A RAB27A 5′ untranslated region structural variant associated with late-onset hemophagocytic lymphohistiocytosis and normal pigmentation Bianca Tesi,

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Presentation transcript:

A RAB27A 5′ untranslated region structural variant associated with late-onset hemophagocytic lymphohistiocytosis and normal pigmentation Bianca Tesi, MD, PhD, Jelena Rascon, MD, PhD, Samuel C.C. Chiang, PhD, Birute Burnyte, PhD, Alexandra Löfstedt, MD, Anders Fasth, MD, PhD, Miriam Heizmann, Mbiol, Sandra Juozapaite, MD, Rosita Kiudeliene, MD, Egle Kvedaraite, MD, Valdone Miseviciene, MD, Audrone Muleviciene, MD, Martha-Lena Müller, PhD, Magnus Nordenskjöld, MD, PhD, Reda Matuzeviciene, MD, PhD, Ruta Samaitiene, MD, PhD, Carsten Speckmann, MD, Sigita Stankeviciene, MD, Vytautas Zekas, MD, Matthias Voss, PhD, Stephan Ehl, MD, PhD, Nerija Vaiciene-Magistris, MD, PhD, Jan-Inge Henter, MD, PhD, Marie Meeths, MD, PhD, Yenan T. Bryceson, PhD Journal of Allergy and Clinical Immunology Volume 142, Issue 1, Pages 317-321.e8 (July 2018) DOI: 10.1016/j.jaci.2018.02.031 Copyright © 2018 The Authors Terms and Conditions

Fig 1 Clinical and laboratory findings. A, Family pedigrees and RAB27A genotype. B, Brain axial magnetic resonance imaging FLAIR images of P1 at diagnosis of HLH showed nonspecific multifocal hyperintense white matter lesions (arrows). C, H&E stain of a skin biopsy from P3 reveals granulomatous infiltrates in the dermis. A nonnecrotizing granuloma (boxed area, left) is presented at a higher magnification (right). D, NK-cell cytotoxic activity of P3 was defective compared with relatives and controls. NK-cell exocytosis (E) and T-cell exocytosis (F) were reduced in P3. NK-cell cytotoxicity (G) and NK (H) and T-cell exocytosis (I) were defective in P4. dup-inv, Duplication/inversion; H&E, hematoxylin and eosin; n.a., not applicable/available; wt, wild type. Journal of Allergy and Clinical Immunology 2018 142, 317-321.e8DOI: (10.1016/j.jaci.2018.02.031) Copyright © 2018 The Authors Terms and Conditions

Fig 2 Genetic findings. A, Genome browser view over the region chr15:55,467,465-55,656,511 (hg19) including RAB27A and PIGB genes, with screenshots for P1 and P2 showing discordant read pairs. B, Model for the complex SV. C, Segregation analysis by MLPA. D, Rab27a expression in PBMCs evaluated by Western blot in P3, relatives, and healthy controls. E, mRNA expression of RAB27A in PBMCs and melanocytes. The expression of the transcript NM_183235.2 (long) was compared with the total expression of RAB27A. dup-inv, Duplication/inversion; GAPDH, glyceraldehyde 3-phosphate dehydrogenase. Journal of Allergy and Clinical Immunology 2018 142, 317-321.e8DOI: (10.1016/j.jaci.2018.02.031) Copyright © 2018 The Authors Terms and Conditions

Fig E1 A, Brain MRI of P1 at onset of disease, axial series. B, Brain MRI of P3 at onset of disease. C, Lung computed tomography scan of P3. D, Photo of P3 showing normally pigmented hair. Journal of Allergy and Clinical Immunology 2018 142, 317-321.e8DOI: (10.1016/j.jaci.2018.02.031) Copyright © 2018 The Authors Terms and Conditions

Fig E2 A, NK-cell cytotoxicity assay in IL-2–stimulated PBMCs from P3 and relatives. B, NK-cell degranulation assay in IL-2–stimulated PBMCs from P3 and relatives. C, CD8+CD57+ T-cell degranulation assay in IL-2–stimulated PBMCs from P3 and relatives. D, NK-cell cytotoxicity assay in IL-2–stimulated PBMCs from P4 and relatives. E, NK-cell degranulation assay in IL-2–stimulated PBMCs from P4 and relatives. F, CD8+CD57+ T-cell degranulation assay in IL-2–stimulated PBMCs from P4 and relatives. G, Western blot analysis of Rab27a in P4 and relatives. H, Western blot analysis of Rab27a in P5. Journal of Allergy and Clinical Immunology 2018 142, 317-321.e8DOI: (10.1016/j.jaci.2018.02.031) Copyright © 2018 The Authors Terms and Conditions

Fig E3 A, Sanger trace for breakpoint C-invE in all patients. B, Quantitative PCR of PIGB to quantify RNA from PBMCs isolated in P3 and relatives. C, UCSC Genome browser screenshot showing localization of the RAB27A TSS according to FANTOM5 CAGE data from human cells. p1 is the TSS for the isoform NM_183235.2. D, Tags per million at the different RAB27A TSS from the FANTOM5 CAGE data. E, Tags per million at the different RAB27A TSS during differentiation of human embryonic stem cells into pigmented melanocytes (d, day). CAGE, Cap analysis gene expression. Journal of Allergy and Clinical Immunology 2018 142, 317-321.e8DOI: (10.1016/j.jaci.2018.02.031) Copyright © 2018 The Authors Terms and Conditions