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ScienceWeek
MEDICAL BIOLOGY: GENOMICS AS DISEASE PROBES: TWO EXAMPLES
The following points are made by Wylie Burke (New Engl. J. Med. 2003 349:969):
1) Although our understanding of pathology has grown rapidly in recent decades, the underlying mechanisms of many diseases remain obscure. Genomic research offers a new opportunity for determining how diseases occur, by taking advantage of experiments of nature and a growing array of sophisticated research tools to identify the molecular abnormalities underlying disease processes.(1)
2) Before the advent of therapy for hemophilia A, some affected patients had only moderate bleeding problems, lived to adulthood, and led relatively normal lives in the absence of trauma or surgery.(2) Others had severe, spontaneous bleeding beginning in early childhood and rarely survived to adulthood; still others had disease of intermediate clinical severity. The main cause of this variation is the different mutations of the hemophilia A gene that cause hemophilia. When a mutation results in the complete loss of factor VIII protein -- usually because a large gene deletion or genetic inversion results in the failure of gene transcription -- severe hemophilia occurs.(2) The absence of endogenous factor VIII also increases the likelihood of an immune response when factor VIII–replacement therapy is used.(3) This immune response is a severe complication because it can prevent effective treatment. In contrast, other mutations, such as those in which there is a small change in the DNA sequence of the gene, lead to amino acid substitutions in the factor VIII protein. Depending on the nature of the substitution and its effect on the function of factor VIII, these mutations cause mild-to-moderate disease. This example demonstrates that there is often a logical relation between a person's DNA sequence (genotype) and health outcome (phenotype). The functional effect of the genotype is the key factor, providing a molecular explanation for the severity of a given disease.
3) Duchenne's muscular dystrophy is caused by mutations in the dystrophin gene -- usually deletions or gene inversions -- that produce total or near-total loss of the dystrophin protein from skeletal muscle, resulting in early and progressive loss of muscle function.(5) Mutations in the dystrophin gene that cause less severe deficits in the final protein product result in Becker's muscular dystrophy, a milder disease that was historically considered a separate clinical entity. This disorder differs from Duchenne's muscular dystrophy in its later onset and milder course.(5) When genomic research showed that these two clinically distinct disorders involved the same gene, a family of clinical disorders known as dystrophinopathies was identified.(4) A third dystrophinopathy, X-linked dilated cardiomyopathy, was subsequently discovered. This disorder is caused by specific mutations in the dystrophin gene that lead to the selective loss of dystrophin from cardiac muscle, while dystrophin levels in skeletal muscles remain normal or nearly normal.(4) These mutations appear to affect one of the promoter regions of the gene, resulting in the selective loss of gene transcription in cardiac tissue.(4) Discovery of the gene coding for dystrophin thus provided the means to understand a molecular relation among three seemingly different clinical disorders. As with hemophilia A, the relation between the genotype and the clinical outcome is the result of the functional effect of different mutations on dystrophin.
References (abridged):
1. Guttmacher AE, Collins FS. Genomic medicine -- a primer. N Engl J Med 2002;347:1512-1520
2. Hoyer LW. Hemophilia A. N Engl J Med 1994;330:38-47
3. Goodeve AC, Williams I, Bray GL, Peake IR. Relationship between factor VIII mutation type and inhibitor development in a cohort of previously untreated patients treated with recombinant factor VIII (Recombinate). Thromb Haemost 2000;83:844-848
4. Blake DJ, Weir A, Newey SE, Davies KE. Function and genetics of dystrophin and dystrophin-related proteins in muscle. Physiol Rev 2002;82:291-329
5. Korf BR, Darras BT, Urion DK. Dystrophinopathies [includes: Duchenne muscular dystrophy (DMD), pseudohypertrophic muscular dystrophy, Becker muscular dystrophy (BMD), and X-linked dilated cardiomyopathy (XLDCM)]. Seattle: University of Washington, 2003. Accessed August 8, 2003, at http://www.geneclinics.org/profiles/dbmd/details.html
New Engl. J. Med. http://www.nejm.org
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POLYGLUTAMINE SEQUENCES AND NEURODEGENERATIVE DISEASES
The following points are made by Gillian P. Bates (Nature 2001 413:691,739):
1) A potentially deadly repetitive sequence of nucleotides, CAGCAGCAG... (cytosine-adenine-guanine...), lies at the start of the huntingtin gene associated with Huntington's disease. The triplet CAG codes for the amino acid glutamine, and the repetitive sequence therefore codes for a stretch of polyglutamine at one end of the huntingtin protein. People with more than 40 glutamines in the sequence will develop Huntington's disease, while those with fewer than 38 glutamines in the sequence will be unaffected.
2) The elongated polyglutamine tract is associated with the progressive degeneration and death of neurons characteristic of Huntington's disease, and new work by Steffan et al (2001) demonstrates that the expanded tract interferes with the apparatus for switching on and regulating genes.
3) There are currently 9 neurodegenerative diseases apparently caused by the expansion of a polyglutamine tract in one protein or another, and all of these disorders are associated with the formation in nerve cells of insoluble aggregates containing the affected protein. However, stretches of polyglutamine are not always harmful: such polyglutamine sequences are also occur normally in many of the proteins that constitute transcription factor complexes that regulate gene expression. For example, an acetyltransferase enzyme known as CBP contains a tract of 18 glutamines. Acetyltransferases activate transcription by adding acetyl groups to histones, the proteins that help to package DNA into a compact form.
Nature http://www.nature.com/nature
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DNA INSTABILITY AND NEURODEGENERATIVE DISEASES
The following points are made by Richard R. Sinden (Nature 2001 411:757):
1) Many neurological and neurodegenerative diseases, such as *Huntington's disease and *fragile X syndrome, share a similar apparent genetic basis -- the lengthening of tracts of repeated DNA sequence. The molecular mechanisms that cause this "repeat instability" have attracted much attention but have remained elusive. Currently, however, there is some excitement among researchers concerning new evidence that proteins that repair damaged DNA may be responsible for generating repeat instability in cells that are not dividing.
2) At least 14 human diseases have been associated with the lengthening (expansion) of tracts of nucleotide triplets in various human genes. As well as Huntington's disease and fragile X syndrome, these diseases include *myotonic dystrophy type 1, several *spinocerebellar ataxias, and *Friedreich's ataxia. The pathological bases of these diseases vary, but DNA repeat expansion is the underlying mutation in all of them.
3) Two principal classes of repeat instability are associated with these diseases: a) When the tracts of repeats occur within non-protein-coding regions of an affected gene, the tracts can expand by a factor of 10 to 20, or even more, between generations. This large-scale expansion occurs in fragile X syndrome, myotonic dystrophy, certain spinocerebellar ataxias, and Friedreich's ataxia. b) Small-scale expansion of cytosine-adenine-guanine (CAG) repeats can cause disease when the repeats encode a tract of polyglutamine amino acids within an affected protein. For example, the presence of 30 CAG repeats in the gene encoding the huntingtin protein is in the normal range, whereas more than 36 CAG repeats cause Huntington's disease.
Nature http://www.nature.com/nature
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Notes:
Huntington's disease: (Huntington's chorea) First described by George Huntington (1850-1916), the disease attacks specific regions of the brain (e.g., caudate nucleus and putamen), and leads to insanity and eventual death.
fragile X syndrome: An chromosome X-linked recessive syndrome with mental retardation as the most important characteristic. The incidence is approximately 1 in 2000, which makes it second only to Down syndrome among genetically identifiable sources of mental retardation.
myotonic dystrophy type 1: Myotonic dystrophy (Steinert's disease) is the most common adult muscular disorder, characterized by progressive muscle weakness and wasting. The genetic defect has been localized to the long arm of chromosome 19.
spinocerebellar ataxias: In general, an ataxia is an inability to coordinate muscle activity during voluntary movement. Spinocerebellar ataxia is the most common hereditary ataxia. The spinocerebellar degenerative disorders are a group of diseases involving neurons in several nervous system structures, including the spinal cord and cerebellum.
Friedreich's ataxia: A spinal ataxia due to a mutation on chromosome 9. Gait unsteadiness usually begins between the ages of 5 and 15 years.
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