Somatic reversion in dedicator of cytokinesis 8 immunodeficiency modulates disease phenotype

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:133

Article

Jing, Huie¹  Zhang, Qian¹  Zhang, Yu¹  Hill, Brenna J.³  Dove, Christopher G.¹  Gelfand, Erwin W.⁴  Atkinson, T. Prescott⁵  Uzel, Gulbu²  Mustillo, Peter J.⁶  Lewis, David B.⁷  Kavadas, Fotini D.^8,9  Hanson, I. Celine¹⁰  Kumar, Ashish R.^11,12  Geha, Raif S.^13,14,15  Douek, Daniel C.³  Holland, Steven M.²  Freeman, Alexandra F.²  Su, Helen C.¹ 

[1] NIAID, Lab Host Def, Div Intramural Res, NIH, Bethesda, MD 20892 USA

[2] NIAID, Lab Clin Infect Dis, Div Intramural Res, NIH, Bethesda, MD 20892 USA

[3] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA

[4] Natl Jewish Hlth, Div Cell Biol, Dept Pediat, Div Allergy & Immunol, Denver, CO USA

[5] Univ Alabama Birmingham, Dept Pediat, Birmingham, AL USA

[6] Nationwide Childrens Hosp, Div Infect Dis & Immunol, Columbus, OH USA

[7] Stanford Univ, Div Immunol Allergy & Rheumatol, Dept Pediat, Stanford, CA 94305 USA

[8] Alberta Childrens Prov Gen Hosp, Dept Pediat, Sect Clin Immunol & Allergy, Calgary, AB, Canada

[9] Univ Calgary, Calgary, AB T2N 1N4, Canada

[10] Texas Childrens Hosp, Baylor Coll Med, Dept Pediat, Sect Allergy & Immunol, Houston, TX 77030 USA

[11] Cincinnati Childrens Hosp Med Ctr, Div Bone Marrow Transplantat & Immune Deficiency, Canc & Blood Dis Inst, Cincinnati, OH 45229 USA

[12] Univ Cincinnati, Cincinnati, OH 45221 USA

[13] Childrens Hosp, Div Immunol, Boston, MA 02115 USA

[14] Childrens Hosp, Dept Pediat, Boston, MA 02115 USA

[15] Harvard Univ, Sch Med, Boston, MA USA

关键词: Dedicator of cytokinesis 8;    reversion;    somatic repair;    recombination;    gene conversion;    intragenic single crossover;    T cell;    natural killer cell;    allergy;    immunodeficiency;   

DOI  :  10.1016/j.jaci.2014.03.025

来源: Elsevier

【 摘 要 】

Background: Autosomal recessive loss-of-function mutations in dedicator of cytokinesis 8 (DOCK8) cause a combined immunodeficiency characterized by atopy, recurrent infections, and cancer susceptibility. A genotype-phenotype explanation for the variable disease expression is lacking. Objective: We investigated whether reversions contributed to the variable disease expression. Methods: Patients followed at the National Institutes of Health's Clinical Center were studied. We performed detailed genetic analyses and intracellular flow cytometry to detect DOCK8 protein expression within lymphocyte subsets. Results: We identified 17 of 34 DOCK8-deficient patients who had germline mutations with variable degrees of reversion caused by somatic repair. Somatic repair of the DOCK8 mutations resulted from second-site mutation, original-site mutation, gene conversion, and intragenic crossover. Higher degrees of reversion were associated with recombination-mediated repair. DOCK8 expression was restored primarily within antigen-experienced T cells or natural killer cells but less so in naive T or B cells. Several patients exhibited multiple different repair events. Patients who had reversions were older and had less severe allergic disease, although infection susceptibility persisted. No patients were cured without hematopoietic cell transplantation. Conclusions: In patients with DOCK8 deficiency, only certain combinations of germline mutations supported secondary somatic repair. Those patients had an ameliorated disease course with longer survival but still had fatal complications or required hematopoietic cell transplantation. These observations support the concept that some DOCK8-immunodeficient patients have mutable mosaic genomes that can modulate disease phenotype over time.

【 授权许可】

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