Homozygous DBF4 mutation as a cause of severe congenital neutropenia

被引:5
作者
Willemsen, Mathijs [1 ,2 ]
Barber, John S. [1 ,2 ]
Van Nieuwenhove, Erika [1 ,2 ,3 ]
Staels, Frederik [1 ,4 ]
Gerbaux, Margaux [1 ,5 ]
Neumann, Julika [1 ,2 ]
Prezzemolo, Teresa [1 ,2 ]
Pasciuto, Emanuela [1 ,2 ]
Lagou, Vasiliki [1 ,2 ]
Boeckx, Nancy [6 ]
Filtjens, Jessica [7 ]
De Visscher, Amber [7 ]
Matthys, Patrick [7 ]
Schrijvers, Rik [4 ]
Tousseyn, Thomas [8 ]
O'Driscoll, Mark [9 ]
Bucciol, Giorgia [10 ,11 ]
Schlenner, Susan [1 ]
Meyts, Isabelle [10 ,11 ]
Humblet-Baron, Stephanie [1 ]
Liston, Adrian [1 ,2 ,12 ]
机构
[1] Katholieke Univ Leuven, Dept Microbiol Immunol & Transplantat, Lab Adapt Immun, Leuven, Belgium
[2] VIB KU Leuven, Ctr Brain & Dis Res, Leuven, Belgium
[3] Univ Hosp Leuven, Dept Pediat, Leuven, Belgium
[4] Katholieke Univ Leuven, Dept Microbiol Immunol & Transplantat, Allergy & Clin Immunol Res Grp, Leuven, Belgium
[5] Univ Libre Bruxelles, Acad Children Hosp Queen Fabiola, Pediat Dept, Brussels, Belgium
[6] Univ Hosp Leuven, Dept Lab Med, Leuven, Belgium
[7] Katholieke Univ Leuven, Rega Inst Med Res, Dept Microbiol Immunol & Transplantat, Lab Immunobiol, Leuven, Belgium
[8] Univ Hosp Leuven, Dept Pathol, Leuven, Belgium
[9] Univ Sussex, Genome Damage & Stabil Ctr, Human DNA Damage Response Disorders Grp, Brighton, England
[10] Katholieke Univ Leuven, Dept Microbiol Immunol & Transplantat, Lab Inborn Errors Immun, Leuven, Belgium
[11] Univ Hosp Leuven, Dept Pediat, Div Primary Immunodeficiencies, Leuven, Belgium
[12] Babraham Inst, Immunol Programme, Babraham Res Campus, Cambridge, England
基金
英国生物技术与生命科学研究理事会;
关键词
DBF4; DNA replication; inborn errors of immunity; pri-mary immunodeficiency; neutropenia; perturbed growth; facial dys-morphism; genetics; mutation; REPLICATION ORIGIN ACTIVATION; DNA-REPLICATION; CDC7; KINASE; S-PHASE; GROWTH-RETARDATION; MYELOID DIFFERENTIATION; HEMATOPOIETIC STEM; PROTEIN-KINASE; SHORT STATURE; PHOSPHORYLATION;
D O I
10.1016/j.jaci.2023.02.016
中图分类号
R392 [医学免疫学];
学科分类号
100102 ;
摘要
Background: Severe congenital neutropenia presents with recurrent infections early in life as a result of arrested granulopoiesis. Multiple genetic defects are known to block granulocyte differentiation; however, a genetic cause remains unknown in approximately 40% of cases.Objective: We aimed to characterize a patient with severe congenital neutropenia and syndromic features without a genetic diagnosis.Methods: Whole exome sequencing results were validated using flow cytometry, Western blotting, coimmunoprecipitation, quantitative PCR, cell cycle and proliferation analysis of lymphocytes and fibroblasts and granulocytic differentiation of primary CD34+ and HL-60 cells.Results: We identified a homozygous missense mutation in DBF4 in a patient with mild extra-uterine growth retardation, facial dysmorphism and severe congenital neutropenia. DBF4 is the regulatory subunit of the CDC7 kinase, together known as DBF4-dependent kinase (DDK), the complex essential for DNA replication initiation. The DBF4 variant demonstrated impaired ability to bind CDC7, resulting in decreased DDK-mediated phosphorylation, defective S-phase entry and progression and impaired differentiation of granulocytes associated with activation of the p53 -p21 pathway. The introduction of wild-type DBF4 into patient CD34+ cells rescued the promyelocyte differentiation arrest.Conclusion: Hypomorphic DBF4 mutation causes autosomal-recessive severe congenital neutropenia with syndromic features. (J Allergy Clin Immunol 2023;152:266-77.)
引用
收藏
页码:266 / 277
页数:12
相关论文
共 83 条
[1]   A method and server for predicting damaging missense mutations [J].
Adzhubei, Ivan A. ;
Schmidt, Steffen ;
Peshkin, Leonid ;
Ramensky, Vasily E. ;
Gerasimova, Anna ;
Bork, Peer ;
Kondrashov, Alexey S. ;
Sunyaev, Shamil R. .
NATURE METHODS, 2010, 7 (04) :248-249
[2]   A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q-syndrome [J].
Barlow, Jillian L. ;
Drynan, Lesley F. ;
Hewett, Duncan R. ;
Holmes, Luke R. ;
Lorenzo-Abalde, Silvia ;
Lane, Alison L. ;
Jolin, Helen E. ;
Pannell, Richard ;
Middleton, Angela J. ;
Wong, See Heng ;
Warren, Alan J. ;
Wainscoat, James S. ;
Boultwood, Jacqueline ;
McKenzie, Andrew N. J. .
NATURE MEDICINE, 2010, 16 (01) :59-U93
[3]   Mutations in the SRP54 gene cause severe congenital neutropenia as well as Shwachman-Diamond-like syndrome [J].
Bellanne-Chantelot, Christine ;
Schmaltz-Panneau, Barbara ;
Marty, Caroline ;
Fenneteau, Odile ;
Callebaut, Isabelle ;
Clauin, Severine ;
Docet, Aurelie ;
Damaj, Gandhi-Laurent ;
Leblanc, Thierry ;
Pellier, Isabelle ;
Stoven, Cecile ;
Souquere, Sylvie ;
Antony-Debre, Ileana ;
Beaupain, Blandine ;
Aladjidi, Nathalie ;
Barlogis, Vincent ;
Bauduer, Frederic ;
Bensaid, Philippe ;
Boespflug-Tanguy, Odile ;
Berger, Claire ;
Bertrand, Yves ;
Carausu, Liana ;
Fieschi, Claire ;
Galambrun, Claire ;
Schmidt, Aline ;
Journel, Hubert ;
Mazingue, Francoise ;
Nelken, Brigitte ;
Thuan Chong Quah ;
Oksenhendler, Eric ;
Ouachee, Marie ;
Pasquet, Marlene ;
Saada, Veronique ;
Suarez, Felipe ;
Pierron, Gerard ;
Vainchenker, William ;
Plo, Isabelle ;
Donadieu, Jean .
BLOOD, 2018, 132 (12) :1318-1331
[4]   Spotlight on the Replisome: Aetiology of DNA Replication-Associated Genetic Diseases [J].
Bellelli, Roberto ;
Boulton, Simon J. .
TRENDS IN GENETICS, 2021, 37 (04) :317-336
[5]   Replication Protein A phosphorylation and the cellular response to DNA damage [J].
Binz, SK ;
Sheehan, AM ;
Wold, MS .
DNA REPAIR, 2004, 3 (8-9) :1015-1024
[6]   Mutations in topoisomerase IIβ result in a B cell immunodeficiency [J].
Broderick, Lori ;
Yost, Shawn ;
Li, Dong ;
McGeough, Matthew D. ;
Booshehri, Laela M. ;
Guaderrama, Marisela ;
Brydges, Susannah D. ;
Kucharova, Karolina ;
Patel, Niraj C. ;
Harr, Margaret ;
Hakonarson, Hakon ;
Zackai, Elaine ;
Cowell, Ian G. ;
Austin, Caroline A. ;
Hugle, Boris ;
Gebauer, Corinna ;
Zhang, Jianguo ;
Xu, Xun ;
Wang, Jian ;
Croker, Ben A. ;
Frazer, Kelly A. ;
Putnam, Christopher D. ;
Hoffman, Hal M. .
NATURE COMMUNICATIONS, 2019, 10 (1)
[7]   RADIATION-INDUCED CELL-CYCLE ARREST COMPROMISED BY P21 DEFICIENCY [J].
BRUGAROLAS, J ;
CHANDRASEKARAN, C ;
GORDON, JI ;
BEACH, D ;
JACKS, T ;
HANNON, GJ .
NATURE, 1995, 377 (6549) :552-557
[8]   The FoxO code [J].
Calnan, D. R. ;
Brunet, A. .
ONCOGENE, 2008, 27 (16) :2276-2288
[9]   Bone Marrow Failure in Fanconi Anemia Is Triggered by an Exacerbated p53/p21 DNA Damage Response that Impairs Hematopoietic Stem and Progenitor Cells [J].
Ceccaldi, Raphael ;
Parmar, Kalindi ;
Mouly, Enguerran ;
Delord, Marc ;
Kim, Jung Min ;
Regairaz, Marie ;
Pla, Marika ;
Vasquez, Nadia ;
Zhang, Qing-Shuo ;
Pondarre, Corinne ;
de Latour, Regis Peffault ;
Gluckman, Eliane ;
Cavazzana-Calvo, Marina ;
Leblanc, Thierry ;
Larghero, Jerome ;
Grompe, Markus ;
Socie, Gerard ;
D'Andrea, Alan D. ;
Soulier, Jean .
CELL STEM CELL, 2012, 11 (01) :36-49
[10]   Polymerase δ deficiency causes syndromic immunodeficiency with replicative stress [J].
Conde, Cecilia Dominguez ;
Petronczki, Oezlem Yuece ;
Baris, Safa ;
Willmann, Katharina L. ;
Girardi, Enrico ;
Salzer, Elisabeth ;
Weitzer, Stefan ;
Ardy, Rico Chandra ;
Krolo, Ana ;
Ijspeert, Hanna ;
Kiykim, Ayca ;
Karakoc-Aydiner, Elif ;
Forster-Waldl, Elisabeth ;
Kager, Leo ;
Pickl, Winfried F. ;
Superti-Furga, Giulio ;
Martinez, Javier ;
Loizou, Joanna, I ;
Ozen, Ahmet ;
van der Burg, Mirjam ;
Boztug, Kaan .
JOURNAL OF CLINICAL INVESTIGATION, 2019, 129 (10) :4194-4206