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01-10-2016 | Original Article

Fatal Lymphoproliferative Disease in Two Siblings Lacking Functional FAAP24

Authors: Svenja Daschkey, Kirsten Bienemann, Volker Schuster, Hans Wolfgang Kreth, René Martin Linka, Andrea Hönscheid, Gerhard Fritz, Christian Johannes, Bernhard Fleckenstein, Bettina Kempkes, Michael Gombert, Sebastian Ginzel, Arndt Borkhardt

Published in: Journal of Clinical Immunology | Issue 7/2016

Abstract

Hereditary defects in several genes have been shown to disturb the normal immune response to EBV and to give rise to severe EBV-induced lymphoproliferation in the recent years. Nevertheless, in many patients, the molecular basis of fatal EBV infection still remains unclear. The Fanconi anemia-associated protein 24 (FAAP24) plays a dual role in DNA repair. By association with FANCM as component of the FA core complex, it recruits the FA core complex to damaged DNA. Additionally, FAAP24 has been shown to evoke ATR-mediated checkpoint responses independently of the FA core complex. By whole exome sequencing, we identified a homozygous missense mutation in the FAAP24 gene (cC635T, pT212M) in two siblings of a consanguineous Turkish family who died from an EBV-associated lymphoproliferative disease after infection with a variant EBV strain, expressing a previously unknown EBNA2 allele.

In order to analyze the functionality of the variant FAAP24 allele, we used herpes virus saimiri-transformed patient T cells to test endogenous cellular FAAP24 functions that are known to be important in DNA damage control. We saw an impaired FANCD2 monoubiquitination as well as delayed checkpoint responses, especially affecting CHK1 phosphorylation in patient samples in comparison to healthy controls. The phenotype of this FAAP24 mutation might have been further accelerated by an EBV strain that harbors an EBNA2 allele with enhanced activities compared to the prototype laboratory strain B95.8. This is the first report of an FAAP24 loss of function mutation found in human patients with EBV-associated lymphoproliferation.

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Coffey AJ, Brooksbank RA, Brandau O, Oohashi T, Howell GR, Bye JM, et al. Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene. Nat Genet. 1998;20(2):129–35.CrossRefPubMed

Hauck F, Randriamampita C, Martin E, Gerart S, Lambert N, Lim A, et al. Primary T-cell immunodeficiency with immunodysregulation caused by autosomal recessive LCK deficiency. J Allergy Clin Immunol. 2012;130(5):1144–52. e11.CrossRefPubMed

Huck K, Feyen O, Niehues T, Ruschendorf F, Hubner N, Laws HJ, et al. Girls homozygous for an IL-2-inducible T cell kinase mutation that leads to protein deficiency develop fatal EBV-associated lymphoproliferation. J Clin Invest. 2009;119(5):1350–8. Pubmed Central PMCID: 2673872.CrossRefPubMedPubMedCentral

Moshous D, Martin E, Carpentier W, Lim A, Callebaut I, Canioni D, et al. Whole-exome sequencing identifies coronin-1A deficiency in 3 siblings with immunodeficiency and EBV-associated B-cell lymphoproliferation. J Allergy Clin Immunol. 2013;131(6):1594–603. Pubmed Central PMCID: 3824285.CrossRefPubMed

Nichols KE, Harkin DP, Levitz S, Krainer M, Kolquist KA, Genovese C, et al. Inactivating mutations in an SH2 domain-encoding gene in X-linked lymphoproliferative syndrome. Proc Natl Acad Sci U S A. 1998;9(23):13765–70. Pubmed Central PMCID: 24894.CrossRef

Rigaud S, Fondaneche MC, Lambert N, Pasquier B, Mateo V, Soulas P, et al. XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. Nature. 2006;444(7115):110–4.CrossRefPubMed

Salzer E, Daschkey S, Choo S, Gombert M, Santos-Valente E, Ginzel S, et al. Combined immunodeficiency with life-threatening EBV-associated lymphoproliferative disorder in patients lacking functional CD27. Haematologica. 2013;98(3):473–8. Pubmed Central PMCID: 3659923.CrossRefPubMedPubMedCentral

van Montfrans JM, Hoepelman AI, Otto S, van Gijn M, van de Corput L, de Weger RA, et al. CD27 deficiency is associated with combined immunodeficiency and persistent symptomatic EBV viremia. J Allergy Clin Immunol. 2012;129(3):787–93. Pubmed Central PMCID: 3294016, e6.CrossRefPubMed

Li FY, Lenardo MJ, Chaigne-Delalande B. Loss of MAGT1 abrogates the Mg2+ flux required for T cell signaling and leads to a novel human primary immunodeficiency. Magnes Res. 2011;24(3):S109–14. Pubmed Central PMCID: 3732466.PubMedPubMedCentral

10.

Martin E, Palmic N, Sanquer S, Lenoir C, Hauck F, Mongellaz C, et al. CTP synthase 1 deficiency in humans reveals its central role in lymphocyte proliferation. Nature. 2014;510(7504):288–92.CrossRefPubMed

11.

Ciccia A, Ling C, Coulthard R, Yan Z, Xue Y, Meetei AR, et al. Identification of FAAP24, a Fanconi anemia core complex protein that interacts with FANCM. Mol Cell. 2007;25(3):331–43.CrossRefPubMed

12.

Collis SJ, Ciccia A, Deans AJ, Horejsi Z, Martin JS, Maslen SL, et al. FANCM and FAAP24 function in ATR-mediated checkpoint signaling independently of the Fanconi anemia core complex. Mol Cell. 2008;32(3):313–24.CrossRefPubMed

13.

Schwab RA, Blackford AN, Niedzwiedz W. ATR activation and replication fork restart are defective in FANCM-deficient cells. EMBO J. 2010;29(4):806–18. Pubmed Central PMCID: 2829160.CrossRefPubMedPubMedCentral

14.

Schuster V, Kreth HW, Muller-Hermelink HK, Huppertz HI, Feller AC, Neumann-Haefelin D, et al. Epstein-Barr virus infection rapidly progressing to monoclonal lymphoproliferative disease in a child with selective immunodeficiency. Eur J Pediatr. 1990;150(1):48–53.CrossRefPubMed

15.

Schuster V, Seidenspinner S, Kreth HW. Detection of a nuclear antigen 2 (EBNA2)-variant Epstein-Barr virus strain in two siblings with fatal lymphoproliferative disease. J Med Virol. 1996;48(1):114–20.CrossRefPubMed

16.

Li H, Durbin R. Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics. 2010;26(5):589–95. Pubmed Central PMCID: 2828108.CrossRefPubMedPubMedCentral

17.

Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, et al. The sequence alignment/map format and SAMtools. Bioinformatics. 2009;25(16):2078–9. Pubmed Central PMCID: 2723002.CrossRefPubMedPubMedCentral

18.

Duraku LS, Hossaini M, Schuttenhelm BN, Holstege JC, Baas M, Ruigrok TJ, et al. Re-innervation patterns by peptidergic substance-P, non-peptidergic P2X3, and myelinated NF-200 nerve fibers in epidermis and dermis of rats with neuropathic pain. Exp Neurol. 2013;241:13–24.CrossRefPubMed

19.

DePristo MA, Banks E, Poplin R, Garimella KV, Maguire JR, Hartl C, et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet. 2011;43(5):491–8. Pubmed Central PMCID: 3083463.CrossRefPubMedPubMedCentral

20.

McLaren W, Pritchard B, Rios D, Chen Y, Flicek P, Cunningham F. Deriving the consequences of genomic variants with the Ensembl API and SNP effect predictor. Bioinformatics. 2010;26(16):2069–70. Pubmed Central PMCID: 2916720.CrossRefPubMedPubMedCentral

21.

Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7(4):248–9. Pubmed Central PMCID: 2855889.CrossRefPubMedPubMedCentral

22.

Kumar P, Henikoff S, Ng PC. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc. 2009;4(7):1073–81.CrossRefPubMed

23.

Biesinger B, Muller-Fleckenstein I, Simmer B, Lang G, Wittmann S, Platzer E, et al. Stable growth transformation of human T lymphocytes by herpesvirus saimiri. Proc Natl Acad Sci U S A. 1992;89(7):3116–9. Pubmed Central PMCID: 48815.CrossRefPubMedPubMedCentral

24.

Linka RM, Risse SL, Bienemann K, Werner M, Linka Y, Krux F, et al. Loss-of-function mutations within the IL-2 inducible kinase ITK in patients with EBV-associated lymphoproliferative diseases. Leukemia. 2012;26(5):963–71.CrossRefPubMed

25.

Ben-Bassat H, Goldblum N, Mitrani S, Goldblum T, Yoffey JM, Cohen MM, et al. Establishment in continuous culture of a new type of lymphocyte from a "Burkitt like" malignant lymphoma (line D.G.-75). Int J Cancer. 1977;19(1):27–33.CrossRefPubMed

26.

Minoguchi S, Taniguchi Y, Kato H, Okazaki T, Strobl LJ, Zimber-Strobl U, et al. RBP-L, a transcription factor related to RBP-Jkappa. Mol Cell Biol. 1997;17(5):2679–87.CrossRefPubMedPubMedCentral

27.

Wang Y, Han X, Wu F, Leung JW, Lowery MG, Do H, et al. Structure analysis of FAAP24 reveals single-stranded DNA-binding activity and domain functions in DNA damage response. Cell Res. 2013;23(10):1215–28. Pubmed Central PMCID: 3790240.CrossRefPubMedPubMedCentral

28.

Garcia-Higuera I, Taniguchi T, Ganesan S, Meyn MS, Timmers C, Hejna J, et al. Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway. Mol Cell. 2001;7(2):249–62.CrossRefPubMed

29.

Andreassen PR, D'Andrea AD, Taniguchi T. ATR couples FANCD2 monoubiquitination to the DNA-damage response. Genes Dev. 2004;18(16):1958–63. Pubmed Central PMCID: 514175.CrossRefPubMedPubMedCentral

30.

Deans AJ, West SC. FANCM connects the genome instability disorders Bloom's syndrome and Fanconi anemia. Mol Cell. 2009;36(6):943–53.CrossRefPubMed

31.

Wang Y, Leung JW, Jiang Y, Lowery MG, Do H, Vasquez KM, et al. FANCM and FAAP24 maintain genome stability via cooperative as well as unique functions. Mol Cell. 2013;49(5):997–1009. Pubmed Central PMCID: 3595374.CrossRefPubMedPubMedCentral

32.

Meetei AR, Medhurst AL, Ling C, Xue Y, Singh TR, Bier P, et al. A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M. Nat Genet. 2005;37(9):958–63. Pubmed Central PMCID: 2704909.CrossRefPubMedPubMedCentral

33.

Singh TR, Bakker ST, Agarwal S, Jansen M, Grassman E, Godthelp BC, et al. Impaired FANCD2 monoubiquitination and hypersensitivity to camptothecin uniquely characterize Fanconi anemia complementation group M. Blood. 2009;114(1):174–80. Pubmed Central PMCID: 2710946.PubMedPubMedCentral

34.

Horejsi Z, Collis SJ, Boulton SJ. FANCM-FAAP24 and HCLK2: roles in ATR signalling and the Fanconi anemia pathway. Cell Cycle. 2009;8(8):1133–7.CrossRefPubMed

35.

Kutler DI, Wreesmann VB, Goberdhan A, Ben-Porat L, Satagopan J, Ngai I, et al. Human papillomavirus DNA and p53 polymorphisms in squamous cell carcinomas from Fanconi anemia patients. J Natl Cancer Inst. 2003;95(22):1718–21.CrossRefPubMed

36.

Park JW, Pitot HC, Strati K, Spardy N, Duensing S, Grompe M, et al. Deficiencies in the Fanconi anemia DNA damage response pathway increase sensitivity to HPV-associated head and neck cancer. Cancer Res. 2010;70(23):9959–68. Pubmed Central PMCID: 2999655.CrossRefPubMedPubMedCentral

37.

Gregorek H, Chrzanowska KH, Dzierzanowska-Fangrat K, Wakulinska A, Pietrucha B, Zapasnik A, et al. Nijmegen breakage syndrome: long-term monitoring of viral and immunological biomarkers in peripheral blood before development of malignancy. Clin Immunol. 2010;135(3):440–7.CrossRefPubMed

38.

Kulinski JM, Leonardo SM, Mounce BC, Malherbe L, Gauld SB, Tarakanova VL. Ataxia telangiectasia mutated kinase controls chronic gammaherpesvirus infection. J Virol. 2012;86(23):12826–37. Pubmed Central PMCID: 3497635.CrossRefPubMedPubMedCentral

39.

Lankisch P, Adler H, Borkhardt A. Testing for herpesvirus infection is essential in children with chromosomal-instability syndromes. J Virol. 2013;87(6):3616–7. Pubmed Central PMCID: 3592146.CrossRefPubMedPubMedCentral

40.

Kondo N, Inoue R, Orii T. Responses of lymphocytes to Epstein-Barr virus in patients with primary immunodeficiencies. J Investig Allergol Clin Immunol. 1994;4(4):182–4.PubMed

41.

Gruhne B, Sompallae R, Marescotti D, Kamranvar SA, Gastaldello S, Masucci MG. The Epstein-Barr virus nuclear antigen-1 promotes genomic instability via induction of reactive oxygen species. Proc Natl Acad Sci U S A. 2009;106(7):2313–8. Pubmed Central PMCID: 2650153.CrossRefPubMedPubMedCentral

42.

Cohen JI, Wang F, Kieff E. Epstein-Barr virus nuclear protein 2 mutations define essential domains for transformation and transactivation. J Virol. 1991;65(5):2545–54. Pubmed Central PMCID: 240611.PubMedPubMedCentral

43.

Schuster V, Ott G, Seidenspinner S, Kreth HW. Common Epstein-Barr virus (EBV) type-1 variant strains in both malignant and benign EBV-associated disorders. Blood. 1996;87(4):1579–85.PubMed

Title: Fatal Lymphoproliferative Disease in Two Siblings Lacking Functional FAAP24
Authors: Svenja Daschkey
Kirsten Bienemann
Volker Schuster
Hans Wolfgang Kreth
René Martin Linka
Andrea Hönscheid
Gerhard Fritz
Christian Johannes
Bernhard Fleckenstein
Bettina Kempkes
Michael Gombert
Sebastian Ginzel
Arndt Borkhardt
Publication date: 01-10-2016
Publisher: Springer US
Published in: Journal of Clinical Immunology / Issue 7/2016
Print ISSN: 0271-9142
Electronic ISSN: 1573-2592
DOI: https://doi.org/10.1007/s10875-016-0317-y

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