RESUMEN
The information gained from the Human Genome Project and related genetic research will undoubtedly create significant changes in healthcare practice. It is becoming increasingly clear that nurses in all areas of clinical practice will require a fundamental understanding of basic genetics. This article provides the oncology nurse with an overview of basic genetic concepts, including inheritance patterns of single gene conditions, pedigree construction, chromosome aberrations, and the multifactorial basis underlying the common diseases of adulthood. Normal gene structure and function are introduced and the biochemistry of genetic errors is described.
Asunto(s)
Genética Médica , Aberraciones Cromosómicas/genética , Expresión Génica/genética , Enfermedades Genéticas Congénitas/genética , Pruebas Genéticas , Humanos , Biología Molecular , MutaciónRESUMEN
Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of lymphocyte homeostasis and immunological tolerance. Most patients have a heterozygous mutation in the APT1 gene, which encodes Fas (CD95, APO-1), mediator of an apoptotic pathway crucial to lymphocyte homeostasis. Of 17 unique APT1 mutations in unrelated ALPS probands, 12 (71%) occurred in exons 7-9, which encode the intracellular portion of Fas. In vitro, activated lymphocytes from all 17 patients showed apoptotic defects when exposed to an anti-Fas agonist monoclonal antibody. Similar defects were found in a Fas-negative cell line transfected with cDNAs bearing each of the mutations. In cotransfection experiments, Fas constructs with either intra- or extracellular mutations caused dominant inhibition of apoptosis mediated by wild-type Fas. Two missense Fas variants, not restricted to patients with ALPS, were identified. Variant A(-1)T at the Fas signal-sequence cleavage site, which mediates apoptosis less well than wild-type Fas and is partially inhibitory, was present in 13% of African American alleles. Among the ALPS-associated Fas mutants, dominant inhibition of apoptosis was much more pronounced in mutants affecting the intracellular, versus extracellular, portion of the Fas receptor. Mutations causing disruption of the intracellular Fas death domain also showed a higher penetrance of ALPS phenotype features in mutation-bearing relatives. Significant ALPS-related morbidity occurred in 44% of relatives with intracellular mutations, versus 0% of relatives with extracellular mutations. Thus, the location of mutations within APT1 strongly influences the development and the severity of ALPS.
Asunto(s)
Enfermedades Autoinmunes/genética , Trastornos Linfoproliferativos/genética , Mutación/genética , Penetrancia , Receptor fas/genética , Alelos , Apoptosis/genética , Enfermedades Autoinmunes/mortalidad , Enfermedades Autoinmunes/patología , Población Negra/genética , Línea Celular , Salud de la Familia , Femenino , Genes Dominantes/genética , Variación Genética/genética , Genotipo , Humanos , Linfocitos/metabolismo , Linfocitos/patología , Trastornos Linfoproliferativos/mortalidad , Trastornos Linfoproliferativos/patología , Masculino , Polimorfismo Genético/genética , Síndrome , Transfección , Receptor fas/química , Receptor fas/fisiologíaRESUMEN
Autoimmune lymphoproliferative syndrome (ALPS) is characterized by chronic, histologically benign splenomegaly and generalized lymphadenopathy, hypergammaglobulinemia, and autoantibody formation. ALPS has been attributed to defective programmed cell death of lymphocytes, most often arising as a result of mutations in the gene encoding the lymphocyte apoptosis receptor Fas/APO-l/CD95. We identified a novel mutation in the intracellular apoptosis signaling domain of Fas in 11 members of a family, individual members of which have been monitored for up to 25 years, with 1 or more features of ALPS. This study of a large number of family members carrying the same Fas defect demonstrates that ALPS is inherited in an autosomal dominant fashion but with a high degree of variability in clinical expression. Although 1 affected individual died of postsplenectomy sepsis and 1 has been treated for lymphoma, the Fas mutation in this family has been compatible with a healthy adulthood, as clinical features of ALPS have receded with increasing age.
Asunto(s)
Apoptosis/genética , Enfermedades Autoinmunes/genética , Trastornos Linfoproliferativos/genética , Receptores del Factor de Necrosis Tumoral/genética , Linfocitos T/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Apoptosis/inmunología , Enfermedades Autoinmunes/inmunología , Relación CD4-CD8 , Niño , Preescolar , Análisis Mutacional de ADN , Femenino , Tamización de Portadores Genéticos , Humanos , Trastornos Linfoproliferativos/inmunología , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Pronóstico , Receptor fasRESUMEN
The information gained from the Human Genome Project and related genetic research will undoubtedly create significant changes in health care practice. It is becoming increasing clear that nurses in all areas of clinical practice will require a fundamental understanding of basic genetics. This self-learning module provides the oncology nurse with an overview of basic genetic concepts including inheritance patterns of single gene conditions, pedigree construction, chromosome aberrations, and the multifactorial basis underlying many common diseases of adulthood. Normal gene structure and function will be introduced and the biochemistry of genetic errors will be described.
Asunto(s)
Aberraciones Cromosómicas/genética , Enfermedades Genéticas Congénitas/genética , Genética Médica , Trastornos de los Cromosomas , Expresión Génica/genética , Genes Dominantes , Genes Recesivos , Humanos , Biología Molecular , Enfermería Oncológica , LinajeRESUMEN
Programmed cell death (apoptosis) of activated lymphocytes is critical to immune homeostasis. The cell surface protein Fas (CD95) and its ligand play a pivotal role in regulating lymphocyte apoptosis, and defective expression of either Fas or Fas ligand results in marked over accumulation of mature lymphocytes and autoimmune disease in mice. The results of recent studies suggest that defective lymphocyte apoptosis caused by mutations of the Fas gene can result in a severe autoimmune lymphoproliferative syndrome (ALPS) in humans. To define the clinical, genetic, and immunologic spectrum of ALPS, 9 patients and their families were extensively evaluated with routine clinical studies, lymphocyte phenotyping, genotyping, and in vitro assays for lymphocyte apoptosis. Individual patients were followed up for 3 months to 6 years. ALPS was identified in 9 unrelated children as manifested by moderate to massive splenomegaly and lymphadenopathy, hypergammaglobulinemia, autoimmunity, B-cell lymphocytosis, and the expansion of an unusual population of CD4- CD8- T cells that express the alpha/beta T-cell receptor (TCR). All patients showed defective lymphocyte apoptosis in vitro. Heterozygous mutations of the Fas gene were detected in 8 patients. One ALPS patient lacked a Fas gene mutation. Healthy relatives with Fas mutations were identified in 7 of 8 ALPS kindreds. These relatives also showed in vitro abnormalities of Fas-mediated lymphocyte apoptosis, but clinical features of ALPS were not present in the vast majority of these individuals. ALPS is a unique clinical syndrome in which in vitro abnormalities of lymphocyte apoptosis are associated with abnormal lymphoproliferation and autoimmunity. These findings provide evidence that apoptosis of activated lymphocytes is an important mechanism for maintaining immunologic homeostasis and self-tolerance in humans. Fas gene mutations account for impaired lymphocyte apoptosis in only a subset of patients with ALPS.