Predicting the diagnosis of autism spectrum disorder using gene pathway analysis

Skafidas, Efstratios; Testa, Renée; Zantomio, Daniela; Chana, Gursharan; Everall, Ian; Pantelis, Christos

doi:10.1038/mp.2012.126

Cited by 134 publications

(153 citation statements)

References 48 publications

Supporting

Mentioning

142

Contrasting

Unclassified

Order By: Relevance

“…Dysregulation of BK channel isoform expression has also been linked to a mild form of autosomal recessive nonsyndromal mental retardation (37). Probably the most compelling evidence comes from another report showing that the SNPs with the highest risk for autism spectrum disorder were found in KCNMB4, the gene encoding the β4-subunit of the BK channel (38). BK channels have also been implicated in epilepsy and seizure disorders in numerous cases through both loss-of-function and gain-of-function mechanisms (39).…”

Section: Discussionmentioning

confidence: 88%

Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures

Myrick¹,

Deng²,

Hashimoto³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

107

131

View full text Add to dashboard Cite

Fragile X syndrome (FXS) results in intellectual disability (ID) most often caused by silencing of the fragile X mental retardation 1 (FMR1) gene. The resulting absence of fragile X mental retardation protein 1 (FMRP) leads to both pre-and postsynaptic defects, yet whether the pre-and postsynaptic functions of FMRP are independent and have distinct roles in FXS neuropathology remain poorly understood. Here, we demonstrate an independent presynaptic function for FMRP through the study of an ID patient with an FMR1 missense mutation. This mutation, c.413G > A (R138Q), preserves FMRP's canonical functions in RNA binding and translational regulation, which are traditionally associated with postsynaptic compartments. However, neuronally driven expression of the mutant FMRP is unable to rescue structural defects at the neuromuscular junction in fragile x mental retardation 1 (dfmr1)-deficient Drosophila, suggesting a presynaptic-specific impairment. Furthermore, mutant FMRP loses the ability to rescue presynaptic action potential (AP) broadening in Fmr1 KO mice. The R138Q mutation also disrupts FMRP's interaction with the large-conductance calciumactivated potassium (BK) channels that modulate AP width. These results reveal a presynaptic-and translation-independent function of FMRP that is linked to a specific subset of FXS phenotypes.F ragile X syndrome (FXS) is the most common single-gene disorder responsible for intellectual disability (ID) in patients (1). Along with cognitive dysfunction, the syndrome typically presents with several other comorbidities, including behavioral and social impairments (anxiety and autism spectrum disorder), neurological defects (seizures and abnormal sleep patterns), and morphological abnormalities (dysmorphic facies and macroorchidism). Most patients inherit the syndrome through a maternal repeat expansion mutation that transcriptionally silences the FMR1 gene and results in loss of the gene product, FMRP.FMRP has complex multifaceted functions at synapses both in pre-and postsynaptic compartments. As an RNA binding protein, FMRP is best known for its function as a translation regulator in dendrites (2). Loss of FMRP has been linked to various forms of long-term synaptic plasticity defects that depend on local protein synthesis in the postsynaptic neuron (3). In addition to disrupted metabotropic glutamate receptor signaling, which has been shown across multiple brain regions (4-7), FMRP is necessary for activitydependent protein synthesis downstream of other signaling receptor pathways, including ACh, dopamine, and TrkB (8-10).Although postsynaptic control of translation is believed to be the dominant function of FMRP, it is unable to explain all of the pathophysiology observed in FXS animal models. For instance, in Drosophila, presynaptic expression of the FMR1 homolog, dfmr1, completely rescues the synaptic overgrowth phenotype at the neuromuscular junction (NMJ) in dfmr1-null mutants (11-13). In rodent brain, FMRP has been found in structures called fragile-X granules, which are ...

show abstract

Section: Discussionmentioning

confidence: 88%

Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures

Myrick¹,

Deng²,

Hashimoto³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

107

131

View full text Add to dashboard Cite

show abstract

“…A relevant study based on the analysis of signaling pathways implicated in ASD etiology of 1000 individuals with ASD from the Autism Genetic Resource Exchange (AGRE) identified SNPs in 146 genes. From 15 high‐risk SNPs linked to ASD found in the study, two of them are found in CACNA1A encoding Ca V 2.1 of Ca 2+ channel and in CACNA2D3 gene encoding for α 2 δ 3 subunit of voltage‐gated Ca 2+ channel (Skafidas et al., 2014). A recent study in Chinese Han population reported for the first time the association of two markers (rs7249246 and rs12609735) in CACNA1A gene with patients with ASD (Li et al., 2015).…”

Section: Reviewmentioning

confidence: 99%

“…This variation causes the substitution of isoleucine to phenylalanine at codon 199 (p.I199F) leading to significant depolarizing shifts in the voltage dependence of activation and inactivation of the channel (Calhoun, Vanoye, Kok, George, & Kearney, 2017; Table 2). The regulatory β 4 subunit gene of BK Ca channel ( KCNMB4 ) was classified as one of the three predictive genes in ASD as it was strongly associated with SNPs‐ASD‐associated in a large meta‐analysis study (Skafidas et al., 2014; Table 3). On the other hand, a variation of KCNQ3 gene mapped to chromosome 8q24, encoding the voltage‐gated potassium channel K v 7.3, has been linked to epilepsy.…”

Section: Reviewmentioning

confidence: 99%

Autism throughout genetics: Perusal of the implication of ion channels

et al. 2018

View full text Add to dashboard Cite

BackgroundAutism spectrum disorder (ASD) comprises a group of neurodevelopmental psychiatric disorders characterized by deficits in social interactions, interpersonal communication, repetitive and stereotyped behaviors and may be associated with intellectual disabilities. The description of ASD as a synaptopathology highlights the importance of the synapse and the implication of ion channels in the etiology of these disorders.MethodsA narrative and critical review of the relevant papers from 1982 to 2017 known by the authors was conducted.ResultsGenome‐wide linkages, association studies, and genetic analyses of patients with ASD have led to the identification of several candidate genes and mutations linked to ASD. Many of the candidate genes encode for proteins involved in neuronal development and regulation of synaptic function including ion channels and actors implicated in synapse formation. The involvement of ion channels in ASD is of great interest as they represent attractive therapeutic targets. In agreement with this view, recent findings have shown that drugs modulating ion channel function are effective for the treatment of certain types of patients with ASD.ConclusionThis review describes the genetic aspects of ASD with a focus on genes encoding ion channels and highlights the therapeutic implications of ion channels in the treatment of ASD.

show abstract

“…(Gai et al 2012) Specific genes that have been suggested to be implicated include GRM5, which codes for mGluR5, and several genes that code for proteins involved in the signaling cascade downstream of mGluR5 (Kelleher et al 2012;Skafidas et al 2012). Although findings are not uniformly consistent, behavioral pharmacology studies show that mGluR5 antagonists or negative allosteric modulators of mGluR5 rescue the impairments in social behavior that are seen in several putative mouse models of ASD, such as the BTBR mouse (Silverman et al 2012), the Nlgn3-knockout mouse (Baudouin et al 2012), and mice exposed prenatally to valproic acid (Gandal et al 2010).…”

Section: Introductionmentioning

confidence: 99%

STX209 (Arbaclofen) for Autism Spectrum Disorders: An 8-Week Open-Label Study

Erickson

Veenstra‐VanderWeele

Melmed

et al. 2013

J Autism Dev Disord

108

View full text Add to dashboard Cite

STX209 (arbaclofen), a selective GABA-B agonist, is hypothesized to modulate the balance of excitatory to inhibitory neurotransmission, and has shown preliminary evidence of benefit in fragile X syndrome. We evaluated its safety, tolerability, and efficacy in non-syndromic autism spectrum disorders, in an 8-week open-label trial enrolling 32 children and adolescents with either Autistic Disorder or Pervasive Developmental Disorder-Not Otherwise Specified, and a score ≥17 on the Aberrant Behavior Checklist (ABC)-Irritability subscale. STX209 was generally well-tolerated. The most common adverse events were agitation and irritability, which typically resolved without dose changes, and were often felt to represent spontaneous variation in underlying symptoms. Improvements were observed on several outcome measures in this exploratory trial, including the ABC-Irritability (the primary endpoint) and the Lethargy/Social Withdrawal subscales, the Social Responsiveness Scale, the CY-BOCS-PDD, and clinical global impression scales. Placebo-controlled study of STX209 is warranted.

show abstract

Predicting the diagnosis of autism spectrum disorder using gene pathway analysis

Cited by 134 publications

References 48 publications

Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures

Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures

Autism throughout genetics: Perusal of the implication of ion channels

STX209 (Arbaclofen) for Autism Spectrum Disorders: An 8-Week Open-Label Study

Contact Info

Product

Resources

About