Genetics of bone biology and skeletal disease / edited by Rajesh V. Thakker [and three others].

Format:

Book

Contributor:

Thakker, R. V., editor.

Language:

English

Subjects (All):

Bones--Diseases--Genetic aspects.

Bones.

Physical Description:

1 online resource (880 pages) : illustrations

Edition:

Second edition.

Place of Publication:

London, England : Academic Press, 2018.

Summary:

Genetics of Bone Biology and Skeletal Disease, Second Edition, is aimed at students of bone biology and genetics and includes general introductory chapters on bone biology and genetics. More specific disease orientated chapters comprehensively summarize the clinical, genetic, molecular, animal model, molecular pathology, diagnostic, counseling, and treatment aspects of each disorder. The book is organized into five sections that each emphasize a particular theme, general background to bone biology, general background to genetics and epigenetics, disorders of bone and joint, parathyroid and related disorders, and vitamin D and renal disorders.The first section is specifically devoted to providing an overview of bone biology and structure, joint and cartilage biology, principles of endocrine regulation of bone, and the role of neuronal regulation and energy homeostasis. The second section reviews the principles and progress of medical genetics and epigenetics related to bone disease, including genome-wide association studies (GWAS), genomic profiling, copy number variation, prospects of gene therapy, pharmacogenomics, genetic testing and counseling, as well as the generation and utilizing of mouse models.The third section details advances in the genetics and molecular biology of bone and joint diseases, both monogenic and polygenic, as well as skeletal dysplasias, and rarer bone disorders. The fourth section highlights the central role of the parathyroids in calcium and skeletal homeostasis by reviewing the molecular genetics of: hyperparathyroidism, hypoparathyrodism, endocrine neoplasias, and disorders of the PTH and calcium-sensing receptors. The fifth section details molecular and cellular advances across associated renal disorders such as vitamin D and rickets.- Identifies and analyzes the genetic basis of bone disorders in humans and demonstrates the utility of mouse models in furthering the knowledge of mechanisms and evaluation of treatments- Demonstrates how the interactions between bone and joint biology, physiology, and genetics have greatly enhanced the understanding of normal bone function as well as the molecular pathogenesis of metabolic bone disorders- Summarizes the clinical, genetic, molecular, animal model, molecular pathology, diagnostic, counseling, and treatment aspects of each disorder

Contents:

Cover

Title page

Copyright page

Contents

List of Contributors

Preface to the Second Edition

Preface to the First Edition

Section 1 - General Background to Genetics

Chapter 1 - Introduction to Genetics of Skeletal and Mineral Metabolic Diseases

1 - Introduction

2 - Genetics of skeletal and mineral metabolic diseases

2.1 - Modes of Inheritance

2.2 - Genetic Heterogeneity and Monogenic Skeletal Diseases

2.3 - Identifying Genetic Abnormalities Causing Monogenic Diseases

2.4 - Identifying Genes Causing Polygenic Traits

2.5 - Molecular Insights From the Investigation of Monogenic Disorders and Polygenic Traits

2.6 - Genetic Understanding and Application to Development of Novel Therapeutics

3 - Approach to the patient with genetic skeletal/mineral metabolic disease

3.1 - Clinical Approach

3.2 - Medical History and Physical Examination

3.3 - Family Medical History for Determining Mode of Disease Inheritance

4 - Current genetic tests, their clinical utility, and interpretation

4.1 - Clinical Value of Genetic Testing

4.2 - Pretest Considerations-Which Test?

4.3 - Detection of Chromosomal Abnormalities, Copy Number Variations, and Mutations Causing Disease

4.3.1 - Karyotype

4.3.2 - Fluorescence In Situ Hybridization (FISH)

4.3.3 - Multiplex-Ligation Dependent Probe Amplification (MLPA)

4.3.4 - Whole Genome Arrays

4.3.5 - Microarray-Comparative Genomic Hybridization (aCGH)

4.3.6 - Single Nucleotide Polymorphism Arrays

4.3.7 - Single Gene Testing (Sanger Sequencing)

4.3.8 - Next-Generation Sequencing or Second-Generation Sequencing

4.4 - Challenges of Data Interpretation and Approaches to the Analysis of Variants Identified by NGS Platforms

4.4.1 - Variant Identification

4.4.2 - Variant Interpretation

4.5 - Special Circumstances for Genetic Testing.

4.5.1 - Detection of Mosaicism

4.5.2 - Prenatal Diagnosis

4.6 - Informed Consent and Ethical Considerations

5 - Conclusions

References

Chapter 2 - Epigenetics

2 - Epigenetic control mechanisms

2.1 - Histone Modifications and Chromatin Remodeling

2.2 - Histone Variants

2.3 - DNA Methylation

2.4 - Noncoding RNAs (ncRNAs)

3 - Transgenerational epigenetic inheritance

4 - Epigenetics and human disease

4.1 - Imprinting Disorders

4.2 - Cancer

4.3 - Other Diseases

4.4 - Epigenetic Therapy

Chapter 3 - Genome-Wide Association Studies

2 - Linkage disequilibrium mapping

3 - Study design issues in genome-wide association studies

3.1 - Quality Control

4 - The "missing heritability" question

5 - Rare variant study designs

6 - Conclusions

Chapter 4 - Copy Number Variation

1.1 - Potential Mechanisms for Formation of CNVs

2 - CNV detection

3 - CNV and disease

3.1 - Obesity

3.2 - Schizophrenia

3.3 - Autism

3.4 - Cancer

3.5 - Congenital Heart Disease

4 - CNV and osteoporosis

Acknowledgments

Chapter 5 - Genomic Profiling in Bone

1.1 - Profiling Skeletal Cells and Bone Metabolism

1.2 - Profiling Location and Age Dependent Changes in Skeletal Gene Expression

1.3 - Profiling Biomechanical Effects on Bone

1.4 - Profiling Gene Expression Changes Occurring as a Function of Altered Bone Metabolism

1.4.1 - Profiling Bone in Animal Models With Impaired Bone Metabolism

1.4.2 - Profiling Osteoporosis in Humans

1.5 - Profiling Noncoding RNA Expression in Bone

2 - Conclusions

Chapter 6 - Functional Genomics

1 - What is functional genomics?.

2 - Annotating the genome-an emerging picture

2.1 - Encode and Roadmap: An Overview

2.2 - DNase-seq

2.3 - ChIP-seq and Chromatin Profiling

2.3.1 - SP7/Osterix is Restricted to Bone-Forming Vertebrates Where it Acts as a Dlx Cofactor in Osteoblast Specification

2.3.2 - Distinct Transcriptional Programs Underlie Sox9 Regulation of the Mammalian Chondrocyte

2.3.3 - The Osteoblast-to-Osteocyte Transition: Epigenetic Changes and Response to the Vitamin D3 Hormone

2.3.4 - The Binding of Runx2 During Osteoblastogenesis

2.3.5 - Chromatin Profiling of Parathyroid Glands

3 - From annotated sequences to function

3.1 - In Situ Saturating Mutagenesis With CRISPR/Cas9

3.2 - Multiplexed Reporter Assays (MPRA) to Assess Function of Expression-Modulating Variants

4 - Interrogation of cellular function: genome-wide gain- and loss-of-function screening in mammalian cells

4.1 - RNAi-Based Functional Genomics

4.2 - The Orfeome: A Tool for Gain-of-Function Screening

4.3 - Genetic Screens Using CRISPR/Cas9: The Next Frontier

5 - Outlook

6 - Summary

Chapter 7 - Mouse Models: Approaches to Generate In Vivo Models for Hereditary Disorders of Mineral and Skeletal Homeostasis

2 - Methods for generating mouse models

2.1 - Nontargeted Strategies

2.2 - Targeted Knock-Out Strategies

2.3 - Targeted Knock-In Strategies

3 - Genetic bone diseases associated with defective calcium homeostasis

3.1 - Disorders of Parathyroid Development

3.2 - Models for the DiGeorge Syndrome Type 1 Due to TBX1 Mutations

3.3 - Models for Familial Isolated Hypoparathyroidism Due to PTH and GCMB Mutations

3.4 - Disorders of PTH Signaling

3.5 - Blomstrand's Chondrodysplasia

3.6 - Jansen's Disease

3.7 - Pseudohypoparathyroidism

3.8 - Disorders of the Calcium-Sensing Receptor (CaSR).

3.9 - FHH and NSHPT Due to Loss-of-Function CaSR Mutations

3.10 - ADHH Due to Gain-of-Function CaSR Mutations

4 - Conclusions

Chapter 8 - Prospects of Gene Therapy for Skeletal Diseases

2 - Vectors in skeletal gene therapy

2.1 - Adenovirus

2.2 - Adeno-Associated Virus

2.3 - Retrovirus and Lentivirus

2.4 - Nonviral Vectors

2.5 - Conclusions

3 - Methods of gene delivery

3.1 - In Vivo Delivery

3.2 - Ex Vivo Delivery

4 - The immune response to gene therapy vectors

4.1 - The Innate Immune Response

4.2 - The Adaptive Immune Response

4.3 - Strategies to Limit Immune Reactions to Gene Therapy Vectors

5 - Gene therapy for pathologies of the skeletal system

5.1 - Bone

5.1.1 - Bone Healing and Osteogenesis

5.1.2 - Implant Stability and Aseptic Loosening

5.1.3 - Osteoporosis

5.1.4 - Osteogenesis Imperfecta

5.2 - Cartilage

5.2.1 - Osteoarthritis

5.2.2 - Rheumatoid Arthritis

5.3 - Tendon

5.4 - Intervertebral Disc

Chapter 9 - Pharmacogenetics and Pharmacogenomics of Osteoporosis: Personalized Medicine Outlook

1 - Complexity of phenotypes

2 - Genetics of osteoporosis

2.1 - Candidate Genes

2.2 - Genome-Wide Studies

2.3 - Pathways

3 - Gene-gene interaction and "missing heritability"

4 - Pharmacogenetics of therapeutic response

5 - Toward individualized assessment and individualized treatment decisions

Chapter 10 - Genetic Testing and Counseling

1 - Genetic testing

1.1 - Small-Scale Variants

1.2 - Large-Scale Variants

1.3 - Evolving Approaches to DNA-Based Genetic Testing

2 - Genetic testing for skeletal disorders

2.1 - Genetic Tests Available

2.2 - When to Order Genetic Testing

3 - Genetic counseling

3.1 - History.

3.2 - The Genetic Counseling Process

3.3 - The Genetic Counseling Session

3.3.1 - Family History

3.3.2 - Genetic Testing

3.3.3 - Communicating the Facts

3.3.4 - Counseling and Support

Section 2 - General Background to Bone Biology

Chapter 11 - Biology of Bone and Cartilage

2 - Osteoclasts

2.1 - Regulation of Osteoclast Formation: The RANKL-RANK-OPG Pathway

2.2 - Transcription Factor Regulation of Osteoclastogenesis

2.3 - Costimulatory Signaling-Mediated Osteoclastogenesis

2.4 - RANKL/RANK Downstream Signaling

2.5 - Regulation of Osteoclast Activation

2.6 - Negative Regulation of Osteoclast Formation and Function

2.7 - Osteoclast Apoptosis

3 - Osteoblasts

3.1 - Transcription Factors and Signal Pathways

3.1.1 - BMP/RUNX2 Signaling

3.1.2 - Wingless (Wnt)-β-Catenin

3.1.3 - Notch

3.2 - Epigenetic Modifications

3.2.1 - DNA Methylation

3.2.2 - Histone Modification

3.2.3 - Micro-RNA

3.3 - Regulation of Osteoblast/Osteoclast Communication

3.3.1 - Ephrins

3.3.2 - Semaphorins

4 - Cartilage

4.1 - Chondrocyte Formation

4.2 - Endochondral Ossification

4.3 - Endochondral Ossification in the Adult Skeleton

4.4 - Formation of Articular Cartilage

4.5 - Cartilage Degeneration

Chapter 12 - Overview of Bone Structure and Strength

2 - Bone biomechanics and the determinants of whole-bone strength

2.1 - Structural Versus Material Properties of Bone

2.2 - Mechanical Properties of Bone Tissue Depend on Loading Direction

2.3 - Determinants of Biomechanical Properties of Trabecular and Cortical Bone

3 - Contribution of bone geometry to bone strength

3.1 - Age-Related Changes in Bone Size and Shape

4 - Age-related changes in trabecular and cortical bone microarchitecture.

5 - Contribution of bone microarchitecture to bone strength.

Notes:

Includes bibliographical references at the end of each chapters.

Description based on online resource; title from PDF title page (EBC, viewed December 2, 2017).

ISBN:

0-12-804198-6

0-12-804182-X