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Recent years have seen rapid advances in our understanding of genetic diseases in terms of their molecular origins. The book focuses on DNA mutations which give rise to abnormalities of protein structure and function in genetic disease.
Contributors
Abbreviations
Preface
Foreword
1 Mutation and protein dysfunction.
Introduction
Loss of function
Conformational changes
Post-translational processing
Multimeric proteins
Protein complexes
Gain-of-function mutations
Allelic interactions
Analysis of protein structure and crystallography
References
2 Haemoglobin.
Introduction
Structure and function of normal haemoglobin
Haemoglobin disorders
Conclusions
References
3 Glucose 6-phosphate dehydrogenase.
Introduction
Enzymology of normal human G6PD
Biochemistry and physiology of G6PD
Structural and functional changes in human G6PD variants
Conclusions
References
4 Glycogen storage disease due to phosphorylase kinase deficiency.
Glycogen metabolism: physiology, biochemistry and genetics
Biochemistry and genetics of phosphorylase kinase
Matching phenotypes and genotypes: defining candidate genes and finding mutations
Common aspects of liver Phk deficiency: three genes, one phenotype
Unresolved issues of Phk deficiency
Conclusions
References
5 Factor VIII and haemophilia A.
Introduction
Factor VIII structure and function
Biosynthesis and metabolism of factor VIII
Structural requirements for factor VIII function
Regulation of factor VIII activity
Genetic defects that cause haemophilia A
Carrier and antenatal diagnosis
The future for haemophilia A therapy
References
6 GM2 gangliosidosis and structure-function relationships in β-hexosaminidase.
Introduction
Mutations associated with the GM2 gangliosidoses
Structure and function of the active sites of chitobiase and Hex
References
7 The low-density lipoprotein (LDL) receptor and familial hypercholesterolaemia.
Introduction
Structure and intracellular processing of the LDL receptor
Regulation of LDL receptor gene transcription
Classes of functional LDL receptor defects
Class 1: failure to produce immunoprecipitable receptor protein
Class 2: impairment of intracellular movement
Class 3: receptor with reduced ligand-binding capacity
Class 4: internalization defective receptors
Class 5: recycling-defective receptors
Mutations causing as yet undefined functional defects
Mutations producing multiple forms of abnormal receptor
High mutability of the LDL-receptor locus
Conclusions
References
8 Fibroblast growth factor receptors and their role in human dysmorphogenesis.
Introduction
Autosomal-dominant skeletal disorders caused by FGFR mutations
The process of bone ossification
The FGF-FGFR signalling pathway
FGFRs in mammalian embryonic development
Human FGFR mutations
Unravelling the functional role of the FGF receptor family
Summary
References
9 The retinoblastoma tumour suppressor protein and cancer.
The retinoblastoma susceptibility gene (RBI)
pRb and E2F/DP transcription factors
Cell cycle-dependent regulation of pRb function
Mouse models, pRb in development
Other pocket proteins
The pRb pathway and cancer
References
10 Rhodopsin mutations in photoreceptor degeneration: implications for protein dysfunction.
The aetiology of retinitis pigmentosa
Structure of the retina
Rhodopsin structure and biochemical properties
Phototransduction
Rhodopsin mutations in retinitis pigmentosa
Correlating phenotype with genotype
Rhodopsin mutations: implications for protein dysfunction
References
11 Spectrin and other red cell membrane proteins in hereditary elliptocytosis and spherocytosis.
Introduction
Spectrin defects in HE and definition of the self-association site
A common low expression allele of SPTA1: allele αLELY
Other examples of complex effects of multiple mutations
References
12 Dystrophin and the molecular genetics of muscular dystrophy.
Introduction
Duchenne muscular dystrophy: pathology
Dystrophin
Dystrophin-associated proteins
Dystrophin-related proteins
Dystrophin-associated proteins and synapse formation
The limb girdle and congenital muscular dystrophies
Concluding remarks and future perspectives
References
13 Fatal familial insomnia, Creutzfeldt-Jakob disease and the prion protein.
Introduction
FFI and CJD178: effect of an intragenic polymorphism
Protease-resistant prion protein in FFI and CJD178: implications for prion strains
Effect of the Aspl78Asn mutation on prion protein processing
Concluding remarks
References
Index