Assuntos
Agamaglobulinemia/história , Doenças Genéticas Ligadas ao Cromossomo X/história , Proteínas Tirosina Quinases/história , Tirosina Quinase da Agamaglobulinemia , Agamaglobulinemia/enzimologia , Linfócitos B/enzimologia , Linhagem da Célula , Cromossomos Humanos X/genética , Doenças Genéticas Ligadas ao Cromossomo X/enzimologia , História do Século XX , Humanos , Masculino , Células Mieloides/enzimologia , Proteínas Tirosina Quinases/química , Proteínas Tirosina Quinases/deficiência , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/isolamento & purificaçãoRESUMO
PURPOSE: To further elucidate the cataract phenotype, and identify the gene and mutation for autosomal dominant cataract (ADC) in an American family of European descent (ADC2) by sequencing the major intrinsic protein gene (MIP), a candidate based on linkage to chromosome 12q13. DESIGN: Observational case series and laboratory experimental study. METHODS: We examined two at-risk individuals in ADC2. We PCR-amplified and sequenced all four exons and all intron-exon boundaries of the MIP gene from genomic and cloned DNA in affected members to confirm one variant as the putative mutation. RESULTS: We found a novel single deletion of nucleotide (nt) 3223 (within codon 235) in exon four, causing a frameshift that alters 41 of 45 subsequent amino acids and creates a premature stop codon. CONCLUSIONS: We identified a novel single base pair deletion in the MIP gene and conclude that it is a pathogenic sequence alteration.
Assuntos
Aquaporinas/genética , Sequência de Bases , Catarata/genética , Proteínas do Olho/genética , Mutação da Fase de Leitura/genética , Glicoproteínas de Membrana/genética , Deleção de Sequência/genética , Cromossomos Humanos Par 12/genética , Códon/genética , Análise Mutacional de DNA , Feminino , Genes Dominantes , Ligação Genética , Humanos , Masculino , Linhagem , Fenótipo , Reação em Cadeia da PolimeraseRESUMO
We analyzed the role of 4 genes, TCL-1, MTCP-1, TML-1 and ATM, in the early pathogenesis of T cell leukemia, with particular interest in the characteristics of long-standing non-leukemic clonal proliferations in ataxia-telangiectasia (A-T) patients. Five patients were studied: 4 patients had A-T (2 of whom had non-leukemic clonal proliferations [ATCP]), 1 had B cell lymphoma and 1 had T-ALL; a fifth patient with T-PLL did not have A-T. We measured the levels of expression for TCL-1, MTCP-1 and TML-1. TCL-1, not expressed in unstimulated mature T cells, was upregulated in the peripheral blood leukocytes (PBL) of the 2 A-T patients with ATCP. It was also expressed in the malignant cells of the A-T patient with B cell lymphoma and the T-PLL cells of the patient without A-T. In the same cells, MTCP-1 type A was expressed equally in all 5 patients, as well as in the controls; MTCP-1 type B transcripts were not observed. TML-1, also not expressed in unstimulated T cells, was expressed in the PBL of one A-T patient with ATCP and in the leukemic cells of the non-A-T T-PLL patient. These expression patterns were compared to cellular immunophenotypes. The non-leukemic clonal T cell populations had the characteristics of immature T cells. We conclude that TCL-1 and TML-1 play a role in cell proliferation and survival but are not pivotal genes in the progression to malignancy, even when the ATM gene is mutated. Additional genetic alterations must occur to initiate tumorigenesis.
