Somatic reversion in dedicator of cytokinesis 8 immunodeficiency modulates disease phenotype

Huie Jing, Qian Zhang, Yu Zhang, Brenna J. Hill, Christopher G. Dove, Erwin W. Gelfand, T. Prescott Atkinson, Gulbu Uzel, Helen F. Matthews, Peter J. Mustillo, David B. Lewis, Fotini D. Kavadas, I. Celine Hanson, Ashish R. Kumar, Raif S. Geha, Daniel C. Douek, Steven M. Holland, Alexandra F. Freeman, Helen C. Su

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1667-1675
Number of pages9
JournalJournal of Allergy and Clinical Immunology
Volume133
Issue number6
DOIs
Publication statusPublished - 2014
Externally publishedYes

Fingerprint

Cytokinesis
Phenotype
Mutation
Germ-Line Mutation
Cell Transplantation
T-Lymphocytes
Recombinational DNA Repair
Gene Conversion
Lymphocyte Subsets
National Institutes of Health (U.S.)
Infection
Natural Killer Cells
Flow Cytometry
B-Lymphocytes
Genotype
Genome
Antigens
Survival

Keywords

  • allergy
  • Dedicator of cytokinesis 8
  • gene conversion
  • immunodeficiency
  • intragenic single crossover
  • natural killer cell
  • recombination
  • reversion
  • somatic repair
  • T cell

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Somatic reversion in dedicator of cytokinesis 8 immunodeficiency modulates disease phenotype. / Jing, Huie; Zhang, Qian; Zhang, Yu; Hill, Brenna J.; Dove, Christopher G.; Gelfand, Erwin W.; Atkinson, T. Prescott; Uzel, Gulbu; Matthews, Helen F.; Mustillo, Peter J.; Lewis, David B.; Kavadas, Fotini D.; Hanson, I. Celine; Kumar, Ashish R.; Geha, Raif S.; Douek, Daniel C.; Holland, Steven M.; Freeman, Alexandra F.; Su, Helen C.

In: Journal of Allergy and Clinical Immunology, Vol. 133, No. 6, 2014, p. 1667-1675.

Research output: Contribution to journalArticle

Jing, H, Zhang, Q, Zhang, Y, Hill, BJ, Dove, CG, Gelfand, EW, Atkinson, TP, Uzel, G, Matthews, HF, Mustillo, PJ, Lewis, DB, Kavadas, FD, Hanson, IC, Kumar, AR, Geha, RS, Douek, DC, Holland, SM, Freeman, AF & Su, HC 2014, 'Somatic reversion in dedicator of cytokinesis 8 immunodeficiency modulates disease phenotype', Journal of Allergy and Clinical Immunology, vol. 133, no. 6, pp. 1667-1675. https://doi.org/10.1016/j.jaci.2014.03.025
Jing, Huie ; Zhang, Qian ; Zhang, Yu ; Hill, Brenna J. ; Dove, Christopher G. ; Gelfand, Erwin W. ; Atkinson, T. Prescott ; Uzel, Gulbu ; Matthews, Helen F. ; Mustillo, Peter J. ; Lewis, David B. ; Kavadas, Fotini D. ; Hanson, I. Celine ; Kumar, Ashish R. ; Geha, Raif S. ; Douek, Daniel C. ; Holland, Steven M. ; Freeman, Alexandra F. ; Su, Helen C. / Somatic reversion in dedicator of cytokinesis 8 immunodeficiency modulates disease phenotype. In: Journal of Allergy and Clinical Immunology. 2014 ; Vol. 133, No. 6. pp. 1667-1675.
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title = "Somatic reversion in dedicator of cytokinesis 8 immunodeficiency modulates disease phenotype",
abstract = "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.",
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T1 - Somatic reversion in dedicator of cytokinesis 8 immunodeficiency modulates disease phenotype

AU - Jing, Huie

AU - Zhang, Qian

AU - Zhang, Yu

AU - Hill, Brenna J.

AU - Dove, Christopher G.

AU - Gelfand, Erwin W.

AU - Atkinson, T. Prescott

AU - Uzel, Gulbu

AU - Matthews, Helen F.

AU - Mustillo, Peter J.

AU - Lewis, David B.

AU - Kavadas, Fotini D.

AU - Hanson, I. Celine

AU - Kumar, Ashish R.

AU - Geha, Raif S.

AU - Douek, Daniel C.

AU - Holland, Steven M.

AU - Freeman, Alexandra F.

AU - Su, Helen C.

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

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