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Supplemental Material 1 (PDF) Supplementary Figure 1. Murine and human GATA2 promoter alignment shows highly conserved regions. Brackets delimit the highly conserved regions in both genomes, as graphics obtained from ECR Browser show: large areas marked in red indicate highly similar intergenic sequences, repetitive sequences in green, exonic sequences in yellow, and intronic sequences in salmon color. Horizontal axis represents base positions in the genome and the vertical axis represents the percentage identity between the human and mouse genomes. GATA2 binding sites are indicated in red within the brackets, and they were located using the TFSearch, Match and MatInspector transcription factor binding site finder algorithms. Comparison of GATA2 binding sites between both genomes and several surrounding nucleotides is shown in the middle, where GATA2 binding site core sequences are shown in italic and underlined. Two GATA2 binding sites at -2.8 belonged to a highly conserved region spanning 389 bp, with 87.7% homology with the human GATA2 promoter. Similarly, other two GATA2 binding sites at -1.8 were located within a 282 bp region with 75.5% homology. Additionally, a third 142 bp region was taken into account containing the -2992 GATA2 binding site, which showed 68.3% homology. Supplementary Table I: List of reported germline GATA2 mutations and associated syndromes. Mutation (DNA)* Affected exon Mutation (protein) Mutation type Affected ZF Reference Cases/families Associated syndrome c.1-200_871+527del2033 4, 5 p.Met1_Ser290del In-frame deletion None 4,7,20,S1 2/1 MonoMAC c.121C>G 4 p.Pro41Ala Missense (NC) None 17 3/1 Familial MDS/AML c.230-1_230insC 5 p.Arg78ProfsX107 Frameshift Not translated S3 3/1 Emberger syndrome c.243_244delAinsGC 5 p.Gly81GlyfsX103 Frameshift Not translated 4,7,20,21 1/1 MonoMAC c.257_258delGC 5 p.Arg86ProfsX98 Frameshift Not translated 6 1/1 GATA2 deficiency c.302delG 5 p.Gly101AlafsX16 Frameshift Not translated 7 1/1 MonoMAC 17 2/1 Familial MDS/AML c.310_311insCC 5 p.Leu105ProfsX15 Frameshift Not translated S2 5/1 Emberger syndrome c.318_319insT 5 p.Ala106CysfsX78 Frameshift Not translated 6 2/1 GATA2 deficiency c.579_580insA 5 p.Ala194SerfsX8 Frameshift Not translated S2 1/1 Emberger syndrome c.586_593dup 5 p.Gly199LeufsX20 Frameshift Not translated 7 1/1 MonoMAC c.594delG 5 p.Gly200ValfsX19 Frameshift Not translated 6 3/1 GATA2 deficiency c.599_600insG 5 p.Ser201X Nonsense Not translated 3,7 2/1 DCML c.610C>T 5 p.Arg204X Nonsense Not translated 18 1/1 MonoMAC c.670G>T 5 p.Glu224X Nonsense Not translated 18 1/1 MonoMAC c.735_736insC 5 p.Ile246HisfsX36 Frameshift Not translated 6 1/1 GATA2 deficiency c.751C>T 5 p.Pro254Leu Missense (NC) None 4,7 1/1 MonoMAC c.769_778dup 5 p.Tyr260CysfsX24 Frameshift Not translated 4,7,21 1/1 MonoMAC c.941_951dup 6 p.Asn317fsX11 Frameshift 1 4,7 1/1 MonoMAC 18 4/1 MonoMAC c.988C>T 6 p.Arg330X Nonsense 1 5 2/1 GATA2 deficiency c.992_993insGACC 6 p.Leu332ThrfsX53 Frameshift 1 S1 1/1 MonoMAC/DCML S2 1/1 Emberger syndrome c.1009C>T 6 p.Arg337X Nonsense 1 5,7 1/1 MonoMAC c.1017+512del28 None None Intron 5 deletion None 7,20,S3 3/1 MonoMAC c.1017+572C>T None None Intron 5 SNV None 6,7 10/4 MonoMAC 4 1/1 MonoMAC c.1018-1G>T 7a p.Thr340_Thr381del In-frame deletion 1, 2 3 1/1 DCML S2 1/1 Emberger syndrome c.1018-3_1031del17 7a p.Ala341ArgfsX38 Frameshift 1 6 1/1 GATA2 deficiency c.1019_1022delCGGC 7a p.Ala341ProfsX45 Frameshift 1 S2 1/1 Emberger syndrome c.1024G>A 7a p.Ala342Thr Missense (NC) 1 S4 3/1 Pediatric de novo AML-M0 Supplementary Table I (cont.) Mutation (DNA)* Affected exon Mutation (protein) Mutation type Affected ZF Reference Cases/families Associated syndrome 4,7,20,21,S5 5/3 MonoMAC S1 3/1 MonoMAC/DCML 16 18/3 Familial MDS/AML c.1061C>T 7a p.Thr354Met Missense (C) 2 17 4/1 Familial MDS/AML 3 1/1 DCML S6 6/1 GATA2 deficiency 6 5/1 GATA2 deficiency c.1063_1065delACA 7a p.Thr355del In-frame deletion 2 16 2/1 Familial MDS/AML 5,7 1/1 MonoMAC c.1081C>T 7a p.Arg361Cys Missense (NC) 2 6 1/1 GATA2 deficiency c.1082G>C 7a p.Arg361Leu Missense (NC) 2 S2 1/1 Emberger syndrome c.1083_1094del12 7a p.Arg362_Asn365del In-frame deletion 2 4,20 1/1 MonoMAC c.1099_1100insG 7a p.Asp367GlyfsX15 Frameshift 2 5 2/1 GATA2 deficiency c.1103_1104insG 7a p.Val369CysfsX13 Frameshift 2 7 1/1 MonoMAC c.1113C>G 7a p.Asn371Lys Missense(NC) 2 4,20 1/1 MonoMAC c.1114G>A 7a p.Ala372Thr Missense (NC) 2 6 1/1 GATA2 deficiency c.1116_1130del15 7a p.Cys373del5 In-frame deletion 2 5 3/1 GATA2 deficiency c.1117T>C 7a p.Cys373Arg Missense (NC) 2 S2 1/1 Emberger syndrome c.1162A>G 8 p.Met388Val Missense (NC) 2 7,S1 2/1 MonoMAC/DCML c.1163T>C 8 p.Met388Thr Missense (C) 2 5,7 3/1 MonoMAC c.1168_1170delAAG 8 p.Lys390del In-frame deletion 2 6 1/1 GATA2 deficiency 4,5,7,20 2/1 MonoMAC c.1186C>T 8 p.Arg396Trp Missense (NC) 2 S7 1/1 MonoMAC 4,21 1/1 MonoMAC 5,7 6/2 MonoMAC c.1187G>A 8 p.Arg396Gln Missense (NC) 2 19 1/1 MonoMAC/Emberger syndrome 17 3/1 Familial MDS/AML 18 4/1 MonoMAC 4,7,20,21 6/5 MonoMAC c.1192C>T 8 p.Arg398Trp Missense (NC) 2 3,6 4/2 DCML c.1193G>A 8 p.Arg398Gln Missense (NC) 2 6 5/1 GATA2 deficiency 18 1/1 MonoMAC 1/1 MonoMAC/DCML Complete deletion† All Complete deletion Complete deletion Not translated S1 1/1 MonoMAC/DCML 1/1 MonoMAC/DCML C indicates conserved amino acid type in missense mutation; NC non-conserved amino acid type; MonoMAC, monocytopenia and mycobacterial infection syndrome; DCML, dendritic cell, monocyte, B and NK lymphoid deficiency; SNV, single nucleotide variant. *The RefSeq sequence used as reference was NM_032638.4. †Although deletions are different in each case, all include a heterozygous deletion of the entire GATA2 locus. SUPPLEMENTARY REFERENCES S1. Kazenwadel J., G.A. Secker, Y.J. Liu, J.A. Rosenfeld, R.S. Wildin, J. Cuellar-Rodriguez, A.P. Hsu, S. Dyack, C.V. Fernandez, C.E. Chong, M. Babic, P.G. Bardy, A. Shimamura, M.Y. Zhang, T. Walsh, S.M. Holland, D.D. Hickstein, M.S. Horwitz, C.N. Hahn, H.S. Scott, and N.L. Harvey. 2012. Loss-of-function germline GATA2 mutations in patients with MDS/AML or MonoMAC syndrome and primary lymphedema reveal a key role for GATA2 in the lymphatic vasculature. Blood 119: 1283-1291. S2. Ostengaard P., M.A. Simpson, F.C. Connell, C.G. Steward, G. Brice, W.J. Woollard, D. Dafou, T. Kilo, S. Smithson, P. Lunt, V.A. Murday, S. Hodgson, R. Keenan, D.T. Pilz, I. Martinez-Corral, T Makinen, P.S. Mortimer, S. Jeffery, R.C. Trembath, and S. Mansour. 2011. Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome). Nat. Genet. 43: 929-931. S3. Johnson K.D., A.P. Hsu, M.J. Ryu, J. Wang, X. Gao, M.E. Boyer, Y. Liu, Y. Lee, K.R. Calvo, S. Keles, J. Zhang, S.M. Holland, and E.H. Bresnick. 2012. Cis-element mutated in GATA2- dependent immunodeficiency governs hematopoiesis and vascular integrity. J. Clin. Invest. 122: 3692-3704. S4. Shiba N., M. Funato, K. Ohki, M.J. Park, Y. Mizushima, S. Adachi, M. Kobayashi, A. Kinoshita, M. Sotomatsu, H. Arakawa, A. Tawa, K. Horibe, I, Tsukimoto, and Y. Hayashi..2013. Mutations of the GATA2 and CEBPA genes in paediatric acute myeloid leukaemia. Br. J. Haematol. [Epub ahead of print]. S5. Mace E.M., A.P. Hsu, L. Monaco-Shawver, G. Makedonas, J.B. Rosen, L. Dropulic, J.I. Cohen, E.P. Frenkel, J.C. Bagwell, J.L. Sullivan, C.A. Biron, C. Spalding, C.S. Zerbe, G. Uzel, S.M. Holland, and J.S. Orange. 2013. Mutations in GATA2 cause human NK cell deficiency with specific loss of the CD56(bright) subset. Blood 121: 2669-2677. S6. Bödör C., A. Renneville, M. Smith, A. Charazac, S. Iqbal, P. Etancelin, J. Cavenagh, M.J. Barnett, K. Kramarzová, B. Krishnan, A. Matolcsy, C. Preudhomme, J. Fitzgibbon, and C. Owen. 2012. Germline GATA2 p.THR354MET mutation in familial myelodysplastic syndrome with acquired monosomy 7 and ASXL1 mutation demonstrating rapid onset and poor survival. Haematologica 97: 890-894. S7. Camargo J.F., S.A. Lobo, A.P. Hsu, C.S. Zerbe, G.P. Wormser, and S.M. Holland. 2012. MonoMAC Syndrome in a Patient With a GATA2 Mutation: Case Report and Review of the Literature. Clin. Infect. Dis. 57: 697-699. Supplementary Table II. Summary of germline GATA2 mutations. Complete Missense Frameshift Non-sense In-frame deletion Intronic mutation deletion of Total GATA2 locus 15 17 5 6 2 4 50 2 conservative 1 deletion of 28 bp 13 non-conservative 1 single nucleotide variant 2 before ZF1 11 before ZF1 3 before ZF1 1 before ZF1 1 located in ZF1 4 located in ZF1 2 located in ZF1 1 overlaps ZF1 and ZF2 12 located in ZF2 2 located in ZF2 4 located in ZnF2 38 families reported 17 families reported 7 families reported 7 families reported 5 families reported 4 families reported Supplementary Table III. Revised literature showing the data of patients with p.Arg396Gln mutation.
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