Genetic disarray follows mutant KLF1-E325K expression in a congenital dyserythropoietic anemia patient.
Journal
Haematologica
ISSN: 1592-8721
Titre abrégé: Haematologica
Pays: Italy
ID NLM: 0417435
Informations de publication
Date de publication:
12 2019
12 2019
Historique:
received:
22
10
2018
accepted:
12
03
2019
pubmed:
16
3
2019
medline:
5
8
2020
entrez:
16
3
2019
Statut:
ppublish
Résumé
Congenital dyserythropoietic anemia type IV is caused by a heterozygous mutation, Glu325Lys (E325K), in the KLF1 transcription factor. Molecular characteristics of this disease have not been clarified, partly due to its rarity. We expanded erythroid cells from a patient's peripheral blood and analyzed its global expression pattern. We find that a large number of erythroid pathways are disrupted, particularly those related to membrane transport, globin regulation, and iron utilization. The altered genetics lead to significant deficits in differentiation. Glu325 is within the KLF1 zinc finger domain at an amino acid critical for site specific DNA binding. The change to Lys is predicted to significantly alter the target site recognition sequence, both by subverting normal recognition and by enabling interaction with novel sites. Consistent with this, we find high level ectopic expression of genes not normally present in the red cell. These altered properties explain patients' clinical and phenotypic features, and elucidate the dominant character of the mutation.
Identifiants
pubmed: 30872368
pii: haematol.2018.209858
doi: 10.3324/haematol.2018.209858
pmc: PMC6959163
doi:
Substances chimiques
Kruppel-Like Transcription Factors
0
erythroid Kruppel-like factor
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2372-2380Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK046865
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL134684
Pays : United States
Informations de copyright
Copyright© 2019 Ferrata Storti Foundation.
Références
IUBMB Life. 2010 Dec;62(12):886-90
pubmed: 21190291
Blood. 2008 Aug 1;112(3):576-84
pubmed: 18523154
Eur J Haematol. 2018 Sep;101(3):368-378
pubmed: 29901818
Curr Opin Hematol. 2012 Nov;19(6):486-93
pubmed: 22954727
Blood. 2017 Dec 21;130(25):2699-2708
pubmed: 29051181
Blood. 2010 Nov 11;116(19):3972-80
pubmed: 20720183
Blood Adv. 2017 Apr 25;1(11):685-692
pubmed: 29296711
Int J Lab Hematol. 2015 May;37 Suppl 1:78-84
pubmed: 25976964
J Pediatr Hematol Oncol. 2018 Aug;40(6):e405-e409
pubmed: 29300242
Blood. 2014 Dec 4;124(24):3636-45
pubmed: 25339359
Blood. 1994 Feb 1;83(3):860-8
pubmed: 7507739
Blood. 2016 Sep 22;128(12):1631-41
pubmed: 27480112
Mol Cell Biol. 1993 May;13(5):2776-86
pubmed: 7682653
Nat Genet. 2010 Jan;42(1):53-61
pubmed: 20010836
Blood. 2016 Oct 6;128(14):1899-1902
pubmed: 27540014
Blood. 2017 Jun 8;129(23):3111-3120
pubmed: 28377399
Blood. 2008 Sep 1;112(5):2081-8
pubmed: 18487511
Genes Dev. 2004 Oct 15;18(20):2485-90
pubmed: 15489291
Blood. 2011 Sep 15;118(11):3137-45
pubmed: 21778342
Cell Rep. 2018 Nov 20;25(8):2083-2093.e4
pubmed: 30463007
Science. 1991 Sep 20;253(5026):1367, 1393
pubmed: 1896847
Blood Cells Mol Dis. 2002 Mar-Apr;28(2):169-80
pubmed: 12064913
Blood. 2015 Apr 9;125(15):2405-17
pubmed: 25724378
Nat Protoc. 2009;4(1):44-57
pubmed: 19131956
Blood. 2008 Nov 15;112(10):3939-48
pubmed: 18988878
Blood. 2016 Apr 14;127(15):1856-62
pubmed: 26903544
Blood. 2011 Aug 25;118(8):2044-54
pubmed: 21613252
Eur J Hum Genet. 2015 Oct;23(10):1341-8
pubmed: 25585695
Blood. 2013 Sep 26;122(13):2162-6
pubmed: 23940284
Blood. 2014 Mar 6;123(10):1586-95
pubmed: 24443441
J Allergy Clin Immunol. 2006 Mar;117(3):590-6
pubmed: 16522458
Blood. 2014 May 29;123(22):3466-77
pubmed: 24637361
J Pediatr Hematol Oncol. 2018 Aug;40(6):e389-e391
pubmed: 29200155
Hum Mutat. 2013 Jan;34(1):221-8
pubmed: 23125034
Mol Cell Biol. 2007 Dec;27(24):8547-60
pubmed: 17938210
Blood. 1993 Mar 15;81(6):1636-40
pubmed: 7680924
Mol Cell Biol. 2010 Jun;30(11):2811-22
pubmed: 20368355
Am J Hum Genet. 2010 Nov 12;87(5):721-7
pubmed: 21055716
Proc Natl Acad Sci U S A. 2010 Sep 28;107(39):16846-51
pubmed: 20837550
Inflammopharmacology. 2013 Dec;21(6):397-406
pubmed: 23846739
Haematologica. 2010 Jan;95(1):144-7
pubmed: 19850899
Br J Haematol. 1991 Oct;79(2):322-30
pubmed: 1659863
Haematologica. 2011 May;96(5):635-8
pubmed: 21531944
Clin Case Rep. 2017 Jan 28;5(3):248-252
pubmed: 28265383
Blood. 2016 Feb 18;127(7):801-9
pubmed: 26758915
Blood. 2014 Jul 31;124(5):803-11
pubmed: 24829204
Blood Cells Mol Dis. 2013 Aug;51(2):71-5
pubmed: 23522491
Blood. 2007 Dec 1;110(12):3871-80
pubmed: 17715392
Development. 2017 Feb 1;144(3):430-440
pubmed: 28143845
Sci Rep. 2018 Aug 24;8(1):12793
pubmed: 30143664
Curr Opin Hematol. 2013 May;20(3):193-200
pubmed: 23474875
J Biol Chem. 1994 Jan 14;269(2):1493-500
pubmed: 8288615
Nucleic Acids Res. 2017 Feb 17;45(3):1130-1143
pubmed: 28180284
Mol Cell Biol. 2013 Jan;33(1):4-13
pubmed: 23090966
Cell Transplant. 2010;19(4):453-69
pubmed: 20149301
Blood. 2017 Aug 31;130(9):1168-1169
pubmed: 28754684
Curr Opin Hematol. 2017 May;24(3):183-190
pubmed: 28157724
Science. 2016 Jan 15;351(6270):285-9
pubmed: 26816381
Haematologica. 2012 Dec;97(12):1786-94
pubmed: 23065504
Blood. 2017 Aug 31;130(9):1165-1168
pubmed: 28615220
Genomics. 2010 Nov;96(5):303-7
pubmed: 20691777
Nucleic Acids Res. 2014 Apr;42(6):4031-42
pubmed: 24442673
Nat Genet. 2010 Sep;42(9):742-4
pubmed: 20676097
J Clin Invest. 1994 Sep;94(3):1050-8
pubmed: 7521883
Proc Natl Acad Sci U S A. 2010 Aug 24;107(34):15151-6
pubmed: 20696915
Nat Genet. 2010 Sep;42(9):801-5
pubmed: 20676099