ISSN:0892-6638    

DOI:10.1096/fasebj.6.10.1634038

出版商:Wiley    

年代:1992

数据来源: WILEY

摘要:

Germline mutations cause or predispose to most diseases. Hemophilia B is a useful model for studying the underlying pattern of recent germline mutations in humans because the observed pattern of mutation in factor IX more closely reflects the underlying pattern of mutation than the observed pattern for many other genes. In addition, it is possible to identify and correct for biases inherent in ascertaining only those mutations that cause hemophilia. Aspects of the pattern of germline mutation in the factor IX gene are becoming clear:1) in the United States, two‐thirds of mutations causing mild disease arose from three founders whereas almost all the mutations resulting in either moderate or severe disease arose independently, generally within the past 150 years;2) direct estimates of the rates of mutation in humans indicate that transitions are more frequent than transversions, which in turn are more frequent than deletions and insertions;3) transitions at CpG are elevated approximately 24‐fold relative to transitions at non‐CpG dinucleotides;4) transversions at CpG are elevated approximately eightfold relative to transversions at non‐CpG dinucleotides;5) the sum total of the dinucleotide mutation rates produces a bias against G and C bases that would be sufficient to maintain the G+C content of the factor IX gene at its evolutionarily conserved level of 40%; and6) the pattern of mutation is similar for Caucasians residing in the United States and for Asians residing in Asia. Two ideas emerge from this and from an analysis of the pattern of recent deleterious mutations compared with ancient neutral mutations that have been fixed during evolution into the factor IX gene. First, the bulk of germline mutations are likely to arise from endogenous processes rather than environmental mutagens. Second, the factor IX protein is composed mostly of two classes of amino acids: critical residues in which all single‐base missense changes will disrupt protein function, and “spacer” residues in which the precise nature of the residue is unimportant but the peptide bond is necessary to keep the critical residues in register. More work is necessary to assess the veracity and generality of these ideas.— Sommer, S. S. Assessing the underlying pattern of human germline mutations: lessons from the factor IX gene.FASEB J.6: 2767‐2774; 1992.

ISSN:0892-6638    

DOI:10.1096/fasebj.6.10.1634040

出版商:Wiley    

年代:1992

数据来源: WILEY

摘要:

Cystic fibrosis (CF) is an inherited disorder causing pancreatic, pulmonary, and sinus disease in children and young adults. Abnormal viscosity of mucous secretions is a hallmark of the disease, and is believed to be the result of altered electrolyte transport across epithelial cell membranes. The monogenic etiology of this disease has been apparent for more than 40 years, but the defective gene has only recently been identified. This was made possible because of a revolution in genetic technology, called positional cloning, which can pinpoint disease genes without previous knowledge of the abnormal protein product. The protein encoded by the gene defective in CF has been termed the CF transmembrane conductance regulator (CFTR) because of its postulated role in electrolyte transport. Studies investigating the normal function of CFTR and how mutations affect that function, thereby causing CF, have required the combined skills of clinicians, geneticists, molecular biologists, and physiologists. From this collaborative effort a greater understanding of the pathogenesis of this disorder is now emerging. It may soon be possible to introduce novel therapies derived from this new knowledge that will be aimed directly at the basic defect. An ever‐increasing number of genes of unknown function will be identified by continuing advances in molecular genetic technology and the advent of the genome sequencing project. The experience in cystic fibrosis research may prove to be a paradigm for investigation of the function of genes isolated by positional cloning methods.— McIntosh, I.; Cutting, G. R. CFTR and the etiology and pathogenesis of cystic fibrosis.FASEB J.6: 2775‐2782; 1992.

ISSN:0892-6638    

DOI:10.1096/fasebj.6.10.1378801

出版商:Wiley    

年代:1992

数据来源: WILEY

摘要:

During the past decade, the powerful techniques of molecular biology and genetics have been applied to the study of human cancer. Colorectal tumors have proved to be an excellent system in which to search for and study the mutations involved in the development and progression of a common human cancer because of their natural history and several inherited syndromes that strongly predispose to colorectal cancer. A current view is that colorectal cancer results, at least in part, from the accumulation of multiple mutations in oncogenes and tumor suppressor genes in an affected cell. Although the genetic alterations often occur in a preferred sequence, the total accumulation of changes, rather than their order with respect to one another, appears to be a critical determinant of the biological properties of the tumor cell. Study of the inherited and somatic mutations in colorectal tumor cells may provide insights not only into the pathogenesis of cancer, but may also lead to future understanding of the mechanisms of the origin of mutations and the role of environmental and dietary factors in colorectal tumor development.— Fearon, E. R.; Jones, P. A. Progressing toward a molecular description of colorectal cancer development.FASEB J.6: 2783‐2790; 1992.

ISSN:0892-6638    

DOI:10.1096/fasebj.6.10.1321771

出版商:Wiley    

年代:1992

数据来源: WILEY

摘要:

A number of human diseases have been attributed to defects in oxidative phosphorylation (OXPHOS) resulting from mutations in the mitochondrial DNA (mtDNA). One such disease is Leber's hereditary optic neuropathy (LHON), a neurodegenerative disease of young adults that results in blindness due to atrophy of the optic nerve. The etiology of LHON is genetically heterogeneous and in some cases multifactorial. Eleven mtDNA mutations have been associated with LHON, all of which are missense mutations in the subunit genes for the subunits of the electron transport chain complexes I, III, and IV. Molecular, biochemical, and population genetic studies have categorized these mutations as high risk (class I), low risk (class II), or intermediate risk (class I/II). Glass I mutations appear to be primary genetic causes of LHON, while class II mutations are frequently found associated with class I genotypes and may serve as exacerbating genetic factors. Different LHON pedigrees can harbor different combinations of class I, II, or I/II mtDNA mutations, as shown by the complete sequence analysis of the mtDNAs of four LHON probands. The various mtDNA genotypes included an isolated class I mutation, combined class I + II mutations, and combined class I/II + II mutations. The occurrence of such genotypes supports the hypothesis that LHON may result from the additive effects of various genetic and environmental insults to OXPHOS, each of which increases the probability of blindness.— Brown, M. D., Voljavec, A. S., Lott, M. T., MacDonald, I., Wallace, D. C. Leber's hereditary optic neuropathy: a model for mitochondrial neurodegenerative diseases.FASEB J.6: 2791‐2799; 1992.

ISSN:0892-6638    

DOI:10.1096/fasebj.6.10.1634041

出版商:Wiley    

年代:1992

数据来源: WILEY

摘要:

Family and population studies indicate that several different genes can increase susceptibility to autoimmune diseases. Established genetic risk factors include genes encoding histocompatibility molecules, complement proteins, immunoglobulins, peptide transporter proteins, and genes controlling the production of sex hormones. Each factor may independently enhance the immunogenicity of autoantigens, either by increasing their processing and presentation by B lymphocytes and macrophages or by increasing the chance for recognition by autoreactive T and B lymphocytes. Genetic factors may also influence immune responses to infectious agents that can trigger autoimmunity. Because of the somatic generation of immune diversity, genetically identical individuals have different immune systems. The ability of genetic diagnosis to predict autoimmune disease in out‐bred populations cannot easily exceed the disease concordance rates in monozygotic twins, which usually are less than 50%. However, genetic diagnosis can target populations that should be monitored for serologic evidence of autoimmunity, which may precede clinical signs and symptoms. In the future, it may be possible to match different forms of immunotherapy with specific genetic defects.— Carson, D. A. Genetic factors in the etiology and pathogenesis of autoimmunity.FASEB J.6: 2800‐2805; 1992.

ISSN:0892-6638    

DOI:10.1096/fasebj.6.10.1634042

出版商:Wiley    

年代:1992

数据来源: WILEY

摘要:

This paper examines the pathways by which new genetic tests will become available to the public. In view of the scarcity of genetic specialists, the pathway is likely to involve primary care physicians. Other pathways entail state‐mandated testing, community‐based programs, or testing by laboratories without much involvement of primary care physicians. When testing does become available the “destination” will be either family‐centered testing or population‐oriented screening. The deterrent to screening will not be the inability to detect disease‐causing mutations but the costs and attitudes of providers and the public. When tests are provided primarily to provide information about risks to future children, some people will oppose screening on religious or moral grounds. When there are no inexpensive treatments, some will fear that insurance companies and employers will use tests to deny them health care coverage. Some may not want to know their risks for disorders about which little can be done. For common, multifactorial disorders, genetic tests will have low predictive value. Because of these problems, the decision to be tested, regardless of the destination, requires that “testees” be fully informed and consent to testing. When acceptance rates are low, screening is less likely to be cost‐effective; family‐centered testing becomes the default destination.— Holtzman, N. A. The diffusion of new genetic tests for predicting disease.FASEB J.6: 2806‐2812; 1992.

ISSN:0892-6638    

DOI:10.1096/fasebj.6.10.1634043

出版商:Wiley    

年代:1992

数据来源: WILEY

摘要:

There has been a long‐standing consensus on the principles that should guide screening asymptomatic individuals whether for treatment, counseling, or research. Advances in molecular biology will increase the rate of new opportunities for such screening. The benefits and risks, for individuals as well as the public health, will vary with each new test. As with all new technologies, these benefits and risks will have to be assessed in well‐designed and well‐reviewed studies if individuals are to be allowed to make informed decisions regarding whether or not to be tested.— Fost, N. Ethical implications of screening asymptomatic individuals.FASEB J.6: 2813‐2817; 1992.

ISSN:0892-6638    

DOI:10.1096/fasebj.6.10.1634044

出版商:Wiley    

年代:1992

数据来源: WILEY

摘要:

Huntington's disease is an inherited, neurodegenerative disorder, usually of adult onset. Since the identification of linked markers, more than 1000 presymptomatic tests have been performed worldwide and multiple ethical issues have been encountered in relation to informed consent, testing of children, exclusion testing during pregnancy, and confidentiality. Further ethical problems are anticipated after identification of the causal mutation (or mutations). As Huntington's disease is a model for other disorders of adult onset for which testing is becoming possible, the successful resolution of these ethical issues is of great importance. A failure to do so might discredit genetic testing as a whole.— Ball, D. M.; Harper, P. S. Presymptomatic testing for late onset genetic disorders: lessons from Huntington's disease.FASEB J.6: 2818‐2819; 1992.

ISSN:0892-6638    

DOI:10.1096/fasebj.6.10.1386046

出版商:Wiley    

年代:1992

数据来源: WILEY

摘要:

Huntington's disease represents the first disorder for which positional cloning techniques successfully localized an autosomal gene — in 1983. Events since that time have proved the gene recalcitrant to identification and characterization. Since 1986, presymptomatic and prenatal testing for Huntington's disease has been available internationally, although on a limited basis. Testing for Huntington's disease provides an excellent model for designing service programs for genetic testing for late‐onset, fatal disorders, particularly when the gene is not yet in hand and no therapeutic intervention is possible. Special training and precautions must be in place before presymptomatic genetic testing should be offered.— Wexler, N. S. The Tiresias complex: Huntington's disease as a paradigm of testing for late‐onset disorders.FASEB J.6: 2820‐2825; 1992.

ISSN:0892-6638    

DOI:10.1096/fasebj.6.10.1386047

出版商:Wiley    

年代:1992

数据来源: WILEY