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| Open AccessKdm1a safeguards the topological boundaries of PRC2-repressed genes and prevents aging-related euchromatinization in neurons
Kdm1a is a histone demethylase implicated in intellectual disability. Here, the authors show that removing Kdm1a in neurons of the adult mouse forebrain disrupts silencing of nonneuronal genes and chromatin organization, emphasizing its role in preserving neuronal genome integrity.
- Beatriz del Blanco
- , Sergio Niñerola
- & Ángel Barco
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Article
| Open AccessStructural models of genome-wide covariance identify multiple common dimensions in autism
Studying individuals with autism only, this study investigated the genomic architecture of autism-related phenotypes using a multivariate modelling framework. This work identified distinct genomic factors linked to language performance, behaviour and developmental motor delay.
- Lucía de Hoyos
- , Maria T. Barendse
- & Beate St Pourcain
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| Open AccessCompromised transcription-mRNA export factor THOC2 causes R-loop accumulation, DNA damage and adverse neurodevelopment
THOC2 is an essential subunit of Transcription mRNA Export complex of eukaryotic cells and its compromise causes adverse (neuro)development. Using mouse model and patient cells the authors unravel molecular pathology of the syndrome, from R-loops dysregulation, to altered transcriptome and DNA damage triggered cell death.
- Rudrarup Bhattacharjee
- , Lachlan A. Jolly
- & Jozef Gecz
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Article
| Open AccessVariants in the WDR44 WD40-repeat domain cause a spectrum of ciliopathy by impairing ciliogenesis initiation
A vesicle trafficking Rab11 effector switch is important for ciliogenesis. Here, the authors report a ciliopathy-related disorder caused by variants in WDR44, a Rab11 effector. WDR44 variants show higher affinity for Rab11 and can impair ciliogenesis.
- Andrea Accogli
- , Saurabh Shakya
- & Christopher J. Westlake
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Article
| Open AccessRare X-linked variants carry predominantly male risk in autism, Tourette syndrome, and ADHD
Here, the authors clarify the architecture of genetic risk on chromosome X in three male-biased psychiatric disorders. Leveraging this information they identify an exome-wide significant autism risk gene, MAGEC3, and provide a path forward for future gene discovery on this chromosome.
- Sheng Wang
- , Belinda Wang
- & A. Jeremy Willsey
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Article
| Open AccessSaturation genome editing of DDX3X clarifies pathogenicity of germline and somatic variation
Pathogenic variants of DDX3X are associated with neurodevelopmental disorders (NDD) and cancer. Here, the authors perform saturation genome editing of DDX3X to test the functional impact of 12,776 variants, develop a machine learning classifier to identify variants relevant for NDD, and show that DDX3X predominantly acts as a tumour suppressor in cancer.
- Elizabeth J. Radford
- , Hong-Kee Tan
- & Matthew E. Hurles
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Article
| Open AccessMulti-PGS enhances polygenic prediction by combining 937 polygenic scores
Polygenic scores (PGS) have high potential for clinical use but are currently underpowered for many applications. Here, the authors develop an approach that leverages an agnostic library of hundreds of PGS to increase prediction of complex diseases and other traits. This multi-PGS framework is ideal for emerging biobank data.
- Clara Albiñana
- , Zhihong Zhu
- & Bjarni J. Vilhjálmsson
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Article
| Open AccessA ubiquitin-based effector-to-inhibitor switch coordinates early brain, craniofacial, and skin development
The molecular mechanisms ensuring early face, brain, and skin formation are unclear. Here, the authors uncover a posttranslational pathway that controls cytoskeletal signaling circuits to coordinate ectodermal patterning and neurulation.
- Anthony J. Asmar
- , Shaun R. Abrams
- & Achim Werner
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Article
| Open AccessGain and loss of function variants in EZH1 disrupt neurogenesis and cause dominant and recessive neurodevelopmental disorders
An apparent redundant role with EZH2 has rendered EZH1 as a secondary player in PRC2-mediated homeostasis regulation. Here, the authors report that gain- and loss-of-function variants in EZH1 cause neurodevelopmental disorders, highlighting its functional relevance.
- Carolina Gracia-Diaz
- , Yijing Zhou
- & Naiara Akizu
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Article
| Open AccessVariants in SART3 cause a spliceosomopathy characterised by failure of testis development and neuronal defects
The SART3 gene encodes an RNA-binding protein critical for spliceosome function. Here, the authors find that bi-allelic variants in SART3 underlie a congenital condition characterised by neuro-developmental defects and 46,XY gonadal dysgenesis.
- Katie L. Ayers
- , Stefanie Eggers
- & Andrew H. Sinclair
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Article
| Open AccessPrioritization of potential causative genes for schizophrenia in placenta
The placenta has been proposed to be potentially relevant to schizophrenia risk. Here, the authors use the genetically predicted transcriptome to identify genes expressed in the placenta that could be involved in schizophrenia.
- Gianluca Ursini
- , Pasquale Di Carlo
- & Daniel R. Weinberger
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Article
| Open AccessLinoleic acid improves PIEZO2 dysfunction in a mouse model of Angelman Syndrome
Angelman syndrome (AS) is a neurogenetic disorder. Here, the authors found that PIEZO2 activity is reduced in sensory neurons from a mouse model of AS and used a linoleic acid-enriched diet to enhance PIEZO2 function and ameliorate AS-associated gait deficits.
- Luis O. Romero
- , Rebeca Caires
- & Julio F. Cordero-Morales
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Article
| Open AccessCoordinated cortical thickness alterations across six neurodevelopmental and psychiatric disorders
Neuropsychiatric disorders may have shared features. Here the authors identified hubs of transdiagnostic co-alteration networks using meta-analytical maps of ENIGMA neuroimaging data for six neurodevelopmental and psychiatric disorders.
- M. D. Hettwer
- , S. Larivière
- & S. L. Valk
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Article
| Open AccessDominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish
Disruptions to the ER-Golgi network can lead to neurodevelopmental disorders, though our understanding of these Golgipathies remains incomplete. Here Lauri, Tartaglia and colleagues show that ARF3 mutations cause a rare pediatric neurological disorder and perform detailed molecular characterization in fish.
- Giulia Fasano
- , Valentina Muto
- & Marco Tartaglia
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Article
| Open AccessPathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy
The SMC5/6 complex is critical for genome stability. Here, the authors identify mutations in SLF2 and SMC5 as cause of Atelís Syndrome characterized by microcephaly, short stature, anemia, segmented chromosomes and mosaic variegated hyperploidy.
- Laura J. Grange
- , John J. Reynolds
- & Grant S. Stewart
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Article
| Open AccessSystematic analysis and prediction of genes associated with monogenic disorders on human chromosome X
Discovering disease genes on the X chromosome can be particularly challenging. Here, the authors use features of known disease genes and machine learning to predict genes that remain to be associated with disorders on this chromosome.
- Elsa Leitão
- , Christopher Schröder
- & Christel Depienne
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Article
| Open AccessGenome-wide rare variant score associates with morphological subtypes of autism spectrum disorder
Morphological subtypes of autism spectrum disorder (ASD) may differ in their genetic bases. Chan et al. develop a method for calculating a patient-level, genome-wide rare variant score and find significant differences in rare and common variant associations between dysmorphic and nondysmorphic ASD groups.
- Ada J. S. Chan
- , Worrawat Engchuan
- & Stephen W. Scherer
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| Open AccessMulti-omic brain and behavioral correlates of cell-free fetal DNA methylation in macaque maternal obesity models
In animal models, maternal obesity is associated with development of neurodevelopmental disorder like phenotypes. Here the authors show in a macaque model that in obese dams, cell-free fetal DNA methylation, inflammatory cytokines, and metabolites correlated with infant brain DNA methylation, lipids, and metabolites.
- Benjamin I. Laufer
- , Yu Hasegawa
- & Janine M. LaSalle
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Article
| Open AccessSLITRK2 variants associated with neurodevelopmental disorders impair excitatory synaptic function and cognition in mice
The protein SLITRK2 plays an important role in synaptic communication. This study identifies X-linked SLITRK2 variants that underlie neurodevelopmental disorders by impairing excitatory synapses.
- Salima El Chehadeh
- , Kyung Ah Han
- & Ji Won Um
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| Open AccessAssociation of mitochondrial DNA content, heteroplasmies and inter-generational transmission with autism
Most genetic studies of autism spectrum disorder (ASD) have focused on the nuclear genome. Here, the authors show that variations in mitochondrial DNA, detectable at birth, are also associated with risk of ASD.
- Yiqin Wang
- , Xiaoxian Guo
- & Zhenglong Gu
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Article
| Open AccessTranscription Factor 4 loss-of-function is associated with deficits in progenitor proliferation and cortical neuron content
Transcription Factor 4 (TCF4) has been associated with autism and schizophrenia. Here, the authors demonstrate aberrant proliferation and differentiation in neural cells and organoids carrying mutations in TCF4.
- Fabio Papes
- , Antonio P. Camargo
- & Alysson R. Muotri
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Article
| Open AccessMapping the serum proteome to neurological diseases using whole genome sequencing
Serum proteins are easily accessible biomarkers and drug targets. Here, the authors use whole genome sequencing data to describe the genetic architecture of neurologically-relevant serum proteins and establish causal protein-neurological disease relationships.
- Grace Png
- , Andrei Barysenka
- & Eleftheria Zeggini
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| Open AccessIdentification of disease-linked hyperactivating mutations in UBE3A through large-scale functional variant analysis
UBE3A gene dysregulation is associated with neurodevelopmental disorders, but predicting the function of UBE3A variants remains difficult. The authors use a high-throughput assay to categorize variants by functional activity, and show that UBE3A hyperactivity increases the risk of neurodevelopmental disease.
- Kellan P. Weston
- , Xiaoyi Gao
- & Jason J. Yi
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Article
| Open AccessDiscordant associations of educational attainment with ASD and ADHD implicate a polygenic form of pleiotropy
Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder are co-occurring neurodevelopmental conditions displaying strong, discordant polygenic associations with educational attainment. Here, the authors study genetic mechanisms underlying genome-wide correlation patterns across these traits.
- Ellen Verhoef
- , Jakob Grove
- & Beate St Pourcain
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Article
| Open AccessExtracellular LGALS3BP regulates neural progenitor position and relates to human cortical complexity
Basal progenitors are enriched in gyrencephalic species like humans contributing to neuronal expansion. Here the authors show that LGALS3BP de novo variants are related to reduced cortical complexity and area in humans and that LGALS3BP regulates neural progenitor position in organoids, human fetal tissue and mice.
- Christina Kyrousi
- , Adam C. O’Neill
- & Silvia Cappello
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Article
| Open AccessCDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice
Molecular mechanisms of attention-deficit hyperactivity disorder (ADHD) are not fully understood. Here the authors demonstrate a mutation in CDH2, encoding N-cadherin, that is associated with ADHD, and in a mouse model, delineate molecular electrophysiological characteristics associated with this mutation.
- D. Halperin
- , A. Stavsky
- & O. S. Birk
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Article
| Open AccessSchizophrenia, autism spectrum disorders and developmental disorders share specific disruptive coding mutations
Overlapping genes have been implicated in schizophrenia and neurodevelopmental disorders. Here, the authors overlap de novo variants in the two types of disorders and find variants in these genes with the same functional effect and in some cases the same specific variants.
- Elliott Rees
- , Hugo D. J. Creeth
- & Michael C. O’Donovan
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| Open AccessA generative network model of neurodevelopmental diversity in structural brain organization
The formation of large-scale brain networks represents crucial developmental processes that can drive individual differences in cognition and which are associated with multiple neurodevelopmental conditions. Here, the authors use generative network modelling to provide a computational framework for understanding neurodevelopmental diversity.
- Danyal Akarca
- , Petra E. Vértes
- & Duncan E. Astle
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Article
| Open AccessATR regulates neuronal activity by modulating presynaptic firing
Ataxia Telangiectasia and Rad3-related (ATR) is a key regulator of replication stress response; yet, mutations within the ATR gene cause human ATR-Seckel Syndrome associated with microcephaly and intellectual disability. Here, the authors show neuron-specific ATR deletion increases intrinsic neuronal and epileptiform activity, revealing a function of ATR beyond its role in DNA damage response.
- Murat Kirtay
- , Josefine Sell
- & Zhao-Qi Wang
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Article
| Open AccessFoxG1 regulates the formation of cortical GABAergic circuit during an early postnatal critical period resulting in autism spectrum disorder-like phenotypes
Cortical excitatory/inhibitory (E/I) imbalance is a feature of autism spectrum disorder (ASD). Here, the authors show that FoxG1 regulates the formation of cortical GABAergic circuits affecting social behaviour during a specific postnatal time window in mouse models of ASD.
- Goichi Miyoshi
- , Yoshifumi Ueta
- & Mariko Miyata
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Article
| Open AccessImpaired calcium signaling in astrocytes modulates autism spectrum disorder-like behaviors in mice
Astrocytes contribute to autism spectrum disorder (ASD) pathophysiology. Here, the authors show that IP3R2 conditional KO mice show ASD-like behaviours and identify astrocyte-derived ATP as a modulator of these behaviours in mice.
- Qian Wang
- , Ying Kong
- & Tian-Ming Gao
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Article
| Open AccessRHOA signaling defects result in impaired axon guidance in iPSC-derived neurons from patients with tuberous sclerosis complex
Patients with Tuberous Sclerosis Complex (TSC) show aberrant wiring of neuronal connections. Here, the authors generate iPSC-derived neurons from patients with TSC. TSC2 +/− neurons show impaired mTOR-independent RhoA signaling-mediated axon guidance.
- Timothy S. Catlett
- , Massimo M. Onesto
- & Timothy M. Gómez
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Article
| Open AccessLoss of function mutations in GEMIN5 cause a neurodevelopmental disorder
GEMIN5, an RNA-binding protein, is required for formation of small nuclear ribonucleoproteins. Here, the authors identify loss of function mutations in GEMIN5 that are associated with a human neurodevelopmental disorder.
- Sukhleen Kour
- , Deepa S. Rajan
- & Udai Bhan Pandey
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| Open AccessDefective metabolic programming impairs early neuronal morphogenesis in neural cultures and an organoid model of Leigh syndrome
Leigh syndrome (LS) is a severe neurometabolic disorder which lacks effective models. Here, the authors developed human neuronal models of LS carrying mutations in SURF1 which show impaired neuronal morphogenesis due to metabolic deficiencies.
- Gizem Inak
- , Agnieszka Rybak-Wolf
- & Alessandro Prigione
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Article
| Open AccessNeuronal fragile X mental retardation protein activates glial insulin receptor mediated PDF-Tri neuron developmental clearance
Glia are involved in remodelling of neural circuits during development. Here, the authors show that FMRP is required within neurons to activate glial insulin receptor to facilitate Draper- and Shrub-dependent neuronal clearance during neurodevelopment in Drosophila.
- Dominic J. Vita
- , Cole J. Meier
- & Kendal Broadie
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Article
| Open AccessImpaired eIF5A function causes a Mendelian disorder that is partially rescued in model systems by spermidine
eIF5A is critical for protein synthesis but has not yet been associated with congenital human disease. Here, the authors show that EIF5A variants cause a Mendelian disorder via reduced eIF5A-ribosome interactions and this phenotype is partially corrected by spermidine supplementation in yeast and zebrafish.
- Víctor Faundes
- , Martin D. Jennings
- & Siddharth Banka
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Article
| Open AccessThe contribution of X-linked coding variation to severe developmental disorders
Developmental disorders (DDs) are more prevalent in males, thought to be due to X-linked genetic variation. Here, the authors investigate the burden of X-linked coding variants in 11,044 DD patients, showing that this contributes to ~6% of both male and female cases and therefore does not solely explain male bias in DDs.
- Hilary C. Martin
- , Eugene J. Gardner
- & Matthew E. Hurles
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Article
| Open AccessMINPP1 prevents intracellular accumulation of the chelator inositol hexakisphosphate and is mutated in Pontocerebellar Hypoplasia
Tight regulation of inositol polyphosphate metabolism is essential for proper cell physiology. Here, the authors describe an early-onset neurodegenerative syndrome caused by loss-of-function mutations in the MINPP1 gene, characterised by intracellular imbalance of inositol polyphosphate metabolism.
- Ekin Ucuncu
- , Karthyayani Rajamani
- & Vincent Cantagrel
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Article
| Open AccessEssential omega-3 fatty acids tune microglial phagocytosis of synaptic elements in the mouse developing brain
Altered fatty acid intake during pregnancy is associated with neurodevelopmental disorders. Here, the authors show that maternal omega-3 fatty acids deficiency results in altered microglia-mediated phagocytosis of synaptic elements leading to impaired cognitive functions in the offspring in mice.
- C. Madore
- , Q. Leyrolle
- & S. Layé
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Article
| Open AccessRRP7A links primary microcephaly to dysfunction of ribosome biogenesis, resorption of primary cilia, and neurogenesis
The RRP7A a gene is involved in ribosome biogenesis. Here the authors report a homozygous missense mutation segregating with primary microcephaly, and show that this occurs via functional defects in both nucleoli and primary cilia disrupting cell proliferation and neurogenesis.
- Muhammad Farooq
- , Louise Lindbæk
- & Lars Allan Larsen
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Article
| Open AccessGermline AGO2 mutations impair RNA interference and human neurological development
AGO2 binds to miRNAs to repress expression of cognate target mRNAs. Here the authors report that heterozygous AGO2 mutations result in defects in neurological development and impair RNA interference.
- Davor Lessel
- , Daniela M. Zeitler
- & Hans-Jürgen Kreienkamp
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Article
| Open AccessMutations associated with neuropsychiatric conditions delineate functional brain connectivity dimensions contributing to autism and schizophrenia
The impact of neurodevelopmental mutations on functional brain connectivity is poorly understood. Here the authors identify thalamo-sensorimotor dysconnectivity dimensions shared across 16p11.2 and 22q11.2 copy number variants, autism and schizophrenia, but not ADHD.
- Clara A. Moreau
- , Sebastian G. W. Urchs
- & Sebastien Jacquemont
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Article
| Open AccessIncreased RNA editing in maternal immune activation model of neurodevelopmental disease
Interferon can be induced by the viral mimic PolyI:C, which can in turn activate RNA editing enzymes. Here the authors identify transient changes in A-to-I RNA editing following maternal immune activation in mice.
- Hadas Tsivion-Visbord
- , Eli Kopel
- & Erez Y. Levanon
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Article
| Open AccessLarge-scale targeted sequencing identifies risk genes for neurodevelopmental disorders
For many neurodevelopmental disorder (NDD) risk genes, the significance for mutational burden is unestablished. Here, the authors sequence 125 candidate NDD genes in over 16,000 NDD cases; case-control mutational burden analysis identifies 48 genes with a significant burden of severe ultra-rare mutations.
- Tianyun Wang
- , Kendra Hoekzema
- & Evan E. Eichler
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Article
| Open AccessIntegrative genomics identifies a convergent molecular subtype that links epigenomic with transcriptomic differences in autism
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interactions with repetitive and restrictive behaviours. Here the authors integrate mRNA expression, miRNA expression, DNA methylation, and histone acetylation datasets from a collection of post mortem brain tissues and identify a convergent molecular subtype of ASD.
- Gokul Ramaswami
- , Hyejung Won
- & Daniel H. Geschwind
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Article
| Open AccessThe circadian phase of antenatal glucocorticoid treatment affects the risk of behavioral disorders
Antenatal glucocorticoid therapy is indicated for mothers at risk of preterm delivery. Here, the authors show that the circadian phase of antenatal glucocorticoid treatment affects the risk of behavioral disorders later in life in mice and in a retrospective observational study in human infants.
- Mariana Astiz
- , Isabel Heyde
- & Henrik Oster
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Article
| Open AccessmTADA is a framework for identifying risk genes from de novo mutations in multiple traits
Joint analysis of multiple traits can increase power and provide insights into shared genetic architecture. Here, Nguyen et al. develop multi-trait TADA (mTADA), an extension of TADA (transmission and de novo association test) that jointly analyses de novo mutations of traits for improved risk-gene identification power.
- Tan-Hoang Nguyen
- , Amanda Dobbyn
- & Eli A. Stahl
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Article
| Open AccessFMRP(1–297)-tat restores ion channel and synaptic function in a model of Fragile X syndrome
Fragile X Mental Retardation Protein regulates synaptic plasticity and its loss results in Fragile X Syndrome. Here, the authors show that the FMRP(1-297)-tat peptide can permeate the BBB, restore protein translation and mossy fiber LTP, and reduce elevated levels of activity in Fmr1 KO mice.
- Xiaoqin Zhan
- , Hadhimulya Asmara
- & Ray W. Turner
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Article
| Open AccessMutations in the KIF21B kinesin gene cause neurodevelopmental disorders through imbalanced canonical motor activity
Kinesins regulate intracellular transport and microtubule dynamics. Here, the authors show that KIF21B variants in humans associate with corpus callosum agenesis and microcephaly. Using mice and zebrafish, they showed the cellular mechanisms altered by the missense KIF21B variants.
- Laure Asselin
- , José Rivera Alvarez
- & Juliette D. Godin