Genetic Modifiers in Hemoglobinopathies
ABSTRACT Hereditary anemias show considerable variation in their clinical presentation. In some cases, the causes of these variations are easily apparent. In thalassemia (or in HbE/thalassemia), genetic variation is primarily caused by the severity of the thalassemia mutation. However, not uncommonly, there is variation unexplained by the globin gene mutations themselves, which may be caused by genetic modifiers. In sickle cell disease, the primary mutation is the same in all patients. Therefore, variations in disease severity generally are due to genetic modifiers. In most genetic diseases involving beta globin, the most clearcut influence on phenotype results from elevated fetal hemoglobin levels. In addition, alpha globin gene number can influence disease phenotype. In thalassemia major or intermedia, reduction in the number of alpha globin genes can ameliorate the disease phenotype; conversely, excess alpha globin genes can convert beta thalassemia trait to a clinical picture of thalassemia intermedia. In sickle cell disease, the number of alpha globin genes has both ameliorating and exacerbating effects, depending on which disease manifestation is being examined. Unlinked genetic factors have substantial effects on the phenotype of hereditary anemias, both on the anemia and other disease manifestations. Recently, studies using genome-wide techniques, particularly studying QTLs causing elevated HbF, or affecting HbE/thalassemia, have revealed other genetic elements whose mechanisms are under study. The elucidation of genetic modifiers will hopefully lead to more rational and effective management of these diseases.
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- "Anemias can result from insufficient dietary iron uptake but there are also a multitude of other environmental causes (Umbreit 2005). Mutations in genes coding globin polypeptide chains, iron uptake and processing proteins and other proteins required for the synthesis and assembly of hemoglobin and red blood cells are among the many genetic bases for anemias (Rund and Fucharoen 2008; Camaschella 2009; Iolascon et al. 2009). Symptoms of anemias usually consist of a general feeling of weakness and fatigue due to a lack of oxygen delivery to skeletal muscles combined with other symptoms that are indicative of the underlying cause of the disease. "
ABSTRACT: Transition metal ions are essential nutrients to all forms of life. Iron, copper, zinc, manganese, cobalt and nickel all have unique chemical and physical properties that make them attractive molecules for use in biological systems. Many of these same properties that allow these metals to provide essential biochemical activities and structural motifs to a multitude of proteins including enzymes and other cellular constituents also lead to a potential for cytotoxicity. Organisms have been required to evolve a number of systems for the efficient uptake, intracellular transport, protein loading and storage of metal ions to ensure that the needs of the cells can be met while minimizing the associated toxic effects. Disruptions in the cellular systems for handling transition metals are observed as a number of diseases ranging from hemochromatosis and anemias to neurodegenerative disorders including Alzheimer's and Parkinson's disease. The yeast Saccharomyces cerevisiae has proved useful as a model organism for the investigation of these processes and many of the genes and biological systems that function in yeast metal homeostasis are conserved throughout eukaryotes to humans. This review focuses on the biological roles of iron, copper, zinc, manganese, nickel and cobalt, the homeostatic mechanisms that function in S. cerevisiae and the human diseases in which these metals have been implicated.Biology of Metals 04/2011; 24(5):785-809. DOI:10.1007/s10534-011-9451-4 · 2.69 Impact Factor
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ABSTRACT: Radioactivity induced in detector materials and their immediate surroundings is the major source of discrete-line, gamma-ray background and an important source of continuum background in the performance of remote-sensing, gamma-ray spectroscopy of planetary bodies. In interplanetary space the dominant sources of particles are cosmic rays and their secondaries arising from interactions with the spacecraft and the surface of the target body. In addition, certain future gamma-ray astronomy missions, such as INTEGRAL, are to be located so as to perform their observations in interplanetary space rather than in the traditional low earth orbits. Such location removes contributions from the earth's atmosphere and inner radiation belt at the expense of increased exposure to cosmic rays and solar particle events. Accurate prediction of the activation of key materials by cosmic rays is of the utmost importance for detector design and data interpretation.
Conference Paper: A miniature yaw rate sensor for intelligent chassis control[Show abstract] [Hide abstract]
ABSTRACT: A yaw rate sensor designed for automotive chassis-control and vehicle navigation applications and currently in production for General Motor's StabiliTRAK integrated chassis control system (offered on certain models of the 1997 Cadillac) is described. It consists of a unique micromachined double-ended quartz tuning fork and senses the yaw rate via the Coriolis effect. Electrical and environmental performance data is presented together with salient features of the double-ended tuning fork geometry, associated electronics, sensor construction and calibration methodologyIntelligent Transportation System, 1997. ITSC '97., IEEE Conference on; 12/1997