Xq11.1-11.2 deletion involving ARHGEF9 in a girl with autism spectrum disorder

Bhat, Gifty; LaGrave, Danielle; Millson, Alison; Herriges, John; Lamb, Allen N.; Matalon, Reuben

doi:10.1016/j.ejmg.2016.05.014

Cited by 21 publications

(21 citation statements)

References 18 publications

(27 reference statements)

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“…Here, only the latter was observed in SPICA-null mice (Figures 3E and 4). This finding suggests that SPICA is also potentially responsible for the autism spectrum disorder noted in an individual patient that is associated with deletion of Xq11.1-11.2, which involves the SPICA-encoding exon (Bhat et al, 2016). Also, the global developmental delay diagnosed for this patient is consistent with the reduced body weight of SPICA-null mice ( Figure 4B).…”

Section: Discussionsupporting

confidence: 52%

“…Collybistin participates in inhibitory synapse development by recruiting gephyrin, the main scaffolding protein in inhibitory postsynaptic densities (Grosskreutz et al, 2001;Harvey et al, 2004;Papadopoulos et al, 2007). This well-studied molecular function of collybistin has been used to explain the neurological genetic disorders associated with disruption of the ARHGEF9 locus (Bhat et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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Autonomous functionality of an upstream open reading frame in polycistronic mammalian mRNAs

Kitano

Pratt

Takao

et al. 2018

Preprint

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Upstream open reading frames (uORFs) are established as cis-acting elements for eukaryotic translation of annotated ORFs (anORFs) located on the same mRNAs. Here, we identified a mammalian uORF with functions that are independent from anORF translation regulation. Bioinformatics screening using ribosome profiling data of human and mouse brains yielded 308 neurologically vital genes from which anORF and uORFs are polycistronically translated in both species. Among them, Arhgef9 contains a uORF named SPICA, which is highly conserved among vertebrates and stably translated only in specific brain regions of mice. Disruption of SPICA translation by ATG-to-TAG substitutions did not perturb translation or function of its anORF product, collybistin. SPICA-null mice displayed abnormal maternal reproductive performance and enhanced anxiety-like behavior, characteristic of ARHGEF9-associated neurological disorders. This study demonstrates that mammalian uORFs can be independent genetic units, revising the prevailing dogma of the monocistronic gene in mammals, and even eukaryotes. Keywordsgene expression, upstream open reading frame (uORF), polycistronic translation, behavioral control RESULTS Bicistronic Genes in Human and Mouse BrainsWe first used Ribo-seq data for human and mouse brains (Gonzalez et al., 2014) to search for mammalian mRNAs from which uORF regions and anORFs on individual mRNAs were co-translated at equivalent levels, with the assumption that some uORFs on these mRNAs could be translated in a manner that is not coordinated with anORF translation ( Figure 1A). We obtained 13,602 human and 8,246 mouse mRNAs that are translated mRNAs in the brain, to which either an anORF or merged uORF ( Figure 1B), or both were mapped with reads of at least 1 read per kilobase per million mapped reads (RPKM). Of these, 4,728 human and 4,767 mouse mRNAs (2,522 human and 3,173 mouse genes, respectively) were loaded with translating ribosomes at equivalent densities on both anORFs and the merged uORFs (termed "polycistronic genes"; Figure 1, C and D).Gene ontology (GO) enrichment analysis showed that these polycistronic genes were significantly associated with neural GO terms in both species, especially terms related to the synapse, as compared with all the 13,602 human and 8,246 mouse mRNAs that are translated mRNAs in the brain as the background (Figure 1, E and F). This implies that some of these brain-specific polycistronic genes might be evolutionarily adapted to use uORF translation for establishing and/or regulating synaptic communication underlying brain function.The 1,439 genes that were polycistronically translated in both human and mouse brains were then screened for genes that were previously shown to regulate brain functions by knockout mouse studies, as specified in the Mouse Genome Informatics database (Blake et al., 2009), which resulted in the identification of 308 genes. After filtering the 308 genes based on their length and conservation of amino acid sequences coded in the uORFs (≥31 codons in length and ≥ ...

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Section: Discussionsupporting

confidence: 52%

Section: Introductionmentioning

confidence: 99%

Autonomous functionality of an upstream open reading frame in polycistronic mammalian mRNAs

Kitano

Pratt

Takao

et al. 2018

Preprint

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“…Therefore, ARHGEF9 is an important component of the inhibitory synapses [160]. Several case studies have revealed mutations in the ARHGEF9 gene leading to XLMR, ASD, along with phenotypes such as seizures and epilepsy [131,149,150,151,152,153,160]. A dominant-negative missense mutation, p.G55A, has been linked to severe mental retardation, hyperekplexia, drug-resistant seizures, and premature death in a male patient [160].…”

Section: Regulators Of Rho Gtpases In Neurological Disordersmentioning

confidence: 99%

“…In one of the cases, the mutation led to epilepsy, anxiety, aggression, and MR, while in the other case, the patient had XLMR and sensory hyperarousal [149,152]. Finally, an 82 kb deletion including ARHGEF9 gene has been detected in an 8-year-old female with ASD, intellectual disability, and speech delay [131]. Altogether, these case studies highlight that the role of ARHGEF9 in gephyrin mediated postsynaptic membrane organization in inhibitory synapses is of critical importance during brain development.…”

Section: Regulators Of Rho Gtpases In Neurological Disordersmentioning

confidence: 99%

Regulators of Rho GTPases in the Nervous System: Molecular Implication in Axon Guidance and Neurological Disorders

Niftullayev

Lamarche-Vane

2019

IJMS

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One of the fundamental steps during development of the nervous system is the formation of proper connections between neurons and their target cells—a process called neural wiring, failure of which causes neurological disorders ranging from autism to Down’s syndrome. Axons navigate through the complex environment of a developing embryo toward their targets, which can be far away from their cell bodies. Successful implementation of neuronal wiring, which is crucial for fulfillment of all behavioral functions, is achieved through an intimate interplay between axon guidance and neural activity. In this review, our focus will be on axon pathfinding and the implication of some of its downstream molecular components in neurological disorders. More precisely, we will talk about axon guidance and the molecules implicated in this process. After, we will briefly review the Rho family of small GTPases, their regulators, and their involvement in downstream signaling pathways of the axon guidance cues/receptor complexes. We will then proceed to the final and main part of this review, where we will thoroughly comment on the implication of the regulators for Rho GTPases—GEFs (Guanine nucleotide Exchange Factors) and GAPs (GTPase-activating Proteins)—in neurological diseases and disorders.

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“…Through these domains, collybistin has been shown to interact with gephyrin, neuroligin-2, and the GABA A R α2 subunit, playing an important role in clustering of GABA A Rs at inhibitory synapses ( Saiepour et al, 2010 ). To this point, 18 patients have been described to have either point mutations, chromosomal rearrangements and deletions involving ARHGEF9 , with a range of manifestations including ASD ( Bhat et al, 2016 ; Machado et al, 2016 ), behavior disorders (ADHD, anxiety, aggression; Kalscheuer et al, 2009 ; Lesca et al, 2011 ), intellectual disability ( Kalscheuer et al, 2009 ; Lesca et al, 2011 ; Marco et al, 2011 ; Shimojima et al, 2011 ; de Ligt et al, 2012 ; Lemke et al, 2012 ), hyperekplexia ( Harvey et al, 2004 ; Marco et al, 2008 ), and infantile epilepsy ( Harvey et al, 2004 ; Kalscheuer et al, 2009 ; Lesca et al, 2011 ; Shimojima et al, 2011 ). The majority of patients identified are male, and those that are female have been shown to have a near complete X-inactivation in favor of the affected gene ( Marco et al, 2008 ; Kalscheuer et al, 2009 ).…”

Section: Very Rare Mutations and Associated Disordersmentioning

confidence: 99%

Common Ribs of Inhibitory Synaptic Dysfunction in the Umbrella of Neurodevelopmental Disorders

Rodriguez

Joya

Hines

2018

Front. Mol. Neurosci.

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The term neurodevelopmental disorder (NDD) is an umbrella term used to group together a heterogeneous class of disorders characterized by disruption in cognition, emotion, and behavior, early in the developmental timescale. These disorders are heterogeneous, yet they share common behavioral symptomatology as well as overlapping genetic contributors, including proteins involved in the formation, specialization, and function of synaptic connections. Advances may arise from bridging the current knowledge on synapse related factors indicated from both human studies in NDD populations, and in animal models. Mounting evidence has shown a link to inhibitory synapse formation, specialization, and function among Autism, Angelman, Rett and Dravet syndromes. Inhibitory signaling is diverse, with numerous subtypes of inhibitory interneurons, phasic and tonic modes of inhibition, and the molecular and subcellular diversity of GABAA receptors. We discuss common ribs of inhibitory synapse dysfunction in the umbrella of NDD, highlighting alterations in the developmental switch to inhibitory GABA, dysregulation of neuronal activity patterns by parvalbumin-positive interneurons, and impaired tonic inhibition. Increasing our basic understanding of inhibitory synapses, and their role in NDDs is likely to produce significant therapeutic advances in behavioral symptom alleviation for interrelated NDDs.

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Xq11.1-11.2 deletion involving ARHGEF9 in a girl with autism spectrum disorder

Cited by 21 publications

References 18 publications

Autonomous functionality of an upstream open reading frame in polycistronic mammalian mRNAs

Autonomous functionality of an upstream open reading frame in polycistronic mammalian mRNAs

Regulators of Rho GTPases in the Nervous System: Molecular Implication in Axon Guidance and Neurological Disorders

Common Ribs of Inhibitory Synaptic Dysfunction in the Umbrella of Neurodevelopmental Disorders

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