Here we review the current knowledge about the mutations of the gene encoding the cardiac ryanodine receptor (RyR2) that cause cardiac arrhythmias. Similarities between the mutations identified in the RyR2 gene and those found in the gene RyR1 that cause malignant hyperthermia and central core disease are discussed. In vitro functional characterization of RyR1 and RyR2 mutants is reviewed, with a focus on the contribution that in vitro expression studies have made to our understanding of related human diseases.
Silvia G. Priori, Carlo Napolitano
The transport of anions across cellular membranes is crucial for various functions, including the control of electrical excitability of muscle and nerve, transport of salt and water across epithelia, and the regulation of cell volume or the acidification and ionic homeostasis of intracellular organelles. Given this broad range of functions, it is perhaps not surprising that mutations in Cl– channels lead to a large spectrum of diseases. These diverse pathologies include the muscle disorder myotonia, cystic fibrosis, renal salt loss in Bartter syndrome, kidney stones, deafness, and the bone disease osteopetrosis. This review will focus on diseases related to transepithelial transport and on disorders involving vesicular Cl– channels.
Thomas J. Jentsch, Tanja Maritzen, Anselm A. Zdebik
ATP-sensitive potassium (KATP) channels, so named because they are inhibited by intracellular ATP, play key physiological roles in many tissues. In pancreatic β cells, these channels regulate glucose-dependent insulin secretion and serve as the target for sulfonylurea drugs used to treat type 2 diabetes. This review focuses on insulin secretory disorders, such as congenital hyperinsulinemia and neonatal diabetes, that result from mutations in KATP channel genes. It also considers the extent to which defective regulation of KATP channel activity contributes to the etiology of type 2 diabetes.
Frances M. Ashcroft
The mapping of disease genes to specific loci has received a great deal of attention in the last decade, and many advances in therapeutics have resulted. Here we review family-based and population-based methods for association analysis. We define the factors that determine statistical power and show how study design and analysis should be designed to maximize the probability of localizing disease genes.
Derek Gordon, Stephen J. Finch
Recent advances in statistical methods and genomic technologies have ushered in a new era in mapping clinically important quantitative traits. However, many refinements and novel statistical approaches are required to enable greater successes in this mapping. The possible impact of recent findings pertaining to the structure of the human genome on efforts to map quantitative traits is yet unclear.
Partha P. Majumder, Saurabh Ghosh
The causal chain between a gene and its effect on disease susceptibility cannot be understood until the effect has been localized in the DNA sequence. Recently, polymorphisms incorporated in the HapMap Project have made linkage disequilibrium (LD) the most powerful tool for localization. The genetics of LD, the maps and databases that it provides, and their use for association mapping, as well as alternative methods for gene localization, are briefly described.
Newton E. Morton
Conventional genetic analysis focuses on the genes that account for specific phenotypes, while traditional epidemiology is more concerned with the environmental causes and risk factors related to traits. Genetic epidemiology is an alliance of the 2 fields that focuses on both genetics, including allelic variants in different populations, and environment, in order to explain exactly how genes convey effects in different environmental contexts and to arrive at a more complete comprehension of the etiology of complex traits. In this review, we discuss the epidemiology of diabetes and the current understanding of the genetic bases of obesity and diabetes and provide suggestions for accelerated accumulation of clinically useful genetic information.
M. Alan Permutt, Jonathon Wasson, Nancy Cox
Genetic epidemiological studies suggest that individual variation in susceptibility to schizophrenia is largely genetic, reflecting alleles of moderate to small effect in multiple genes. Molecular genetic studies have identified a number of potential regions of linkage and 2 associated chromosomal abnormalities, and accumulating evidence favors several positional candidate genes. These findings are grounds for optimism that insight into genetic factors associated with schizophrenia will help further our understanding of this disease and contribute to the development of new ways to treat it.
George Kirov, Michael C. O’Donovan, Michael J. Owen
Gene defects play a major role in the pathogenesis of degenerative disorders of the nervous system. In fact, it has been the very knowledge gained from genetic studies that has allowed the elucidation of the molecular mechanisms underlying the etiology and pathogenesis of many neurodegenerative disorders. In this review, we discuss the current status of genetic epidemiology of the most common neurodegenerative diseases: Alzheimer disease, Parkinson disease, Lewy body dementia, frontotemporal dementia, amyotrophic lateral sclerosis, Huntington disease, and prion diseases, with a particular focus on similarities and differences among these syndromes.
Lars Bertram, Rudolph E. Tanzi
The prognosis of heart failure is worse than that of most cancers, but new therapeutic interventions using stem and other cell-based therapies are succeeding in the fight against it, and old drugs, with new twists, are making a comeback. Genetically engineered animal models are driving insights into the molecular mechanisms that cause hearts to fail, accelerating drug discoveries, and inspiring cell-based therapeutic interventions for both acquired and inheritable cardiac diseases.
Ivor J. Benjamin, Michael D. Schneider
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