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Unformatted text preview: Trmucleotide repeat disorders in humans: discussions of 0892-6638/96/0010-1 589/$01 .50 FASEB 1589 mechanisms and medical issues L. T. TIMCHENKO* AND C. THOMAS CASKEY *Department of Medicine, Section of Cardiology, Baylor College of Medicine, Houston, Texas 77030, USA; and Merck Research Laboratories, West Point, Pennsylvania 19486, USA ABSTRACT Several human disorders are now known to be caused by expansion of unstable tn- nucleotide repeat sequences, including fragile X syndrome (FRAX), myotonic dystrophy (DM), spinal and bulbar muscular atrophy (SBMA, also known as Kennedy disease), Huntington disease (HD), denta- torubral-pallidoluysian atrophy (DRPLA), spinocer- ebeilar ataxia type 1 (SCA1), Machado-Joseph disease (MJD), and Friedreich ataxia. As these dis- eases are studied in more detail, important differ- ences have emerged in the nature of the unstable repeats and the mechanism by which the repeat ex- pansions cause disease symptoms. There are already animal models of some of these disorders, and these are important resources for studying pathology and therapeutic strategies. Diagnostic procedures for these disorders are only beginning to be standard- ized, and effective therapy will have to wait for fur- ther information on disease mechanisms. Much has been learned since discovery of the fragile X syndrome gene in 1991, but much remains to be done.-Timchenko, L. T., Caskey, C. T. Tninucle- otide repeat disorders in humans: Discussions of mechanisms and medical issues. FASEB J. 10, 1589-1597 (1996) Key Words: myotonic dystrophy ataxia Huntington disease SPACE LIMITATIONS PREVENT us from undertaking a com- prehensive review of all aspects of trinucleotide repeat disorders. We will therefore focus the majority of the text and references on current investigations into the mecha- nisms of trinucleotide repeat instability and molecular pa- thology. These mechanisms are by no means clear, but this review will outline some of the available data, current hy- potheses, and ongoing studies. The rest of the introduction briefly outlines the seven disorders that are discussed fur- ther in this review. Fragile X syndrome (FRAX)2 is one of the most common causes of inherited mental retardation, with a frequency Correspondence: Merck Research Laboratories, Sumneytown Pike, P.O. Box 4, WP26-2O7, West Point, PA 194.86, USA. 2 Abbreviations: CUG-BP, CUG triplet repeat binding protein; DHPR, dihydropyridine receptor; DM, myotonic dystrophy; DRPLA, of 1 in 1250 for affected males and 1 in 2500 for females (1). The disorder is named because of its association with a rare folate-sensitive fragile site in chromosome Xq27.3 that is detected by cytogenetic methods (2). The mutant sequence for FRAX is an unstable CGG trinucleotide re- peat located in the 5 untranslated region of the FMR1 (fragile X mental retardation-i) gene (3-5). The CGG re- peat is polymorphic but stable in normal individuals, with a size ranging between 6 and 46 repeats. Unaffected car-...
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