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Detection of Prevalent Genetic Alterations Predisposing to Hemochromatosis and Other Common Human Diseases

Departments of Pathology, and Molecular & Medical Genetics, Oregon Health Sciences University, 3181 SW Sam Jackson Park Rd., Portland, OR 97201, Fax 503-494-2025, E-mail pressr@ohsu.edu

The explosion of recent knowledge in basic genetics has spawned numerous clinical follow-up studies that have confirmed an unequivocal association between the presence of specific prevalent genetic alterations and susceptibility to some very common human diseases. In addition, the imminent completion of the Human Genome Project’s sequencing efforts will contribute yet more candidate disease genes that will require both research-based genetic association studies (to confirm suspected disease links) and, if positive, the translation of these disease-genotype associations to routine diagnostic clinical practice. Given this expanding repertoire of confirmed and reputed disease genes (many for common diseases), the demand for rapid, sensitive, specific, inexpensive assays for their clinical- and/or research-based detection is growing quickly. As a consequence, clinical genetic testing laboratories, once accustomed to manual, low-volume, high-labor tests on patients with rare, untreatable classic "genetic" diseases, will soon need to develop more high-throughput, semiautomated methods. In the fast-approaching molecular medicine era, these new genotyping methods will be utilized not only for diagnosing symptomatic patients, but perhaps more importantly, for presymptomatically identifying individuals at risk for common, treatable diseases for whom effective preventative interventions may be available.

A prototypical example of the forthcoming primary public health role of molecular diagnostics is the identification of individuals affected by or at-risk for the iron overload disorder hereditary hemochromatosis. More than 90% of the cases of this most common of all single-gene disorders (present in 0.5% of whites) are caused by the presence of a homozygous well-conserved single nucleotide substitution (nucleotide G845A; amino acid C282Y) in the transferrin receptor binding protein HFE (1). This loss-of-function mutation abolishes HFE’s usual cell surface expression, thus preventing its ability to down-regulate the affinity of transferrin receptor for transferrin-bound iron. The result is a dysregulation of normal cellular iron metabolism and a resulting constitutive intestinal iron absorption. . . . [Full Text of this Article]

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The following articles in journals at HighWire Press have cited this article:

				M. L. Smit, B. A.J. Giesendorf, J. A.M. Vet, F. J.M. Trijbels, and H. J. Blom Semiautomated DNA Mutation Analysis Using a Robotic Workstation and Molecular Beacons Clin. Chem., April 1, 2001; 47(4): 739 - 744. [Abstract] [Full Text] [PDF]