Fragile X syndrome : from genetics to targeted treatment /

Detalles Bibliográficos
Clasificación:Libro Electrónico
Otros Autores: Willemsen, Rob (Editor ), Kooy, R. Frank (Editor )
Formato: Electrónico eBook
Idioma:Inglés
Publicado: London : Academic Press, [2017]
�2017
Temas:
Fragile X syndrome > Treatment.
Fragile X syndrome > Genetic aspects.
Syndrome de l'X fragile > Traitement.
Syndrome de l'X fragile > Aspect g�en�etique.
MEDICAL > Pediatrics.
HEALTH & FITNESS > Children's Health.
Fragile X syndrome
Acceso en línea:Texto completo
Tabla de Contenidos:
  • Section I
  • Clinics, Diagnosis, Epidemiology, Molecular Mechanisms, and Models
  • Chapter 1
  • The Clinical Phenotype of the Fragile X Syndrome and Related Disorders
  • Introduction
  • The fragile X syndrome
  • Background
  • Physical Manifestations
  • Epilepsy
  • Cognition
  • The Behavioral Phenotype
  • Treatment
  • Fragile X tremor ataxia syndrome
  • The fragile X premature ovarian insufficiency
  • Acknowledgments
  • References
  • Chapter 2
  • Fragile X Syndrome Genetics
  • Setting the stage
  • Genetic Oddities
  • Positional cloning of FRAXA and FMR1
  • FMR1 Structure and Function
  • FMRP and mRNA metabolism
  • Resolving the Sherman paradox
  • Premutation disorders
  • Origins of FXS
  • Conclusions and perspectives
  • References
  • Chapter 3
  • Molecular Diagnostics and Genetic Counseling in Fragile X Syndrome and FMR1-Associated Disorders
  • Fragile X syndrome
  • The diagnosis of fragile X syndrome
  • Genetic counseling in FMR1-associated disorders
  • Normal Range
  • Intermediate Alleles or Gray Zone
  • Premutation Alleles
  • Full Mutation Alleles
  • References
  • Chapter 4
  • Epidemiology of Fragile X Syndrome
  • Introduction
  • Prevalence of FXS
  • Prevalence of FXS among subpopulations
  • Factors related to variation in clinical presentation affect the ability to estimate prevalence
  • Deletions and point mutations leading to FXS
  • Conclusions
  • References
  • Chapter 5
  • Mechanisms of Repeat Instability in Fragile X Syndrome
  • Introduction
  • Factors That Affect Expansion Risk
  • Parallels to Other Related Disorders
  • Model Systems to Study Repeat Instability
  • Potential mechanisms for repeat expansion
  • Instability May be Initiated by Secondary Structures Formed by the Repeats.
  • The Effect of These Secondary Structures May be Mediated via Mismatch Repair Proteins
  • S-Phase Dependent Models for Repeat Expansion
  • S-Phase Independent Expansion Models
  • Potential mechanisms for contraction and error-free repair
  • Do chromosome fragility and repeat expansion share a common mechanism?
  • Concluding remarks and future directions
  • Acknowledgments
  • Glossary of terms
  • References
  • Further Reading
  • Chapter 6
  • Modeling Fragile X Syndrome Using Human Pluripotent Stem Cells
  • Human-based models for FXS
  • Modeling FXS in human pluripotent stem cells
  • Human ESCs as a developmental model for FXS
  • iPSCs in modeling fragile X syndrome
  • Neural differentiation of FXS-PSCs
  • PSC modeling of CGG repeat instability
  • The use of FXS-PSCs for targeted drug discovery
  • Conclusions
  • References
  • Chapter 7
  • Animal Models of Fragile X Syndrome
  • Introduction
  • Rodent models of fragile X syndrome
  • Mouse models of fragile X syndrome
  • The phenotypic spectrum of the knockout mouse
  • Neuroanatomical Phenotype in Fmr1 Knockout Mouse
  • Long-Term Potentiation and Long-Term Depression
  • Behavioral Phenotype in Fmr1 Knockout Mouse
  • Seizures and Hypersensitivity
  • Cognitive Functioning
  • Attention and Hyperactivity
  • Social and Emotional Functioning
  • Anxiety
  • Rat models of fragile X syndrome
  • Zebra fish models of fragile X syndrome
  • Drosophila Models of Fragile X Syndrome
  • FMRP Protein is Well-Conserved Between Drosophila and Mammals
  • FXS Fly Model Displays the Defects in Behavior, Synaptogenesis and Spermatogenesis
  • Behavioral Defects
  • Synaptogenesis Defects
  • Spermatogenesis Abnormality
  • Utilities of Fly Model Toward Understanding the Molecular Basis of FXS
  • Concluding remarks
  • References
  • Section II
  • Pathways involved
  • Chapter 8
  • RNA and Protein Targets of FMRP
  • Introduction.
  • Approaches to defining the RNAs/proteins associated with FMRP
  • Molecular Approaches
  • Cell Biology and Proteomic Approaches
  • Computational Approaches
  • FMRP-binding determinants
  • Structural RNA Motifs Targeted by FMRP
  • Sequence Motifs Targeted by FMRP
  • Non-RNA FMRP Interactions
  • Conclusions
  • References
  • Chapter 9
  • The mGluR Theory of Fragile X: From Mice to Men
  • Introduction
  • FMRP negatively regulates translation
  • Animal models of FXS
  • Dysregulation of synaptic protein synthesis in the Fmr1 KO mouse
  • The mGluR theory of FXS
  • Correcting FXS: targeting mGlu5
  • Correcting FXS: targeting translation control
  • Targeting ERK
  • Targeting mTOR
  • Targeting p70 S6K
  • Targeting GSK3[alpha]/[beta]
  • Correcting FXS: other targets
  • From mice to men: clinical trials for FXS
  • Failure in the clinic and what we can learn
  • New directions
  • Beta Arrestins: a Scaffold for Ras-ERK and Modulator of Signaling
  • GSK3[alpha] and GSK[beta]
  • Novel Targets From the FXS Translatome
  • Concluding remarks
  • References
  • Further Reading
  • Chapter 10
  • The GABAergic System Contributions to the Fragile X Syndrome Phenotype
  • Introduction
  • Inhibitory interneuron dysfunction in FXS
  • Synaptic components at GABAergic synapses are dysregulated in FXS
  • Targeting deficiencies of the GABAergic system in FXS as viable treatment options
  • Preventing depolarizing GABAergic potentials in developing circuits
  • Conclusions
  • Acknowledgment
  • References
  • Further reading
  • Chapter 11
  • Intracellular Signaling Networks in Fragile X Syndrome: Approaches to Drug Discovery and Therapeutics
  • Introduction
  • Dysregulated PI3K signaling in FXS
  • PI3K Downstream Signaling is Defective in FXS Mouse Models
  • FMRP Regulates PI3K Activity by Controlling mRNA Translation and Protein Expression of PI3K Catalytic and Regulatory Subunits.
  • Enhanced PI3K Activity in Peripheral Blood Cells and Tissue From Individuals with FXS
  • Dysregulated ERK1/2 signaling in FXS
  • Impaired Stimulus-Induced ERK1/2 Activation: A First Potential Biomarker in FXS
  • Does Defective ERK1/2 Signaling Contribute to the FXS Phenotype?
  • Aberrant ERK1/2 Activation as Potential Biomarker in Clinical Trials
  • Targeting the signaling hub Ras to correct altered signaling in FXS
  • TSC-mTORC1-S6K1-4EBP nexus: a major mRNA translation control node in FXS
  • TSC 1-2 complex is a vital, but understudied signaling node for FXS
  • mTOR is a well-studied candidate in FXS, but may not be suited for direct therapeutic intervention
  • S6K1: a signal integrator and translational regulator with therapeutic potential in FXS
  • S6K1 Shows Subtly Different Effects in Genetic Deletion and Pharmacological Inhibition Studies
  • Modulation eIF4E via Mnk1 offers an alternative to managing FXS phenotypes
  • Challenges and Future Outlook
  • Acknowledgments
  • References
  • Further Reading
  • Chapter 12
  • The Endocannabinoid System in Fragile X Syndrome
  • Introduction
  • The Endocannabinoid System
  • Molecular alterations in FXS
  • Inhibitory neurotransmission
  • Hippocampal DSI
  • Modulation of mGluR5-Coupled Function by Homer
  • Endocannabinoid Modulation of Striatal Neurotransmission
  • Excitatory neurotransmission
  • Endocannabinoid-Mediated Long-Term Depression (eCB-LTD)
  • Findings in Other Nonsyndromic Models
  • Neuroligin 3
  • Endocannabinoid system interventions
  • Conclusions/Perspectives
  • Acknowledgments
  • References
  • Chapter 13
  • Glycogen Synthase Kinase-3: Abnormalities and Therapeutic Potential in Fragile X Syndrome
  • Introduction
  • Fragile X syndrome: etiology and animal models
  • Glycogen synthase kinase-3
  • Morphological and biochemical effects of GSK3 inhibition in Fmr1 knockout mice.
  • Behavioral abnormalities in Fmr1 knockout mice improved by GSK3 inhibitor treatments
  • Cognitive impairments in Fmr1 knockout mice rescued by administration of GSK3 inhibitors
  • Electrophysiological abnormalities in Fmr1 knockout mice improved by GSK3 inhibitors
  • Clinical trials
  • Summary
  • Acknowledgments
  • References
  • Chapter 14
  • Defects in Rho GTPase Signaling to the Spine Actin Cytoskeleton in FMR1 Knockout Mice
  • Introduction
  • Fragile X and Disturbances in Spine Morphology
  • Fmr1 KO Mice Exhibit Hippocampal Synaptic Plasticity Defects
  • Changes in the spine actin cytoskeleton support synaptic plasticity
  • Fmr1 KO defects in Rho GPTase signaling pathwayproteins
  • Cofilin (ADF/Cofilin Family)
  • PAK (p21 Activated Kinase)
  • Cortactin (Cortical Actin Binding Protein)
  • ERK1/2 (Extracellular Signal-Regulated Kinase)
  • Conclusions and future directions
  • Acknowledgments
  • References
  • Chapter 15
  • Matrix Metalloproteinases in Fragile X Syndrome
  • Introduction
  • FMR1-deficiency and dendritic spine morphology
  • Extracellular matrix
  • Metalloproteinases
  • MMP-9 in FXS
  • Conclusions
  • Abbreviations
  • References
  • Further Readings
  • Chapter 16
  • Ion Channel Dysfunction and FXS
  • Introduction
  • Voltage-dependent potassium channels
  • FMRP Regulates Kv3.1 Voltage-Dependent Channels That are Required for High Frequency Firing
  • Kv1 Family Channels
  • Kv4.2 Channels
  • BKCa Channels
  • FMRP Directly Binds Slack KNa1.1 Channels
  • Nonselective cation channels
  • HCN Channels
  • Calcium channels
  • L-Type Ca2+ Channels
  • N-Type Ca2+ Channels
  • Conclusions
  • References
  • Chapter 17
  • Reactivation of the FMR1 Gene
  • Introduction
  • Epigenetic status of premutated alleles
  • Epigenetic silencing of FMR1 full mutation
  • Rare individuals with unmethylated full mutation
  • Treatment options for FXS.

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