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Combined DOCK8 and CLEC7A mutations causing immunodeficiency in 3 brothers with diarrhea, eczema, and infections  Darrell L. Dinwiddie, PhD, Stephen F.

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Presentation on theme: "Combined DOCK8 and CLEC7A mutations causing immunodeficiency in 3 brothers with diarrhea, eczema, and infections  Darrell L. Dinwiddie, PhD, Stephen F."— Presentation transcript:

1 Combined DOCK8 and CLEC7A mutations causing immunodeficiency in 3 brothers with diarrhea, eczema, and infections  Darrell L. Dinwiddie, PhD, Stephen F. Kingsmore, MB, ChB, BAO, DSc, Sonia Caracciolo, PhD, Giuseppe Rossi, MD, Daniele Moratto, PhD, Cinzia Mazza, PhD, Cristiano Sabelli, PhD, Rosa Bacchetta, MD, Laura Passerini, PhD, Chiara Magri, PhD, Callum J. Bell, PhD, Neil A. Miller, BA, Shannon L. Hateley, BA, Carol J. Saunders, PhD, Lu Zhang, BS, Gary P. Schroth, PhD, Sergio Barlati, MD, Raffaele Badolato, MD, PhD  Journal of Allergy and Clinical Immunology  Volume 131, Issue 2, Pages e3 (February 2013) DOI: /j.jaci Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 A, Family tree. The proband is indicated by the arrow. B, Scatter plot of absolute counts of T, B, and natural killer (NK) cells (solid diamond, patient II-1; solid circles, patient II-3; solid square, patient II-4) compared with 20 age-matched healthy donors (open circles; means ± SDs). C, FOXP3 expression in CD4 of patient II-1 versus a healthy donor. MFI, Mean fluorescence intensity. D, Capacity of CD4+CD25+ Treg cells from patients II-1 and II-4 to suppress the autologous CD4+CD25− T-cell response as inhibition percentage of tritiated thymidine incorporation (upper panel) and IFN-γ production (lower panel). Journal of Allergy and Clinical Immunology  , e3DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig E1 A, Columns 1, 2, and 3, GenCol (reference) visualization of chromosome 9 SNP genotypes in the 3 siblings. Absence of blue spots indicates a homozygous region. Column 4, GenCol genotype comparisons of the 3 siblings. SNPs with identical genotypes among the 3 samples are in black, those with 1 identical allele are in red, and those with no identity are in yellow. The black chromosomal region (asterisk) indicates the 9p24 (chromosome 9 nucleotides 1-8,891,000) identical genotypes in all 3 brothers (chromosome 9 nucleotides 1-8,891,000). B, DOCK8: exon 26 c.3193delA, p.Ser1065AlafsX17, and chr9:396936delA by next-generation exome sequencing. C, CLEC7A: exon 6 714T>G, p.Tyr238X, and chr12: T>G by next-generation exome sequencing. Journal of Allergy and Clinical Immunology  , e3DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig E2 GenCol whole-genome visualization. Columns 1 to 3 correspond to the genotype of the 3 siblings, whereas column 4 corresponds to the genotype comparison. In the first 3 columns red, green, and blue spots have been assigned to the AA, BB, and AB genotypes, respectively. Absence of blue pixels for large segments corresponds to regions of homozygosis. In the genotype comparison (column 4) the SNPs with identical genotypes between the siblings are in black, those with 1 shared allele are in red, and those with both alleles different are in yellow. The large black areas correspond to chromosomal regions, with identical genotypes in the 3 brothers. The DOCK8 and CLEC7A genes are included in the black regions (asterisks) of chromosomes 9 and 12, respectively. Journal of Allergy and Clinical Immunology  , e3DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig E3 Sanger sequence analysis and protein expression of DOCK8 in patients with primary immunodeficiency. A, Structure of DOCK8 mRNA, identification of indel mutation in exon 26, and analysis of DOCK8 transcripts. mRNA isolated from lymphocytes was amplified by using RT-PCR, cloned, and sequenced. B, Immunoblots of DOCK8 and β-actin expression in lymphocytes from a control subject (lane C) and the 3 siblings (lanes P1, P2, and P3). C, Structure of CLEC7A mRNA identification of nonsense mutation. Journal of Allergy and Clinical Immunology  , e3DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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