XRCC4 deficiency in human subjects causes a marked neurological phenotype but no overt immunodeficiency Chaowan Guo, PhD, Yuka Nakazawa, PhD, Lisa Woodbine,

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Presentation transcript:

XRCC4 deficiency in human subjects causes a marked neurological phenotype but no overt immunodeficiency Chaowan Guo, PhD, Yuka Nakazawa, PhD, Lisa Woodbine, PhD, Andrea Björkman, PhD, Mayuko Shimada, BS, Heather Fawcett, PhD, Nan Jia, PhD, Kaname Ohyama, PhD, Tao-Sheng Li, MD, PhD, Yuji Nagayama, MD, PhD, Norisato Mitsutake, MD, PhD, Qiang Pan- Hammarström, MD, PhD, Andrew R. Gennery, MD, Alan R. Lehmann, PhD, Penny A. Jeggo, PhD, Tomoo Ogi, PhD Journal of Allergy and Clinical Immunology Volume 136, Issue 4, Pages 1007-1017 (October 2015) DOI: 10.1016/j.jaci.2015.06.007 Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Identification of mutations in the XRCC4 gene in CSL16NG. A, Clinical pictures of CSL16NG. B, Immunoblotting of XRCC4 and LIG4 proteins in indicated cells. Dilutions indicate that the amount of XRCC4 in the patient's cells is less than 2% (detection limit) of normal cells. C, Immunoblots showing expression of LIG4 proteins in 48BR, CSL16NG, and N114P2 (LIG4−/−) cell lines. D, Immunofluorescent staining of endogenous XRCC4 protein using XRCC4 antibody. DAPI, 4′-6-Diamidino-2-phenylindole dihydrochloride. Journal of Allergy and Clinical Immunology 2015 136, 1007-1017DOI: (10.1016/j.jaci.2015.06.007) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 CSL16NG's defects in DNA DSB repair. A, The colony-forming ability of CSL16NG's cells after γ-irradiation was compared with that of normal (1BR.3) and LIG4-defective F07/614 cells. B, Rescue of the inability of CSL16NG's cells to arrest DNA synthesis after IR by using WT XRCC4 overexpression. C, Complementation of the DSB repair defect in CSL16NG's cells by expression of WT or mutant XRCC4 proteins. Error bars = SDs of triplicate experiments. Journal of Allergy and Clinical Immunology 2015 136, 1007-1017DOI: (10.1016/j.jaci.2015.06.007) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 CSL16NG's cells show an exceptionally marked DSB repair defect. A, DSB repair kinetics after IR were determined in normal and various DSB repair–deficient cell lines. Passage number of all fibroblasts used: 5∼9. Error bars = SDs of triplicate experiments. B, Immunoblotting of XRCC4, LIG4, and XLF proteins in normal cells (1BR.3), the patient's cells (CSL16NG), cells from a patient with XLF deficiency (2BN), and cells from a patient with LIG4 syndrome (F07/614 and 2303) cells. C, Diminished LIG4 expression in CSL16NG's cells was confirmed by means of immunofluorescent staining. DAPI, 4′-6-Diamidino-2-phenylindole dihydrochloride. Journal of Allergy and Clinical Immunology 2015 136, 1007-1017DOI: (10.1016/j.jaci.2015.06.007) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Journal of Allergy and Clinical Immunology 2015 136, 1007-1017DOI: (10.1016/j.jaci.2015.06.007) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Journal of Allergy and Clinical Immunology 2015 136, 1007-1017DOI: (10.1016/j.jaci.2015.06.007) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Journal of Allergy and Clinical Immunology 2015 136, 1007-1017DOI: (10.1016/j.jaci.2015.06.007) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Journal of Allergy and Clinical Immunology 2015 136, 1007-1017DOI: (10.1016/j.jaci.2015.06.007) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 Journal of Allergy and Clinical Immunology 2015 136, 1007-1017DOI: (10.1016/j.jaci.2015.06.007) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E6 Journal of Allergy and Clinical Immunology 2015 136, 1007-1017DOI: (10.1016/j.jaci.2015.06.007) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E7 Journal of Allergy and Clinical Immunology 2015 136, 1007-1017DOI: (10.1016/j.jaci.2015.06.007) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E8 Journal of Allergy and Clinical Immunology 2015 136, 1007-1017DOI: (10.1016/j.jaci.2015.06.007) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E9 Journal of Allergy and Clinical Immunology 2015 136, 1007-1017DOI: (10.1016/j.jaci.2015.06.007) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E10 Journal of Allergy and Clinical Immunology 2015 136, 1007-1017DOI: (10.1016/j.jaci.2015.06.007) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E11 Journal of Allergy and Clinical Immunology 2015 136, 1007-1017DOI: (10.1016/j.jaci.2015.06.007) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions