Neurodevelopmental Disorders: From Genetics to Functional Pathways

Trends in Neurosciences, Journal Year: 2020, Volume and Issue: 43(8), P. 608 - 621

Published: June 5, 2020

NDDs are caused by the disruption of essential neurodevelopmental processes. Many genes and mutations associated with NDDs, pointing to a heterogeneous origin these disorders.Genotype–phenotype correlations difficult establish due existence multiple genetic as well environmental factors that influence phenotypical outcome. The two-hit model molecular diagnoses important should be taken into account when addressing NDDs.Most known belong few common frequently affected pathways. Functional studies elucidating how different can disturb converging pathways lead identification potential targets, thereby opening perspectives for future treatment. Neurodevelopmental disorders (NDDs) class affecting brain development function characterized wide clinical variability. In this review, we discuss presentation particular attention gene vulnerability, mutational load, model. Despite complex architecture events various proteins involved appear converge on pathways, such synaptic plasticity/function, chromatin remodelers mammalian target rapamycin (mTOR) pathway. A thorough understanding mechanisms behind will hopefully candidates could targeted treatment approaches. an inability reach cognitive, emotional, motor developmental milestones. Typically, tightly coordinated development. constitute serious health problem in our society, >3% children worldwide [1.Gilissen C. et al.Genome sequencing identifies major causes severe intellectual disability.Nature. 2014; 511: 344-347Crossref PubMed Scopus (573) Google Scholar]. They have etiology impaired cognition, communication, adaptive behavior, psychomotor skills. include autism spectrum disorder (ASD), disability (ID), deficit hyperactivity disorder, epilepsy [2.Niemi M.E.K. al.Common variants contribute risk rare disorders.Nature. 2018; 562: 268-271Crossref (63) Scholar,3.Tărlungeanu D.C. Novarino G. Genomics disorders: avenue personalized medicine.Exp. Mol. Med. 50: 1-7Crossref (5) suggested shared signs characterize [4.Cristino A.S. al.Neurodevelopmental neuropsychiatric represent interconnected system.Mol. Psychiatry. 19: 294-301Crossref (103) Scholar,5.Hormozdiari F. al.The discovery integrated networks related disorders.Genome Res. 2015; 25: 142-154Crossref (123) Accordingly, comorbidity (see Glossary) two or more is observed. For instance, combination ID, ASD, commonly reported individual patients [6.van Bokhoven H. Genetic epigenetic disabilities.Annu. Rev. Genet. 2011; 45: 81-104Crossref (203) Scholar,7.Du X. al.Genetic diagnostic evaluation trio-based whole exome among diagnosed suspected disorder.Front. 9: 594Crossref Identification pathogenic help explain aforementioned eventually effective terms genetics, types mutation been including chromosomal rearrangements, copy number variations, small indels, point mutations. Thus, underlying event, diagnosis, challenging task needs overcome heterogeneity array variations. Some technologies currently used diagnosis summarized Box 1.Box 1Evolution Diagnostic Flowchart NDDsEarly NDD counseling, patient management, medical intervention.Previously, G banded karyotype FMR1 trinucleotide repeat analysis were recommended first-tier test unexplained NDDs. However, yield was low [111.Blesson A. Cohen J.S. counseling disorders.Cold Spring Harb. Perspect. 2019; 10: a036533Google breakthrough next-generation has led significant advancements Scholar,112.Carneiro T.N. al.Utility elucidation basis isolated syndromic disability: illustrative cases.Appl. Clin. 11: 93-98Crossref (7) To date, >900 responsible X-linked, autosomal dominant, recessive [113.Chiurazzi P. Pirozzi Advances - disability.F1000Res. 2016; 5 (Faculty Rev-599): F1000Crossref (37) Scholar,114.Wright C.F. DDD study: scalable genome-wide research data.Lancet. 385: 1305-1314Abstract Full Text PDF (315) Due correlation protein-coding genes, cheaper quicker whole-exome (WES) preferred tool informative whole-genome [115.Clark M.M. al.Meta-analysis utility genome microarray diseases.NPJ Genom. 3: 16Crossref (71) Scholar,116.Srivastava S. multidisciplinary consensus statement: individuals disorders.Genet. 21: 2413-2421Abstract (32) Different highlighted efficiency tool, having up >40% especially both biological parents considered Scholar] Still, also occur noncoding regions, regulatory elements, alter expression levels DNA microarrays detect gross aberrations otherwise not detectable conventional WES [117.Martin C.L. Ledbetter D.H. Chromosomal testing disorders.JAMA. 2017; 317: 2545-2546Crossref Scholar,118.Bhattacharya S.K. al.Chromosomal uncovers variations congenital anomalies.J. Biomed. Sci. 8: 3Google expected estimated ~10–20% distinct Epigenetic alterations, escaping detection, observed presence Therefore, additional methods changes, PCR, tandem mass spectrometry, southern blot. Early intervention. Previously, These challenges notwithstanding, recognition NDD-causing crucial accurate represents first step toward better disorders. This review focuses starting from genetics moving functional level. First, study familial cases improved Second, consider determine phenotype, diagnoses. We highlight relevance context Finally, debate whether cellular allows circumventing issue variability open treatments. vital onset delineation genotype–phenotype monitor progress foresee complications. numerous NDD-causative identified, many still do receive diagnosis. Additionally, phenotype–genotype brought light severity vary substantially overlapping [8.Li Y. al.Genotype phenotype SHANK3 de novo disorders.Am. J. 176: 2668-2676PubMed Scholar,9.Casanova E.L. al.Widespread genotype-phenotype disability.Front. 9535–535Crossref missing heritability multifactorial and/or polygenic nature Familial useful paradigm dissecting contribution nongenetic pathogenesis background. reason, conducted monozygotic twins discordant phenotypes [10.Huang al.Identifying genomic using sequencing.Mol. Ther. Nucleic Acids. 14: 204-211Abstract (4) Scholar, 11.Willfors al.Medical history etiologies autism.Transl. 7e1014Crossref (10) 12.Radley J.A. al.Deep phenotyping 14 new IQSEC2 variants, phenotype.Clin. 95: 496-506Crossref pedigrees where incomplete penetrance offspring [13.Karaca E. al.Phenotypic expansion illuminates multilocus variation.Genet. 20: 1528-1537Abstract (33) line tremendous only mere disease, but protective factors. Furthermore, it establishing correlations. Thanks inherited emerged outcome essentially revolves around main principles: vulnerability load (Figure 1A ). Gene defined capability given tolerate disruptive variants: lower tolerance towards mutations, higher level vulnerability. haploinsufficient striking dosage sensitivity. fall within category highly vulnerable disease risk. Examples DEPDC5, CACNA1A, SCN8A, which discussed later section. Disruption one high probability inducing absence other causative events, thus resulting monogenic forms [14.Iossifov I. al.Low their biased transmission.Proc. Natl. Acad. U. 112: E5600-E5607Crossref (58) normally subject strong negative selective pressure. Hence, population recognized reduced compared loci words, categorized penetrance. end comprises those less sensitive Variants under pressure transmitted families generations Scholar,14.Iossifov Since single nonvulnerable causing per se, they Nonetheless, recent demonstrated portion attributed Scholar,15.Kurki M.I. al.Contribution sub-isolate Northern Finland.Nat. Commun. 410Crossref (6) fact, additive effects result Scholar,16.Pizzo L. al.Rare background modulate cognitive carrying disease-associated variants.Genet. 816-825Abstract (26) cases, however, depends sum physical interactions between (i.e., epistasis) [17.Mitra al.Reverse pathway approach epistasis disorders.PLoS 13e1006516Crossref (19) Scholar,18.Iyer al.Pervasive defects autism-associated 16p11.2 deletion Drosophila melanogaster.Nat. 2548Crossref (13) Epistatic sensitivity strongly correlate concept argues complexity influenced events. example, loss-of-function monoallelic sodium channels CACNA1A SCN8A variety features movement benign infantile seizures 1B) [19.Reinson K. al.Biallelic cause early epileptic encephalopathy progressive cerebral, cerebellar, optic nerve atrophy.Am. 170: 2173-2176Crossref Scholar,20.Wengert E.R. SCN8A-related encephalopathy.Epilepsia. 60: 2277-2285Crossref (2) accordance criteria germline biallelic changes 1C) recently compound heterozygous probands encephalopathy, while siblings exhibit mild impairment without seizure might determined somatic mechanism classic hypothesis, constitutive generates subsequent hit occurring during then already present 1E). One example comes DEPDC5. Germline DEPDC5 refractory focal epilepsies [21.Ribierre T. al.Second-hit mosaic mTORC1 repressor cortical dysplasia-associated epilepsy.J. Investig. 128: 2452-2458Crossref (0) second variant inactivation found dysplasia Scholar,22.Lee W.S. limited dysmorphic neurons type IIA.Ann. Transl. Neurol. 6: 1338-1344Crossref (1) Primary secondary at each other, expanding hypothesis 1D). Several unveiled Scholar,23.Guo al.Inherited autism/developmental delay suggest model.Mol. Autism. 64Crossref (16) 24.Posey J.E. al.Resolution variation.N. Engl. 376: 21-31Crossref (246) 25.Liu al.Reanalysis data.N. 380: 2478-2480Crossref notion analyses established likely [23.Guo disrupting positively correlates Scholar,24.Posey dissected intrafamilial families, explained severely cumulative makes pathological 1F). burden correlated predisposition educational attainment ID data available literature purely exception rather than rule. Most most nature, hence confirming broad Importantly, factors, although discussion beyond scope current review. implementation (NGS) flowchart dramatically increased percentage who ramifications since assessment recurrence gives possibility advances field served roadmap aimed As next, elucidated some offers opportunity complexities variability, develop therapeutic performed past decade shown affect role conserved [26.Sahin M. Sur Genes, circuits, precision therapies disorders.Science. 350aab3897Crossref (108) 27.Parikshak N.N. al.Integrative

Language: Английский

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Spine dynamics in the brain, mental disorders and artificial neural networks

Nature reviews. Neuroscience, Journal Year: 2021, Volume and Issue: 22(7), P. 407 - 422

Published: May 28, 2021

Language: Английский

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Synaptic memory and CaMKII

Physiological Reviews, Journal Year: 2023, Volume and Issue: 103(4), P. 2897 - 2945

Published: June 8, 2023

Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) and long-term potentiation (LTP) were discovered within a decade of each other have been inextricably intertwined ever since. However, like many marriages, it has had its up downs. Based on the unique biochemical properties CaMKII, was proposed as memory molecule before any physiological linkage made to LTP. reviewed here, convincing CaMKII synaptic physiology behavior took decades. New technologies critical in this journey, including vitro brain slices, mouse genetics, single-cell molecular pharmacological reagents, structure, two-photon microscopy, new investigators attracted by exciting challenge. This review tracks journey assesses state marriage 40 years on. The collective literature impels us propose relatively simple model for involving following steps that drive process: 1) entry through N-methyl-d-aspartate (NMDA) receptors activates CaMKII. 2) undergoes autophosphorylation resulting constitutive, -independent activity exposure binding site NMDA receptor subunit GluN2B. 3) Active translocates postsynaptic density (PSD) binds cytoplasmic C-tail 4) CaMKII-GluN2B complex initiates structural rearrangement PSD may involve liquid-liquid phase separation. 5) involves PSD-95 scaffolding protein, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPARs), their transmembrane AMPAR-regulatory (TARP) auxiliary subunits, an accumulation AMPARs underlies potentiation. 6) stability modified is maintained complex. 7) By process exchange or interholoenzyme phosphorylation maintains face turnover. There are important proteins participate enlargement spine modulation maintain In we critically discuss data underlying steps. As will become clear, some these more firmly grounded than others, provide suggestions how evidence supporting can be strengthened or, based data, replaced. Although long one, prospect having detailed cellular understanding learning at hand.

Language: Английский

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SynGAP regulates synaptic plasticity and cognition independently of its catalytic activity

Science, Journal Year: 2024, Volume and Issue: 383(6686)

Published: Feb. 29, 2024

SynGAP is an abundant synaptic GTPase-activating protein (GAP) critical for plasticity, learning, memory, and cognition. Mutations in SYNGAP1 humans result intellectual disability, autistic-like behaviors, epilepsy. Heterozygous Syngap1 -knockout mice display deficits memory exhibit seizures. It unclear whether imparts structural properties at synapses independently of its GAP activity. Here, we report that inactivating mutations within the domain do not inhibit plasticity or cause behavioral deficits. Instead, modulates strength by physically competing with AMPA-receptor-TARP excitatory receptor complex formation molecular condensates scaffolding proteins. These results have major implications developing therapeutic treatments -related neurodevelopmental disorders.

Language: Английский

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Visualizing synaptic plasticity in vivo by large-scale imaging of endogenous AMPA receptors

eLife, Journal Year: 2021, Volume and Issue: 10

Published: Oct. 18, 2021

Elucidating how synaptic molecules such as AMPA receptors mediate neuronal communication and tracking their dynamic expression during behavior is crucial to understand cognition disease, but current technological barriers preclude large-scale exploration of molecular dynamics in vivo. We have developed a suite innovative methodologies that break through these barriers: new knockin mouse line with fluorescently tagged endogenous receptors, two-photon imaging hundreds thousands labeled synapses behaving mice, computer vision-based automatic synapse detection. Using tools, we can longitudinally track the strength populations changes behavior. used this approach generate an unprecedentedly detailed spatiotemporal map undergoing following sensory experience. More generally, tools be optical probe capable measuring functional across entire brain areas any behavioral paradigm, describing complex system-wide precision.

Language: Английский

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O-GlcNAcylation modulates liquid–liquid phase separation of SynGAP/PSD-95

Nature Chemistry, Journal Year: 2022, Volume and Issue: 14(7), P. 831 - 840

Published: May 30, 2022

Language: Английский

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Non-synaptic function of the autism spectrum disorder-associated gene SYNGAP1 in cortical neurogenesis

Nature Neuroscience, Journal Year: 2023, Volume and Issue: 26(12), P. 2090 - 2103

Published: Nov. 9, 2023

Language: Английский

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Emerging roles of O-glycosylation in regulating protein aggregation, phase separation, and functions

Current Opinion in Chemical Biology, Journal Year: 2023, Volume and Issue: 75, P. 102314 - 102314

Published: May 6, 2023

Language: Английский

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SYNGAP1 deficiency disrupts synaptic neoteny in xenotransplanted human cortical neurons in vivo

Neuron, Journal Year: 2024, Volume and Issue: 112(18), P. 3058 - 3068.e8

Published: Aug. 6, 2024

Human brain ontogeny is characterized by a considerably prolonged neotenic development of cortical neurons and circuits. Neoteny thought to be essential for the acquisition advanced cognitive functions, which are typically altered in intellectual disability (ID) autism spectrum disorders (ASDs). neuronal neoteny could disrupted some forms ID and/or ASDs, but this has never been tested. Here, we use xenotransplantation human into mouse model SYNGAP1 haploinsufficiency, one most prevalent genetic causes ID/ASDs. We find that SYNGAP1-deficient display strong acceleration morphological functional synaptic formation maturation alongside plasticity. At circuit level, SYNGAP1-haploinsufficient precocious responsiveness visual stimulation months ahead time. Our findings indicate required cell autonomously neoteny, providing novel links between human-specific developmental mechanisms

Language: Английский

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Dissociation of SYNGAP1 Enzymatic and Structural Roles: Intrinsic Excitability and Seizure Susceptibility

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 14, 2025

SYNGAP1 is a key Ras-GAP protein enriched at excitatory synapses, with mutations causing intellectual disability and epilepsy in humans. Recent studies have revealed that addition to its role as negative regulator of G-protein signaling through GAP enzymatic activity, plays an important structural interaction post-synaptic density proteins. Here, we reveal intrinsic excitability deficits seizure phenotypes heterozygous Syngap1 knockout (KO) mice are differentially dependent on activity. Cortical neurons KO displayed reduced excitability, including lower input resistance, increased rheobase, phenotype recapitulated GAP-deficient mutants. However, severity susceptibility pentylenetetrazol (PTZ)-induced seizures were significantly elevated but unaffected mutants, implicating the rather than regulation. These findings highlight complex interplay between catalytic functions neuronal physiology disease. Mutations gene major cause disability, autism, epilepsy. The constituent postsynaptic specializations, two distinct been characterized: function, carried by C-terminal PDZ domain, organizes composition density, which domain negatively regulates small GTPases. So far, no electrophysiological/behavioral has directly linked describe while activity does not contribute seen haploin-sufficiency, it regulate upper lamina pyramidal cells.

Language: Английский

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