Abstract
While abnormal signaling mediated through metabotropic glutamate receptor 5 (mGluR5) is involved in the pathophysiology of Autism Spectrum Disorder (ASD), Fragile X Syndrome and Tuberous Sclerosis, the role of other mGluRs and their associated signaling network genes in syndromic ASD is unknown. This study sought to determine whether mGluR Copy Number Variants (CNV’s) were overrepresented in children with syndromic ASD and if mGluR “second hit” confers additional risk for ASD in 22q11.2 Deletion Syndrome (22q11DS). To determine whether mGluR network CNV’S are enriched in syndromic ASD, we examined microarrays from children with ASD (n = 539). Patient categorization (syndromic vs nonsyndromic) was done via blinded medical chart review in mGluR positive and randomly selected mGluR negative cases. 11.5% of ASD had mGluR CNV’s vs. 3.2% in controls (p < 0.001). Syndromic ASD was more prevalent in children with mGluR CNVs (74% vs 16%, p < 0.001). A comparison cohort with 22q11DS (n = 25 with ASD, n = 50 without ASD), all haploinsufficient for mGluR network gene RANBP1, were evaluated for “second mGluR hits”. 20% with 22q11.2DS + ASD had “second hits” in mGluR network genes vs 2% in 22q11.2DS-ASD (p < 0.014). We propose that altered RANBP1 expression may provide a mechanistic link for several seemingly unrelated genetic and environmental forms of ASD.Introduction
Autism Spectrum Disorder (ASD) occurs in approximately 1/88 individuals and is characterized by impairment in social communication and repetitive interests and activities1. Approximately 20% of cases occur in the context of an identifiable syndrome2. Genetic syndromes with ASD are heterogeneous, including cytogenetically visible chromosomal alterations (e.g. Trisomy 21), microdeletion and microduplication syndromes (e.g. 22q11.2 deletion syndrome [22q11.2DS]); and monogenic disorders (e.g. Fragile X Syndrome [FXS], Tuberous Sclerosis [TS])3,4,5,6,7,8,9,10,11,12,13. In addition, prenatal exposure to thalidomide, valproic acid, misoprostol, ethanol and maternal rubella infection, have been associated with an elevated risk of ASD14,15,16,17,18,19. The mechanism for the development of ASD in most forms of idiopathic and syndromic forms of ASD remains elusive. Recently, signaling through metabotropic glutamate receptor 5 (mGluR5) as linked to the mTOR pathway has been implicated in the development of ASD in FXS and TS20. In FXS, abnormal production of Fragile X Mental Retardation Protein (FMRP) removes normal inhibition of signaling through the mGluR pathway. Tuberous Sclerosis leads to over-inhibition of signaling. Auerbach and colleagues demonstrated abnormal synaptic learning and atypical behavior in mouse models of FXS and TS, and reversed these effects by breeding the two strains together – mice harboring both mutations had normal mGluR signaling, and learning and behavior that was indistinguishable from control mice20. Other studies have demonstrated normalization of learning and behavior in Fragile X mice by administration of an mGluR5 antagonist21,22. In addition to elucidating the mechanism for cognitive and behavioral differences in FXS and TS, these studies suggest a promising avenue for pharmacological treatment. Evidence from recent human studies and animal models suggest that syndromic forms of ASD have behavioral overlap with idiopathic ASD but that there are identifiable behavioral signatures in each disorder23. Bruining and colleagues used Support Vector Machine learning to assess behavioral profiles on the Autism Diagnostic Interview in six syndromes with elevated risk of ASD: 22q11.2 Deletion Syndrome, Down’s syndrome, Prader-Willi, supernumerary marker chromosome 15, tuberous sclerosis and Klinefelter syndrome23. An identifiable behavioral profile was present within each syndrome for those who met and did not meet criteria for ASD, suggesting a spectrum of severity rather than subgroups of patients with and without ASD in each group. The behavioral signature of children with idiopathic ASD was most similar to children with Tuberous Sclerosis, which the authors propose is due to convergence of many forms of ASD on the mTOR pathway.Read the Full Article Here: http://www.nature.com/articles/srep19372
