Progranulin haploinsufficiency causes biphasic social dominance abnormalities in the tube test

Arrant, Andrew E.; Filiano, Anthony J.; Warmus, Brian A.; Hall, Alicia M.; Roberson, Erik D.

doi:10.1111/gbb.12300

Cited by 43 publications

(80 citation statements)

References 69 publications

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“…3E-F indicating no apparent deficits in short-term memory. Lastly, Scn1a +/KI mice did not show any behavioral deficits in the tube test of social dominance [31] (S4A Fig. ) or threechamber sociability test [32] (S4B-D Fig.).…”

Section: Scn1a +/Ki Mice Exhibit Dravet Syndrome-like Phenotypesmentioning

confidence: 91%

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Aberrant regulation of a poison exon caused by a non-coding variant inScn1a-associated epileptic encephalopathy

Voskobiynyk

Battu

Felker

et al. 2020

Preprint

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Dravet syndrome (DS) is a developmental and epileptic encephalopathy that results from mutations in the Na v 1.1 sodium channel encoded by SCN1A. Most known DS-causing mutations are in coding regions of SCN1A, but we recently identified several disease-associated SCN1A mutations in intron 20 that are within or near to a cryptic and evolutionarily conserved "poison" exon, 20N, whose inclusion leads to transcript degradation. However, it is not clear how these intron 20 variants alter SCN1A transcript processing or DS pathophysiology in an organismal context, nor is it clear how exon 20N is regulated in a tissue-specific and developmental context. We address those questions here by generating an animal model of our index case, NM_006920.4(SCN1A):c.3969+2451G>C, using gene editing to create the orthologous mutation in laboratory mice. Scn1a heterozygous knock-in (+/KI) mice exhibited an ~50% reduction in brain Scn1a mRNA and Na v 1.1 protein levels, together with characteristics observed in other DS mouse models, including premature mortality, seizures, and hyperactivity. In brain tissue from adult Scn1a +/+ animals, quantitative RT-PCR assays indicated that ~1% of Scn1a mRNA included exon 20N, while brain tissue from Scn1a +/KI mice exhibited an ~5-fold increase in the extent of exon 20N inclusion. We investigated the extent of exon 20N inclusion in brain during normal fetal development in RNA-seq data and discovered that levels of inclusion were ~70% at E14.5, declining progressively to ~10% postnatally. A similar pattern exists for the homologous sodium channel Na v 1.6, encoded by Scn8a. For both genes, there is an inverse relationship between the level of functional transcript and the extent of poison exon inclusion. Taken together, our findings suggest that poison exon usage by Scn1a and Scn8a is a strategy to regulate channel expression during normal brain development, and that mutations recapitulating a fetal-like pattern of splicing cause reduced channel expression and epileptic encephalopathy.Correspondence to Gregory Barsh (gbarsh@hudsonalpha.org | hudsonalpha.org/faculty/greg-barsh | @GregBarsh ) Correspondence to Erik Roberson (eroberson@uabmc.edu | robersonlab.net | @RobersonLabUAB) Author SummaryDravet syndrome (DS) is a neurological disorder affecting approximately 1:15,700 Americans[1]. While most patients have a mutation in the SCN1A gene encoding Na v 1.1 sodium channels, about 20% do not have a mutation identified by exome sequencing. Recently, we identified variants in intron 20N, a noncoding region of SCN1A, in some DS patients [2]. We predicted that these variants alter SCN1A transcript processing, decrease Na v 1.1 function, and lead to DS pathophysiology via inclusion of exon 20N, a "poison" exon that leads to a premature stop codon. In this study, we generated a knock-in mouse model, Scn1a+/KI, of one of these variants, NM_006920.4(SCN1A):c.3969+2451G>C, which resides in a genomic region that is extremely conserved across vertebrate species. We found that Scn1a+/KI mice have reduced levels ...

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Section: Scn1a +/Ki Mice Exhibit Dravet Syndrome-like Phenotypesmentioning

confidence: 91%

“…Tube Test for Social Dominance. The tube test for social dominance was conducted as previously described [31].Mice of the same sex, but opposite genotype, were released into opposite ends of a clear plastic tube and allowed to freely interact. Under these conditions, one mouse will force the other out of the tube.…”

Section: Rna-seqmentioning

confidence: 99%

Aberrant regulation of a poison exon caused by a non-coding variant inScn1a-associated epileptic encephalopathy

Voskobiynyk

Battu

Felker

et al. 2020

Preprint

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“…Numerous mouse models with deletions in the mouse homologue Grn have been generated . Behaviourally, homozygous knockout mice present with FTD‐like phenotypes including impaired spatial learning and memory reduced the social recognition and interaction and compulsive behaviours . Heterozygous Grn knockout mice also present with milder social deficits, but still include reduced sociability .…”

Section: Genetic Models Of Ftdmentioning

confidence: 99%

Review: Modelling the pathology and behaviour of frontotemporal dementia

Solomon

Mitchell

Salcher-Konrad

et al. 2019

Neuropathology Appl Neurobio

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Frontotemporal dementia (FTD) encompasses a collection of clinically and pathologically diverse neurological disorders. Clinical features of behavioural and language dysfunction are associated with neurodegeneration, predominantly of frontal and temporal cortices. Over the past decade, there have been significant advances in the understanding of the genetic aetiology and neuropathology of FTD which have led to the creation of various disease models to investigate the molecular pathways that contribute to disease pathogenesis. The generation of in vivo models of FTD involves either targeting genes with known disease‐causative mutations such as GRN and C9orf72 or genes encoding proteins that form the inclusions that characterize the disease pathologically, such as TDP‐43 and FUS. This review provides a comprehensive summary of the different in vivo model systems used to understand pathomechanisms in FTD, with a focus on disease models which reproduce aspects of the wide‐ranging behavioural phenotypes seen in people with FTD. We discuss the emerging disease pathways that have emerged from these in vivo models and how this has shaped our understanding of disease mechanisms underpinning FTD. We also discuss the challenges of modelling the complex clinical symptoms shown by people with FTD, the confounding overlap with features of motor neuron disease, and the drive to make models more disease‐relevant. In summary, in vivo models can replicate many pathological and behavioural aspects of clinical FTD, but robust and thorough investigations utilizing shared features and variability between disease models will improve the disease‐relevance of findings and thus better inform therapeutic development.

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“…It is required for normal lysosome homeostasis, and Grn −/− cells and tissues have increased lysosomal content, based on staining of the lysosomal proteins LAMP1 (4,6,9,10) and CD68 (11). In mice, nervous system phenotypes associated with progranulin deficiency include the accumulation of lipofuscin (10,12–14), behavioral changes (13,15–17), neuroinflammation (9,11–13,15,16,18), increased complement activation (4,10,11), and increased synaptic pruning (11). Grn −/− mice also exhibit decreased bone mass (19).…”

Section: Introductionmentioning

confidence: 99%