Genetics of Bone Biology and Skeletal Disease 2nd Edition by Rajesh Thakker,Michael Whyte 012804182X 9780128041826

Section 1: General Background to Genetics

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

Abstract

1. Introduction

2. Genetics of skeletal and mineral metabolic diseases

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

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

5. Conclusions

Chapter 2: Epigenetics

Abstract

1. Introduction

2. Epigenetic control mechanisms

3. Transgenerational epigenetic inheritance

4. Epigenetics and human disease

5. Conclusions

Chapter 3: Genome-Wide Association Studies

Abstract

1. Introduction

2. Linkage disequilibrium mapping

3. Study design issues in genome-wide association studies

4. The “missing heritability” question

5. Rare variant study designs

6. Conclusions

Chapter 4: Copy Number Variation

Abstract

1. Introduction

2. CNV detection

3. CNV and disease

4. CNV and osteoporosis

5. Conclusions

Acknowledgments

Chapter 5: Genomic Profiling in Bone

Abstract

1. Introduction

2. Conclusions

Acknowledgments

Chapter 6: Functional Genomics

Summary

1. What is functional genomics?

2. Annotating the genome—an emerging picture

3. From annotated sequences to function

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

5. Outlook

6. Summary

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

Abstract

1. Introduction

2. Methods for generating mouse models

3. Genetic bone diseases associated with defective calcium homeostasis

4. Conclusions

Chapter 8: Prospects of Gene Therapy for Skeletal Diseases

Abstract

1. Introduction

2. Vectors in skeletal gene therapy

3. Methods of gene delivery

4. The immune response to gene therapy vectors

5. Gene therapy for pathologies of the skeletal system

6. Conclusions

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

Abstract

1. Complexity of phenotypes

2. Genetics of osteoporosis

3. Gene–gene interaction and “missing heritability”

4. Pharmacogenetics of therapeutic response

5. Toward individualized assessment and individualized treatment decisions

6. Conclusions

Chapter 10: Genetic Testing and Counseling

Abstract

1. Genetic testing

2. Genetic testing for skeletal disorders

3. Genetic counseling

Section 2: General Background to Bone Biology

Chapter 11: Biology of Bone and Cartilage

Abstract

1. Introduction

2. Osteoclasts

3. Osteoblasts

4. Cartilage

5. Conclusions

Chapter 12: Overview of Bone Structure and Strength

Summary

1. Introduction

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

3. Contribution of bone geometry to bone strength

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

5. Contribution of bone microarchitecture to bone strength

6. Contribution of bone structure to fracture risk in humans

7. Conclusions

Chapter 13: Overview of Joint and Cartilage Biology

Abstract

1. Introduction

2. Joint development

3. Joint anatomy

4. Joint homeostasis

5. Joint disease

6. Joint repair

Chapter 14: Osteocyte Biology

Abstract

1. Introduction

2. The fundamental role of osteocytes in skeletal homeostasis

3. Molecular and functional signature of osteocytes

4. Gene deletion and mutations affecting osteocytes

5. Cross talk of bone with other organs/tissues

6. The dying and aging osteocyte

7. Conclusions

Chapter 15: Skeletal Stem Cells/Bone Marrow Stromal Cells

Abstract

1. History and definitions of postnatal stem cells

2. Origins of skeletal stem cells/bone marrow stromal cells

3. Practical considerations—preparation and assessment of SSCs/BMSCs

4. The role of SSCs/BMSCs in postnatal bone turnover

5. The role of SSCs/BMSCs in disease

6. Regulation of SSC/BMSC fate

7. SSCs/BMSCs in tissue engineering and regenerative medicine

8. Conclusions

Acknowledgments

Chapter 16: Osteoimmunology

Abstract

1. Introduction

2. The RANKL/RANK system in bone metabolism

3. Immunological role of the RANKL/RANK system

4. Intracellular signaling for osteoclastogenesis

5. Mechanisms underlying bone destruction in arthritis

6. Bone marrow microenvironment

7. Conclusions

Chapter 17: Integrating Endocrine and Paracrine Influences on Bone; Lessons From Parathyroid Hormone and Parathyroid Hormone-Related Protein

Abstract

1. Bone remodeling and modeling

2. Parathyroid hormone and parathyroid hormone-related protein

3. PTHrP in bone; production in osteoblasts

4. PTHrP function in bone; lessons from PTHrP null mice

5. Anabolic actions of PTH and PTHrP

6. Endocrine PTH, paracrine PTHrP; relationships in development and postnatal life

7. Are osteoclasts involved in the anabolic action of PTH?

8. Growth factors in the local actions of PTH and PTHrP

9. gp130 cytokines as agents of local control of PTH action

10. Sclerostin as a local factor promoting PTH action

11. Other influences of PTH/PTHrP on bone through the bone marrow microenvironment

12. The PTH–PTHrP relationship in vasculature and bone

13. Conclusions

Chapter 18: Genetics of Bone Fat and Energy Regulation

Abstract

1. Introduction

2. The complex relationship of adipose tissue to bone mass

3. A common origin for fat and bone cells

4. Bioenergetics of cells in the bone marrow niche in relation to energy needs and whole body metabolism

5. Control of skeletal and adipose tissue remodeling

6. Anorexia nervosa: energy, bone, and adipose deficiencies

7. Genetics of fat and bone in animal models

8. Genetics of fat and bone in humans

Acknowledgments

Chapter 19: The Cross Talk Between the Central Nervous System, Bone, and Energy Metabolism

Abstract

1. Introduction

2. Specific features of bone and whole-organism physiology

3. Expanding bone biology without premeditation

4. The anticipated functions of osteocalcin

5. Questions raised by the functions of osteocalcin

Chapter 20: Fetal Control of Calcium and Phosphate Homeostasis

Abstract

1. Introduction

2. Overview of fetal and neonatal mineral metabolism

3. Overview of placental mineral transport

4. Overview of endochondral bone development

5. Role of PTHrP

6. Role of PTH

7. Role of PTHrP and PTH in combination

8. Role of estradiol

9. Role of calcitonin

10. Role of vitamin D and calcitriol

11. Role of FGF23

12. Conclusions

Chapter 21: Control of Mineral and Skeletal Homeostasis During Pregnancy and Lactation

Abstract

1. Introduction

2. Skeletal and mineral physiology during pregnancy

3. Disorders of bone and mineral metabolism during pregnancy

4. Skeletal and mineral physiology during lactation

5. Disorders of bone and mineral metabolism during lactation

6. Conclusions

Section 3: Disorders of Bone and Joint

Chapter 22: Osteoporosis Genes Identified by Genome-Wide Association Studies

Abstract

1. Introduction

2. Genome-wide association studies of osteoporosis

3. Genes identified by genome-wide association studies on bone mineral density

4. GWAS in other ethnic groups and for other osteoporosis phenotypes

5. Conclusions

Chapter 23: Osteogenesis Imperfecta

Abstract

1. Introduction

2. Clinical description

3. Genetic description

4. Molecular genetics

5. Animal models

6. Diagnostic aspects

7. Treatment

8. Conclusions

Chapter 24: Osteoarthritis: Genetic Studies of Monogenic and Complex Forms

Abstract

1. Brief clinical description

2. Genetics description

3. Molecular genetics

4. Functional and molecular pathology

5. Diagnostic aspects

6. Treatment

7. Conclusions

Chapter 25: Genetics of Paget’s Disease of Bone

Abstract

1. Clinical features

2. Genetic architecture of Paget’s disease

3. Environmental factors

4. Molecular genetics

5. Animal models

6. Molecular pathology

7. Molecular diagnosis

8. Conclusions

Chapter 26: Mendelian Disorders of RANKL/OPG/RANK/NF-κB Signaling

Abstract

1. Introduction

2. Disorders from constitutive RANK activation

3. Disorders of OPG deficiency

4. Disorders of the NF-κB complex

5. Disorders Of RANKL and RANK deactivation

6. Conclusions

Acknowledgments

Abbreviations

Chapter 27: Skeletal Dysplasias

Abstract

1. Introduction

2. Classification of skeletal dysplasias

3. Diagnosis

4. Multiple epiphyseal dysplasias

5. Metaphyseal dysplasias

6. Conclusions

Chapter 28: Hypophosphatasia and How Alkaline Phosphatase Promotes Mineralization

Abstract

1. Introduction

2. Molecular biology and biochemistry of alkaline phosphatase

3. Physiology of skeletal mineralization

4. Hypophosphatasia

5. Enzyme replacement therapy for HPP

6. Physiological role of alkaline phosphatase explored in hypophosphatasia

Acknowledgments

Abbreviations

Chapter 29: Sclerosing Bone Disorders

Abstract

1. Introduction

2. Clinical aspects of the sclerosing bone disorders

3. Molecular genetics and pathogenic mechanisms

4. Diagnostics, treatment, and genetic counseling

Chapter 30: Fibrodysplasia (Myositis) Ossificans Progressiva

Abstract

1. Introduction

2. Clinical description: fibrodysplasia ossificans progressiva

3. Genetics and molecular genetics of FOP

4. Animal models

5. Functional and molecular pathology

6. Diagnostic aspects

7. Counseling and treatment

8. Conclusions

Acknowledgments

Chapter 31: Thyroid Hormone in Bone and Joint Disorders

Abstract

1. Introduction

2. Thyroid hormone physiology and action

3. Role of thyroid hormones in skeletal growth and development

4. Role of thyroid hormones in bone maintenance and mass

5. Genetically modified mice

6. Role of thyroid hormones in osteoarthritis

7. Conclusions

Acknowledgments

Chapter 32: Disorders and Mechanisms of Ectopic Calcification

Abstract

1. Introduction

2. Disorders of ectopic calcification

3. Animal models

4. Disease mechanisms

5. Conclusions

Section 4: Parathyroid and Related Disorders

Chapter 33: Hyperparathyroidism

Abstract

1. Familial hyperparathyroidism

2. Sporadic hyperparathyroidism

3. Ectopic PTH production

Chapter 34: Hypoparathyroidism

Abstract

1. Introduction

2. Clinical and diagnostic aspects

3. Complex syndromes associated with hypoparathyroidism

4. Abnormalities of the calcium-sensing receptor and G-protein subunit α11

5. Isolated hypoparathyroidism

6. Gene testing in clinical practice

7. Treatment

8. Conclusions

Acknowledgments

Chapter 35: Gsα, Pseudohypoparathyroidism, Fibrous Dysplasia, and McCune–Albright Syndrome

Abstract

1. Introduction

2. Pseudohypoparathyroidism/Albright hereditary osteodystrophy

3. Fibrous dysplasia/McCune–Albright syndrome

Chapter 36: Genetic Disorders Caused by Mutations in the PTH/PTHrP Receptor, its Ligands, and Downstream Effector Molecules

Abstract

1. Introduction

2. The PTH/PTHrP receptor system

3. Human disorders caused by mutations in the PTH-PTHrP signaling pathway

4. Mutations in genes down-stream of the PTH/PTHrP receptor

5. Conclusions

Chapter 37: Genetically Determined Disorders of Extracellular Calcium (Ca2+o) Sensing and Ca2+o Homeostasis

Abstract

1. Introduction

2. Clinical and genetic features of familial hypocalciuric hypercalcemia, including FHH, type 1 (FHH1) (OMIM #145980; alternative designation, HHC1); FHH, type 2 (FHH2) (OMIM #145981; alternative designation, HHC2) and FHH, type 3 (FHH3) (OMIM #600740; alternative designation, HHC3)

3. Clinical and genetic features of neonatal severe primary hyperparathyroidism [OMIM 239200]

4. Clinical and genetic features of autosomal dominant hypoparathyroidism caused by activating mutations of the CaSR [OMIM – #6011298, ADH type 1 (ADH1)] or of GNA11 [OMIM – #615361, ADH type 2 (ADH2)]

5. Clinical and genetic features of Bartter’s syndrome subtype V arising from activating mutations of the CaSR: [OMIM – #601199.0035]

Chapter 38: Multiple Endocrine Neoplasia Syndromes

Abstract

1. Introduction

2. Multiple endocrine neoplasia type 1

3. Multiple endocrine neoplasia types 2 and 3 (MEN2 and MEN3)

4. Multiple endocrine neoplasia type 4 (MEN4)

5. Multiple endocrine and other organ neoplasias (MEONs) syndromes

6. Hyperparathyroidism-jaw tumor syndrome

7. Neurofibromatosis type 1

8. Von Hippel–Lindau disease

9. Carney complex

10. Cowden syndrome

11. McCune–Albright syndrome

Section 5: Vitamin D and Renal Disorders

Chapter 39: Genetic Disorders Of Vitamin D Synthesis and Action

Summary

1. Introduction

2. Biosynthesis of 1,25-dihydroxyvitamin D

3. Hereditary vitamin D–resistant rickets

4. Conclusions

Chapter 40: Heritable Renal Phosphate Wasting Disorders

Abstract

1. Introduction

2. Phosphate homeostasis

3. Phosphate regulation of vitamin D metabolism

4. The heritable renal phosphate wasting disorders

5. Other disorders

6. Conclusions

Acknowledgments

Chapter 41: Renal Fanconi Syndrome, Dent Disease, and Bartter Syndrome

Abstract

1. Brief clinical description

2. Pathophysiology of the disease

3. Etiologies

4. Diagnostic aspects

5. Genetic counseling

6. Treatment

7. Dent disease

8. Bartter’s syndrome

Chapter 42: Inherited Magnesium Disorders

Summary

1. Introduction

2. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC)

3. Primary hypomagnesemia and secondary hypocalcemia (HSH)

4. Isolated autosomal recessive hypomagnesemia (IRH)

5. Autosomal dominant renal hypomagnesemia with hypocalciuria

6. Gitelman syndrome

7. Hypomagnesemia in Bartter syndrome

8. Autosomal dominant hypocalcemia

9. Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME Syndrome)/epilepsy, ataxia, sensorineural deafness, and tubulopathy (EAST syndrome)

10. KCNA1/Kv1.1 mutation and its association with isolated hypomagnesemia

11. Hypomagnesaemia with mitochondrial inheritance

12. CNNM2 mutations in dominant hypomagnesemia

13. Treatment and counseling

Chapter 43: Genetic Hypercalciuria: A Major Risk Factor in Kidney Stones

Abstract

1. Introduction

2. Clinical description and definition

3. Human kidney stones and hypercalciuria: a complex genetic trait

4. Monogenetic causes of hypercalciuria

5. Animal models

6. Clinical pathophysiology

7. Counseling and treatment