of autism remains unknown. The present "case-control" study takes a global approach to understanding the molecular basis of autism spectrum disorders based upon large-scale gene expression profiling. DNA microarray analyses were conducted on lymphoblastoid cell lines from over 20 sib pairs in which one sibling had a diagnosis of autism and the other was not affected in order to identify biochemical and signaling pathways which are differentially regulated in cells from autistic and nonautistic siblings. Bioinformatics and gene ontological analyses of the data implicate genes which are involved in nervous system development, inflammation, and cytoskeletal organization, in addition to genes which may be relevant to gastrointestinal or other physiological symptoms often associated with autism. Moreover, the data further suggests that these processes may be modulated by cholesterol/steroid metabolism, especially at the level of androgenic hormones. Elevation of male hormones, in turn, has been suggested as a possible factor influencing susceptibility to autism, which affects approximately 4 times as many males as females. Preliminary metabolic profiling of steroid hormones in lymphoblastoid cell lines from several pairs of siblings reveals higher levels of testosterone in the autistic sibling, which is consistent with the increased expression of two genes involved in the steroidogenesis pathway. Global gene expression profiling of cultured cells from ASD probands thus serves as a window to underlying metabolic and signaling deficits that may be relevant to the pathobiology of autism.

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Available from: Anhthu Nghiem Nguyen, Dec 30, 2013
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    • "Atypical levels of sex steroid hormones and their biosynthetic pathway have been associated with autism spectrum conditions (ASC) or associated with autistic traits in genetic [1-3], gene expression [4,5], serum [6,7], amniotic fluid [8] and 2D:4D ratio of 2nd digit to 4th digit [9] studies. Elevated levels of prenatal androgens such as fetal testosterone (FT) during a critical period are hypothesized to contribute to the etiology of ASC [10] as FT shapes neurological development [11-13]. "
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    ABSTRACT: Prenatal exposure to increased androgens has been implicated in both polycystic ovary syndrome (PCOS) and autism spectrum conditions (ASC), suggesting that PCOS may be increased among women with ASC. One study suggested elevated steroidopathic symptoms ('steroidopathy') in women with ASC. As the symptoms are not independent, we conducted a latent class analysis (LCA). The objectives of the current study are: (1) to test if these findings replicate in a larger sample; and (2) to use LCA to uncover affected clusters of women with ASC. We tested two groups of women, screened using the Autism Spectrum Quotient - Group 1: n = 415 women with ASC (mean age 36.39 +/- 11.98 years); and Group 2: n = 415 controls (mean age 39.96 +/- 11.92 years). All participants completed the Testosterone-related Medical Questionnaire online. A multiple-group LCA was used to identify differences in latent class structure between women with ASC and controls. There were significant differences in frequency of steroid-related conditions and symptoms between women with ASC and controls. A two-class semi-constrained model best fit the data. Based on response patterns, we identified the classes as 'Typical' and 'Steroidopathic'. The prevalence of the 'Steroidopathic' class was significantly increased within the ASC group (DeltaG2 = 15, df =1, P = 0.0001). In particular, we confirmed higher frequencies of epilepsy, amenorrhea, dysmenorrhea, severe acne, gender dysphoria, and transsexualism, and differences in sexual preference in women with ASC. Women with ASC are at increased risk for symptoms and conditions linked to steroids. LCA revealed this steroidopathy despite the apparent underdiagnosis of PCOS.
    Full-text · Article · Apr 2014 · Molecular Autism
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    • "The top-ranked differentially expressed transcripts (P < 0.001) are listed in Table 1. Strikingly, almost a quarter of these differentially expressed loci have been previously implicated in the aetiology of autism, including Gstm1 (deletion in GSTM1 observed in autism case-parent trios) [16], Ccdc90b (missense mutation associated with autism in a study of cases and their parents) [17], Cd44 (differential expression in autism discordant monozygotic twins) [18], Accn1 (multiple SNPs associated with autism in a familial study) [19], Shh (increased serum SHH expression in autistic patients compared to non-autistic controls) [20], Dus1l (de novo missense mutation observed in autism families) [21] and Ier5l (increased expression in lymphoblast cells from autism patients in discordant sibling pairs) [22]. "
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    ABSTRACT: Advanced paternal age is robustly associated with several human neuropsychiatric disorders, particularly autism. The precise mechanism(s) mediating the paternal age effect are not known, but they are thought to involve the accumulation of de novo (epi)genomic alterations. In this study we investigate differences in the frontal cortex transcriptome in a mouse model of advanced paternal age. Transcriptomic profiling was undertaken for medial prefrontal cortex tissue dissected from the male offspring of young fathers (2 month old, 4 sires, n = 16 offspring) and old fathers (10 month old, 6 sires, n = 16 offspring) in a mouse model of advancing paternal age. We found a number of differentially expressed genes in the offspring of older fathers, many previously implicated in the aetiology of autism. Pathway analysis highlighted significant enrichment for changes in functional networks involved in inflammation and inflammatory disease, which are also implicated in autism. We observed widespread alterations to the transcriptome associated with advanced paternal age with an enrichment of genes associated with inflammation, an interesting observation given previous evidence linking the immune system to several neuropsychiatric disorders including autism.
    Full-text · Article · Mar 2014 · Molecular Autism
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    • "Molecular Tissue Culture Studies Hu et al. (2009) "
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    ABSTRACT: Subjects diagnosed with an autism spectrum disorder (ASD) have a male-female ratio of at least 4:1, and among subjects diagnosed with Asperger’s syndrome (AS), the male-female ratio is as high as 9:1. In addition, studies have revealed hormonal patterns consistent with significantly elevated androgen levels in subjects diagnosed with an ASD relative to controls. As a result, it is important to examine evidence of the association between hyperandrogenism and autistic traits (ATs) among subjects diagnosed with an ASD and to evaluate the effectiveness of antiandrogen therapy as a means to help treat ATs in subjects diagnosed with an ASD. Evidence of hyperandrogenism in subjects diagnosed with an ASD is supported by multiple studies in the areas of psychological framework, brain pathology, tissue culture, and pre- and postnatal androgen levels. Data from subjects diagnosed with other conditions associated with elevated androgens reveals that many of these individuals have ATs. For example, in a placebo-controlled trial of testosterone administration to neurotypical subjects, testosterone was found to increase ATs. In addition, a controlled trial of human transsexuals revealed a significant increase in ATs in female-to-male transsexuals and a decrease in ATs in male-to-female transsexuals. Data from multiple animals and human clinical trials suggest that antiandrogen medications have the ability to significantly reduce ATs in subjects diagnosed with an ASD. In light of the robust association between hyperandrogenism and ASD, subjects diagnosed with an ASD should undergo routine screening for elevated androgens, and appropriate treatment should be initiated for those with significantly elevated androgens.
    Full-text · Chapter · Jan 2014
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