Rare inherited <i>A2BP1</i> deletion in a proband with autism and developmental hemiparesis

Davis, Lea K.; Maltman, Nell; Mosconi, Matthew W.; Macmillan, Carol; Schmitt, Lauren; Moore, Kraig; Francis, Sunday M.; Jacob, Suma; Sweeney, John A.; Cook, Edwin H.

doi:10.1002/ajmg.a.35396

Cited by 37 publications

(42 citation statements)

References 42 publications

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“…In mice, disruption of Rbfox1 in neurons leads to neuronal hyperactivity while loss of Rbfox2 results in cerebellum development defects (Gehman et al, 2012; Gehman et al, 2011). Rbfox1 and Rbfox2 has been implicated in a number of diseases including cancer, diabetes and neurological disorders such as autism, mental retardation and epilepsy (Barnby et al, 2005; Bhalla et al, 2004; Davis et al, 2012; Mikhail et al, 2011; Sebat et al, 2007). In all these examples, the observed phenotypes have been attributed to perturbations in normal mRNA splicing patterns.…”

Section: Introductionmentioning

confidence: 99%

Repression of Pumilio Protein Expression by Rbfox1 Promotes Germ Cell Differentiation

et al. 2016

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RNA-binding Fox (Rbfox) proteins have well-established roles in regulating alternative splicing, but specific Rbfox isoforms lack nuclear localization signals and accumulate in the cytoplasm. The potential splicing-independent functions of these proteins remain unknown. Here we demonstrate that cytoplasmic Drosophila Rbfox1 regulates germ cell development and represses the translation of mRNAs containing (U)GCAUG elements within their 3′ UTRs. During germline cyst differentiation, Rbfox1 targets pumilio mRNA for destabilization and translational silencing, thereby promoting germ cell development. Mis-expression of pumilio results in the formation of germline tumors, which contain cysts that breakdown and dedifferentiate back to single, mitotically active cells. Together these results reveal that cytoplasmic Rbfox family members regulate the translation of specific target mRNAs. In the Drosophila ovary, this activity provides a genetic barrier that prevents germ cells from reverting back to an earlier developmental state. The finding that Rbfox proteins regulate mRNA translation has implications for Rbfox related diseases.

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Section: Introductionmentioning

confidence: 99%

Repression of Pumilio Protein Expression by Rbfox1 Promotes Germ Cell Differentiation

et al. 2016

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“…Among the mRNA targets for miR-980 , we demonstrate that the autism-susceptibility gene, A2bp1 (Ataxin2 binding protein 1, also known as Rbfox-1, Fox-1) is a primary target responsible for miR-980 directed memory suppression. A2bp1 is a known RNA binding protein involved in alternative splicing of a network of critical neuronal genes during development and in adults (Lee et al, 2009; Fogel et al, 2012) and in addition to autism (ASD), is associated with intellectual disability and epilepsy (Bhalla et al, 2004; Martin et al, 2007; Sebat et al, 2007; Mikhail et al, 2011; Davis et al, 2012). Opposite to the role for miR-980 , we identify A2bp1 as a memory-promoting gene.…”

Section: Introductionmentioning

confidence: 99%

MiR-980 Is a Memory Suppressor MicroRNA that Regulates the Autism-Susceptibility Gene A2bp1

et al. 2016

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SUMMARY MicroRNAs have been associated with many different biological functions but little is known about their roles in conditioned behavior. We demonstrate that Drosophila miR-980 is a memory suppressor gene functioning in multiple regions of the adult brain. Memory acquisition and stability were both increased by miR-980 inhibition. Whole cell recordings and functional imaging experiments indicated that miR-980 regulates neuronal excitability. We identified the autism susceptibility gene, A2bp1, as an mRNA target for miR-980. A2bp1 levels varied inversely with miR-980 expression; memory performance was directly related to A2bp1 levels. In addition, A2bp1 knockdown reversed the memory gains produced by miR-980 inhibition, consistent with A2bp1 being a downstream target of miR-980 responsible for the memory phenotypes. Our results indicate that miR-980 represses A2bp1 expression to tune the excitable state of neurons, and the overall state of excitability translates to memory impairment or improvement.

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“…Drosophila Rbfox1 is the single homolog of the human RBFOX family proteins, which have been linked to multiple diseases and pathological conditions; examples are spinocerebellar ataxia, mental retardation, epilepsy, attention-deficit hyperactivity disorder, autism, hand osteoarthritis, congenital heart defects, obesity, diabetes and glioblastoma (Bhalla et al, 2004;Davis et al, 2012;Gehman et al, 2011;Hamada et al, 2015;Joshita et al, 2010;Ma et al, 2010;Martin et al, 2007). Human RBFOX proteins associate with a multimeric complex of proteins called the large assembly of splicing regulators (LASR), which resides in specific nuclear fractions; namely, the insoluble high molecular mass fraction that contains chromatin, nuclear speckles and unspliced RNA .…”

Section: Mirnas Target Alternative Splicing Factorsmentioning

confidence: 99%

miRNA targeting and alternative splicing in the stress response – events hosted by membrane-less compartments

Kucherenko

Shcherbata

2018

Journal of Cell Science

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Stress can be temporary or chronic, and mild or acute. Depending on its extent and severity, cells either alter their metabolism, and adopt a new state, or die. Fluctuations in environmental conditions occur frequently, and such stress disturbs cellular homeostasis, but in general, stresses are reversible and last only a short time. There is increasing evidence that regulation of gene expression in response to temporal stress happens post-transcriptionally in specialized subcellular membrane-less compartments called ribonucleoprotein (RNP) granules. RNP granules assemble through a concentrationdependent liquid-liquid phase separation of RNA-binding proteins that contain low-complexity sequence domains (LCDs). Interestingly, many factors that regulate microRNA (miRNA) biogenesis and alternative splicing are RNA-binding proteins that contain LCDs and localize to stress-induced liquid-like compartments. Consequently, gene silencing through miRNAs and alternative splicing of premRNAs are emerging as crucial post-transcriptional mechanisms that function on a genome-wide scale to regulate the cellular stress response. In this Review, we describe the interplay between these two post-transcriptional processes that occur in liquid-like compartments as an adaptive cellular response to stress.

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Rare inherited A2BP1 deletion in a proband with autism and developmental hemiparesis

Cited by 37 publications

References 42 publications

Repression of Pumilio Protein Expression by Rbfox1 Promotes Germ Cell Differentiation

Repression of Pumilio Protein Expression by Rbfox1 Promotes Germ Cell Differentiation

MiR-980 Is a Memory Suppressor MicroRNA that Regulates the Autism-Susceptibility Gene A2bp1

miRNA targeting and alternative splicing in the stress response – events hosted by membrane-less compartments

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