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N Engl J Med ; 374(11): 1032-1043, 2016 Mar 17.
Artículo en Inglés | MEDLINE | ID: mdl-26981933

RESUMEN

BACKGROUND: Common variable immunodeficiency (CVID) is characterized by late-onset hypogammaglobulinemia in the absence of predisposing factors. The genetic cause is unknown in the majority of cases, and less than 10% of patients have a family history of the disease. Most patients have normal numbers of B cells but lack plasma cells. METHODS: We used whole-exome sequencing and array-based comparative genomic hybridization to evaluate a subset of patients with CVID and low B-cell numbers. Mutant proteins were analyzed for DNA binding with the use of an electrophoretic mobility-shift assay (EMSA) and confocal microscopy. Flow cytometry was used to analyze peripheral-blood lymphocytes and bone marrow aspirates. RESULTS: Six different heterozygous mutations in IKZF1, the gene encoding the transcription factor IKAROS, were identified in 29 persons from six families. In two families, the mutation was a de novo event in the proband. All the mutations, four amino acid substitutions, an intragenic deletion, and a 4.7-Mb multigene deletion involved the DNA-binding domain of IKAROS. The proteins bearing missense mutations failed to bind target DNA sequences on EMSA and confocal microscopy; however, they did not inhibit the binding of wild-type IKAROS. Studies in family members showed progressive loss of B cells and serum immunoglobulins. Bone marrow aspirates in two patients had markedly decreased early B-cell precursors, but plasma cells were present. Acute lymphoblastic leukemia developed in 2 of the 29 patients. CONCLUSIONS: Heterozygous mutations in the transcription factor IKAROS caused an autosomal dominant form of CVID that is associated with a striking decrease in B-cell numbers. (Funded by the National Institutes of Health and others.).


Asunto(s)
Linfocitos B , Inmunodeficiencia Variable Común/genética , Factor de Transcripción Ikaros/genética , Mutación , Adolescente , Adulto , Antígenos CD/análisis , Médula Ósea/inmunología , Examen de la Médula Ósea , Niño , Preescolar , Cromosomas Humanos Par 7 , Inmunodeficiencia Variable Común/inmunología , Exoma , Femenino , Heterocigoto , Humanos , Inmunoglobulina G/sangre , Recuento de Linfocitos , Masculino , Linaje , Análisis de Secuencia de ADN/métodos
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