Myb-like, SWIRM, and MPN domains 1 (MYSM1) deficiency: Genotoxic stress- associated bone marrow failure and developmental aberrations Ehsan Bahrami, MSc,

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Presentation transcript:

Myb-like, SWIRM, and MPN domains 1 (MYSM1) deficiency: Genotoxic stress- associated bone marrow failure and developmental aberrations Ehsan Bahrami, MSc, Maximilian Witzel, MD, Tomas Racek, PhD, Jacek Puchałka, PhD, Sebastian Hollizeck, MSc, Naschla Greif- Kohistani, MD, Daniel Kotlarz, MD, PhD, Hans-Peter Horny, MD, Regina Feederle, PhD, Heinrich Schmidt, MD, Roya Sherkat, MD, Doris Steinemann, PhD, Gudrun Göhring, MD, Brigitte Schlegelbeger, MD, Michael H. Albert, MD, Waleed Al-Herz, MD, Christoph Klein, MD, PhD Journal of Allergy and Clinical Immunology Volume 140, Issue 4, Pages 1112-1119 (October 2017) DOI: 10.1016/j.jaci.2016.10.053 Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Journal of Allergy and Clinical Immunology 2017 140, 1112-1119DOI: (10 Journal of Allergy and Clinical Immunology 2017 140, 1112-1119DOI: (10.1016/j.jaci.2016.10.053) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Pedigree, clinical, and immunologic phenotype of MYSM1-deficient patients. A, Pedigree of the family. B, Clinical phenotype of MYSM1-deficient patients with facial features, including midface hypoplasia, low-set ears, hypoplasia of the orbital floor, short neck (i and vi), magnetic resonance imaging correlates of increased liquor space and reduction of cerebral volume (ii and vii), short left humerus (iv, white line) and osteopenia (iv), brachymetacarpia/broad metacarpal bone D1 left (iii, arrowhead) and deep-set thumb (v and viii, arrowhead), accessory papilla of the breast (ix, arrowhead), and gingiva hyperplasia (x). Journal of Allergy and Clinical Immunology 2017 140, 1112-1119DOI: (10.1016/j.jaci.2016.10.053) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Cytohistopathological analysis of bone marrow (BM) samples. A, Histopathological analyses of BM biopsy specimens (hematoxylin and eosin staining) depicting hypocellular BM with increase in adipocyte values (Pat IV.1:i and Pat IV.2:vii). Cytological studies of BM aspirates (May-Grunwald-Giemsa) showing myelodysplastic features with binucleated and trinucleated erythroblasts (ii [arrow] and iv) and proerythroblast (viii [arrow]), ectopic nuclear morphology of erythroblasts (ii, iii, vi, and vii [all asterisks]), cytoplasm bridge between proerythroblasts (iii [arrow]), and pseudo–Pelger-Huet anomaly (ix). B, Immune phenotype of peripheral blood cells in MYSM1-deficient patients compared with a healthy donor and a parent (III-2). Journal of Allergy and Clinical Immunology 2017 140, 1112-1119DOI: (10.1016/j.jaci.2016.10.053) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Mutation analysis and increased genotoxicity. A, Segregation of MYSM1 mutation in the family. B, Western blot (WB) analysis of MYSM1 protein expression in EBV-LCLs of MYSM1-deficient patients compared with that seen in the heterozygous cells of their parents and 2 healthy control subjects (representative data of 3 independent experiments). C, Flow cytometry and WB detection of γ-H2AX in EBV-LCLs of an MYSM1-deficient patient in comparison with a parent (heterozygous for the mutation) and a healthy control subject (representative data of 3 independent experiments). D, Flow cytometric analysis of γ-H2AX levels in PBMCs of MYSM1-deficient patients compared with healthy control subjects before and after UV-induced DNA damage induction (50 J/m2, representative data of 3 independent experiments). E, WB analysis of p38 MAPK and phospho-p38 (Thr180/Tyr182) MAPK expression in primary fibroblasts of MYSM1-deficient patients and healthy control subjects in response to genotoxic stress (UV irradiation, 50 J/m2; representative data of 2 independent experiments). F, Reconstitution analysis of p38 MAPK activation (phospho-p38, Thr180/Tyr182) in patient IV-2's primary fibroblast transduced by bicistronic lentiviruses expressing MYSM1-RFP or RFP only. After transduction, RFP-expressing cells were sorted and irradiated by UVC, and phospho-p38 and total p38 MAPK (Thr180/Tyr182) expression was analyzed by using WB (representative data of 3 independent experiments). The same results were observed on patient IV-1's MYSM1-corrected fibroblasts. G, Representative experiment of 3 independent flow cytometry–based cell-cycle analyses of MYSM1-deficient fibroblasts from a patient and a healthy control subject after UV irradiation–induced DNA damage (50 J/m2). Journal of Allergy and Clinical Immunology 2017 140, 1112-1119DOI: (10.1016/j.jaci.2016.10.053) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions