Advances in Human Genetics

1 Clinical and Molecular Genetics of Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency.- Introduction: Adrenal Steroidogenesis.- Cholesterol Synthesis, Uptake, and Storage.- Cytochrome P450.- P450scc.- Transport of Electrons to P450scc: Adrenodoxin Reductase and Adrenodoxin.- 3ß-Hydroxysteroid Dehydrogenase/?5 — ?4 Isomerase.- P450cl7.- Electron Transport to P450cl7: P450 Reductase.- P450c21.- P450c11.- The Physiology of 21-Hydroxylase Deficiency.- The Manifestations of 21-Hydroxylase Deficiency.- Clinical Forms of 21-Hydroxylase Deficiency.- Incidence.- Genetics of the 21-Hydroxylase Locus.- HLA Linkage.- 21-Hydroxylase Genes.- C4 Genes.- Other Genes in the 21-Hydroxylase Locus.- Southern Blotting Studies in CAH.- Mapping of P450c21 Genes in Normals and in CAH.- Gene Conversions.- Genetic Alterations in the C4 Genes Associated with CAH.- Strategies for Southern Blotting.- Gene Defects Detectable by Southern Blotting.- No Detectable Abnormalities of the Functional P450c21B Genes.- Abnormalities in the P450c21B Gene Detectable by Southern Blotting.- Common Deletions.- Rare Deletions.- Large Gene Conversions.- Frequency of Lesions Detectable by Southern Blotting.- Pulsed-Field Gel Electrophoresis.- Point Mutations in CAH.- Polymorphisms in the P450c21B Gene.- All Known Deleterious P450c21B Point Mutations Are Actually Small Gene Microconversions.- Effects of Known Point Mutations on 21-Hydroxylase Activity.- Prenatal Diagnosis of CAH.- References.- 2 Genetic Aspects of Amyloidosis.- Amyloidosis: Historical Background.- Amyloidosis: Definition.- Chemical Classification of the Amyloid Syndromes.- Transthyretin-Associated Amyloidosis.- Historical Background.- TTR: Biochemistry and Molecular Biology.- TTR-Amyloidosis: Classification and General Considerations.- TTR Variants Presenting Primarily with Polyneuropathy (FAP).- Disorders in Which TTR-Amyloid Is Deposited Primarily in the Heart [Familial Amyloid Cardiomyopathy and Senile Systemic (Cardiac) Amyloidosis].- TTR Variants Presenting with Both Prominent Cardiomyopathy and Neuropathy.- Other TTR-Amyloidoses, TTR Variants, Intron Polymorphisms, and the Origin of TTR Mutations.- Mechanisms of TTR-Amyloidogenesis.- Familial Mediterranean Fever and Other Hereditary Amyloidoses of the Amyloid A (AA) Type.- Clinicopathologic Features.- Ethnic Distribution.- Genetics of FMF.- FMF and Amyloidosis.- Pathogenesis.- Pathogenesis of AA Amyloid Deposition.- Non-FMF AA Amyloidosis.- ACYS (Cystatin C) Hereditary Cerebral Hemorrhage with Amyloidosis: (HCHWA)-Iceland.- Clinicopathologic Features.- Genetics.- Molecular Pathology.- Molecular Genetics.- Aß Amyloidosis: Dutch-Type HCHWA, Alzheimer’s Disease, and Down Syndrome.- Dutch-Type Hereditary Cerebral Hemorrhage with Amyloidosis.- Alzheimer’s Disease and Down Syndrome.- AGEL: Familial Amyloidosis of the Finnish Type.- Clinicopathologic Features.- Molecular Pathology.- AAPOAI: Familial Amyloid Polyneuropathy, Iowa-(Van Allen).- Clinicopathologic Features.- Molecular Pathology.- AC AL: Multiple Endocrine Neoplasia.- Miscellaneous Hereditary Amyloidoses.- The Treatment of Hereditary Forms of Amyloidosis.- Conclusions.- References.- 3 Huntington’s Disease.- Clinical Characteristics of HD.- Neuropathology and Neurochemistry.- Epidemiology.- A Molecular Genetic Approach to Investigation of HD.- Success of the Linkage Strategy.- Defining the HD Candidate Region.- Isolation of DNA Probes from the Candidate Region.- Fine Structure Physical Mapping of the Candidate Region.- Genetic Mapping of the Candidate Region.- Positioning of the HD Gene by Apparent Crossover Events.- Linkage Disequilibrium.- What Is the HD Gene?.- References.- 4 Biochemical and Molecular Genetics of Cystic Fibrosis.- Early Attempts to Identify Biochemical Markers for CF.- Cellular Metachromasia.- Cystic Fibrosis Factors.- Cellular Drug Resistance.- Protease Activity.- Lysosomal Hydrolases.- Microvillar Enzymes.- Calcium and Mitochondria.- Beta-Adrenergic Responses.- Epithelial Ion Transport.- Studies on Sweat Glands.- Studies with Respiratory Epithelia.- Studies on Cultured Sweat Gland Epithelial Cells.- Studies on Cultured Respiratory Epithelial Cells.- Single-Channel Recordings.- CF Gene Mapping.- Negative Results.- Localization to Chromosome 7.- Identification of the CF Gene.- Cloning Strategies.- Cloning of the CF Gene.- The CF Gene Product (CFTR).- Prediction from Primary Sequence.- Mutation Screening.- Expression of Recombinant CFTR.- Genotype and Phenotype.- Pancreatic Function.- Meconium Ileus.- Sex Difference.- Lung Disease.- Explanations for High CF Gene Frequency.- Genetic Diagnosis.- Tests Based on Linked DNA Markers.- Direct Detection of Mutation.- Concluding Remarks.- References.- 5 Molecular Genetics of von Recklinghausen Neurofibromatosis.- Clinical Features.- Genetics of NF1.- Biochemical and Neurobiological Aspects.- Molecular Genetics.- Linkage Studies.- Physical Mapping.- Cloning Candidate Genes.- The NF1 Gene.- Future Directions.- References.- Addenda.