Research on Genetic Reversion in Primary Immunondefiriency

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We have identified two novel cases of genetic reversion in primary immunodeficiency including leukocyte adhesion deficiency type 1 (LAD-1) and X-linked severe combined immunodeficiency (XSCID).1) LAD-1 is an autosomal recessive disorder caused by mutations in the ITGB2 (CD18) gene, and characterized by recurrent severe infections, impaired pus formation, and defective wound healing. We describe an unusual case of severe phenotypic LAD-1 presenting somatic mosaicism. The patient is a compound heterozygote bearing two different frameshift mutations which abrogate protein expression. CD 18 expression was, however, detected in a small proportion of T cells, but was undetectable in granulocytes, monocytes, B cells, and NK cells. The T cells were not of maternal origin, lacked the paternal mutation, and showed a selective advantage in vivo. Molecular analysis using sorted CD18+ cells revealed them to be derived from a single CD84 T cell carrying T-cell receptor VB22. These findings suggest t … More hat spontaneous in vivo reversion was responsible for the somatic mosaicism in our patient. (Blood 2007)2) XSCID is caused by mutations of the common gamma chain (γc) of cytokine receptors and usually characterized by the absence of T and natural killer (NK) cells and the presence of B Cells. Here, we report an atypical case of XSCID presenting with autologous T and NK cells and Omenn syndrome-like manifestations including erythroderma, lymphadenopathy, hepatosplenomegaly, eosinophilia, low serum IgG, elevated serum IgE, and the presence of activated T cells. The patient carried a splice-site mutation (IVS 1+5G>A) that caused most of the mRNA to be incorrectly spliced but produced normally spliced transcript in lesser amount, leading to residual γc expression and development of T and NK cells. The skin biopsy specimen showed massive infiltration of revertant T cells. Those T cells were found to have a second-site mutation that was located at position +1 of the cryptic donor site activated by the IVS1+5G>A, and to result in complete restoration of correct splicing. These findings suggest that the clinical spectrum of XSCID is quite broad and includes atypical cases mimicking Omenn syndrome, and highlight the importance of revertant mosaicism as a possible cause for variable phenotypic expression. (manuscript in submission)In addition to the clinical researches, we have constructed retroviral vectors expressing reversion mutations. These vectors will be used to evaluate conditions of induction of gene reversion in vitro in future experiments. Less