Mutation in a winged-helix DNA-binding motif causes atypical bare lymphocyte syndrome

Abstract

Bare lymphocyte syndrome (BLS) is an autosomal recessive severe-combined immunodeficiency that can result from mutations in four different transcription factors that regulate the expression of major histocompatibility complex (MHC) class II genes. We have identified here the defective gene that is responsible for the phenotype of the putative fifth BLS complementation group. The mutation was found in the regulatory factor that binds X-box 5 (RFX5) and was mapped to one of the arginines in a DNA-binding surface of this protein. Its wild-type counterpart restored binding of the RFX complex to DNA, transcription of all MHC class II genes and the appearance of these determinants on the surface of BLS cells.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Characterization of MHC class II expression in Ker cells.
Figure 2: Retroviral delivery of wild-type RFX5 rescues expression of MHC class II on the surface of Ker cells.
Figure 3: RFX5 from Ker cells carries a DBD point mutation.
Figure 4: RFX complex from Ker cells shows severely impaired DNA binding.
Figure 5: Wild-type RFX5 rescues transcription of silent genes in Ker cells.
Figure 6: The proposed binding interface between DNA and RFX.

Accession codes

Accessions

Protein Data Bank

References

  1. 1

    Benoist, C. & Mathis, D. Regulation of major histocompatibility complex class-II genes: X, Y and other letters of the alphabet. Annu. Rev. Immunol. 8, 681–715 (1990).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2

    Boss, J.M. Regulation of transcription of MHC class II genes. Curr. Opin. Immunol. 9, 107–113 (1997).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. 3

    Cogswell, J.P., Zeleznik-Le, N. & Ting, J.P. Transcriptional regulation of the HLA-DRA gene. Crit. Rev. Immunol. 11, 87–112 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    Cresswell, P. Assembly, transport, and function of MHC class II molecules. Annu Rev. Immunol. 12, 259–293 (1994).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5

    Glimcher, L.H. & Kara, C.J. Sequences and factors: a guide to MHC class-II transcription. Annu. Rev. Immunol. 10, 13–49 (1992).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6

    Durand, B. et al. RFXAP, a novel subunit of the RFX DNA binding complex is mutated in MHC class II deficiency. EMBO J. 16, 1045–1055 (1997).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7

    Masternak, K. et al. A gene encoding a novel RFX-associated transactivator is mutated in the majority of MHC class II deficiency patients. Nature Genet. 20, 273–277 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8

    DeSandro, A.M., Nagarajan, U.M. & Boss, J.M. Associations and interactions between bare lymphocyte syndrome factors. Mol. Cell. Biol. 20, 6587–6599 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9

    Nekrep, N., Jabrane-Ferrat, N. & Peterlin, B.M. Mutations in the bare lymphocyte syndrome define critical steps in the assembly of the regulatory factor X complex. Mol. Cell. Biol. 20, 4455–4461 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10

    Steimle, V. et al. A novel DNA-binding regulatory factor is mutated in primary MHC class II deficiency (bare lymphocyte syndrome). Genes Dev. 9, 1021–1032 (1995).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11

    Jabrane-Ferrat, N., Fontes, J.D., Boss, J.M. & Peterlin, B.M. Complex architecture of major histocompatibility complex class II promoters: reiterated motifs and conserved protein-protein interactions. Mol. Cell. Biol. 16, 4683–4690 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12

    Steimle, V., Otten, L.A., Zufferey, M. & Mach, B. Complementation cloning of an MHC class II transactivator mutated in hereditary MHC class II deficiency (or bare lymphocyte syndrome). Cell 75, 135–146 (1993).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13

    Fontes, J.D., Kanazawa, S., Nekrep, N. & Peterlin, B.M. The class II transactivator CIITA is a transcriptional integrator. Microbes Infect. 1, 863–869 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14

    Zhu, X.S. et al. Transcriptional scaffold: CIITA interacts with NF-Y, RFX, and CREB to cause stereospecific regulation of the class II major histocompatibility complex promoter. Mol. Cell. Biol. 20, 6051–6061 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15

    Mach, B., Steimle, V., Martinez-Soria, E. & Reith, W. Regulation of MHC class II genes: lessons from a disease. Annu. Rev. Immunol. 14, 301–331 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16

    Reith, W. & Mach, B. The bare lymphocyte syndrome and the regulation of MHC expression. Annu. Rev. Immunol. 19, 331–373 (2001).

    CAS  Article  Google Scholar 

  17. 17

    Villard, J., Masternak, K., Lisowska-Grospierre, B., Fischer, A. & Reith, W. MHC class II deficiency: a disease of gene regulation. Medicine 80, 405–418 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18

    Hauber, I. et al. Molecular characterization of major histocompatibility complex class II gene expression and demonstration of antigen-specific T cell response indicate a new phenotype in class II-deficient patients. J. Exp. Med. 181, 1411–1423 (1995).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19

    Douhan, J. III, Hauber, I., Eibl, M.M. & Glimcher, L.H. Genetic evidence for a new type of major histocompatibility complex class II combined immunodeficiency characterized by a dyscoordinate regulation of HLA-D α and β chains. J. Exp. Med. 183, 1063–1069 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20

    Kelly, P.F., Vandergriff, J., Nathwani, A., Nienhuis, A.W. & Vanin, E.F. Highly efficient gene transfer into cord blood nonobese diabetic/severe combined immunodeficiency repopulating cells by oncoretroviral vector particles pseudotyped with the feline endogenous retrovirus (RD114) envelope protein. Blood 96, 1206–1214 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Emery, P., Durand, B., Mach, B. & Reith, W. RFX proteins, a novel family of DNA binding proteins conserved in the eukaryotic kingdom. Nucleic Acids Res. 24, 803–807 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22

    Gajiwala, K.S. et al. Structure of the winged-helix protein hRFX1 reveals a new mode of DNA binding. Nature 403, 916–921 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23

    Peitsch, M.C. ProMod and Swiss-Model: Internet-based tools for automated comparative protein modelling. Biochem. Soc. Trans. 24, 274–279 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24

    Fontes, J.D., Jabrane-Ferrat, N. & Peterlin, B.M. Assembly of functional regulatory complexes on MHC class II promoters in vivo. J. Mol. Biol. 270, 336–345 (1997).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25

    Jabrane-Ferrat, N., Nekrep, N., Tosi, G., Esserman, L.J. & Peterlin, B.M. MHCII transcriptional platform: Assembly of NFY and RFX on DNA requires RFX5 dimers. Mol. Cell. Biol. 15, 5616–5625 (2002).

    Article  Google Scholar 

  26. 26

    Villard, J. et al. A functionally essential domain of RFX5 mediates activation of major histocompatibility complex class II promoters by promoting cooperative binding between RFX and NF-Y. Mol. Cell. Biol. 20, 3364–3376 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27

    Peretti, M., Villard, J., Barras, E., Zufferey, M. & Reith, W. Expression of the three human major histocompatibility complex class II isotypes exhibits a differential dependence on the transcription factor RFXAP. Mol. Cell. Biol. 21, 5699–5709 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28

    Kobr, M., Reith, W., Herrero-Sanchez, C. & Mach, B. Two DNA-binding proteins discriminate between the promoters of different members of the major histocompatibility complex class II multigene family. Mol. Cell. Biol. 10, 965–971 (1990).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29

    Mach, B., Steimle, V. & Reith, W. MHC class II-deficient combined immunodeficiency: a disease of gene regulation. Immunol. Rev. 138, 207–221 (1994).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30

    Reith, W. et al. Cooperative binding between factors RFX and X2bp to the X and X2 boxes of MHC class II promoters. J. Biol. Chem. 269, 20020–20025 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Clausen, B.E. et al. Residual MHC class II expression on mature dendritic cells and activated B cells in RFX5-deficient mice. Immunity 8, 143–155 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32

    Cavazzana-Calvo, M. et al. Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science 288, 669–672 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33

    Bulger, M. & Groudine, M. Looping versus linking: toward a model for long-distance gene activation. Genes Dev. 13, 2465–2477 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34

    Orphanides, G. & Reinberg, D. A unified theory of gene expression. Cell 108, 439–451 (2002).

    CAS  Article  Google Scholar 

  35. 35

    Scholl, T., Mahanta, S.K. & Strominger, J.L. Specific complex formation between the type II bare lymphocyte syndrome-associated transactivators CIITA and RFX5. Proc. Natl. Acad. Sci. USA 94, 6330–6334 (1997).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36

    Fontes, J.D., Kanazawa, S., Jean, D. & Peterlin, B.M. Interactions between the class II transactivator and CREB binding protein increase transcription of major histocompatibility complex class II genes. Mol. Cell. Biol. 19, 941–947 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 37

    Kretsovali, A. et al. Involvement of CREB binding protein in expression of major histocompatibility complex class II genes via interaction with the class II transactivator. Mol. Cell. Biol. 18, 6777–6783 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38

    Spilianakis, C., Papamatheakis, J. & Kretsovali, A. Acetylation by PCAF enhances CIITA nuclear accumulation and transactivation of major histocompatibility complex class II genes. Mol. Cell. Biol. 20, 8489–8498 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39

    Raval, A. et al. Transcriptional coactivator, CIITA, is an acetyltransferase that bypasses a promoter requirement for TAF(II)250. Mol. Cell 7, 105–115 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40

    Masternak, K. & Reith, W. Promoter-specific functions of CIITA and the MHC class II enhanceosome in transcriptional activation. EMBO J. 21, 1379–1388 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. 41

    Tosi, G. et al. HIV-1 Tat mutants in the cysteine-rich region downregulate HLA class II expression in T lymphocytic and macrophage cell lines. Eur. J. Immunol. 30, 19–28 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42

    Nekrep, N., Geyer, M., Jabrane-Ferrat, N. & Peterlin, B.M. Analysis of ankyrin repeats reveals how a single point mutation in RFXANK results in bare lymphocyte syndrome. Mol. Cell. Biol. 21, 5566–5576 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 43

    Nicholls, A., Sharp, K.A. & Honig, B. Protein folding and association: insights from the interfacial and thermodynamic properties of hydrocarbons. Proteins 11, 281–296 (1991).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank P. Zupanc-Ecimovic for secretarial assistance; E. Vanin for the RD114 retroviral system and advice; G. Tosi for D1.12 and B7.21 antibodies; and other members of our laboratory for helpful discussions. Supported by the Peter und Traudl Engelhorn Stiftung (M. G.) and a grant from Nora Eccles Treadwell Foundation.

Author information

Affiliations

Authors

Corresponding author

Correspondence to B. Matija Peterlin.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Nekrep, N., Jabrane-Ferrat, N., Wolf, H. et al. Mutation in a winged-helix DNA-binding motif causes atypical bare lymphocyte syndrome. Nat Immunol 3, 1075–1081 (2002). https://doi.org/10.1038/ni840

Download citation

Further reading

  • MHC class II deficiency: Report of a novel mutation and special review

    • S. Farrokhi
    • , M. Shabani
    • , Z. Aryan
    • , S. Zoghi
    • , A. Krolo
    • , K. Boztug
    •  & N. Rezaei

    Allergologia et Immunopathologia (2018)

  • Genetics in Sjögren Syndrome

    • Tove Ragna Reksten
    • , Christopher J. Lessard
    •  & Kathy L. Sivils

    Rheumatic Disease Clinics of North America (2016)

  • MHC class I and II deficiencies

    • Suheir Hanna
    •  & Amos Etzioni

    Journal of Allergy and Clinical Immunology (2014)

  • Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjögren's syndrome

    • Christopher J Lessard
    • , He Li
    • , Indra Adrianto
    • , John A Ice
    • , Astrid Rasmussen
    • , Kiely M Grundahl
    • , Jennifer A Kelly
    • , Mikhail G Dozmorov
    • , Corinne Miceli-Richard
    • , Simon Bowman
    • , Sue Lester
    • , Per Eriksson
    • , Maija-Leena Eloranta
    • , Johan G Brun
    • , Lasse G Gøransson
    • , Erna Harboe
    • , Joel M Guthridge
    • , Kenneth M Kaufman
    • , Marika Kvarnström
    • , Helmi Jazebi
    • , Deborah S Cunninghame Graham
    • , Martha E Grandits
    • , Abu N M Nazmul-Hossain
    • , Ketan Patel
    • , Adam J Adler
    • , Jacen S Maier-Moore
    • , A Darise Farris
    • , Michael T Brennan
    • , James A Lessard
    • , James Chodosh
    • , Rajaram Gopalakrishnan
    • , Kimberly S Hefner
    • , Glen D Houston
    • , Andrew J W Huang
    • , Pamela J Hughes
    • , David M Lewis
    • , Lida Radfar
    • , Michael D Rohrer
    • , Donald U Stone
    • , Jonathan D Wren
    • , Timothy J Vyse
    • , Patrick M Gaffney
    • , Judith A James
    • , Roald Omdal
    • , Marie Wahren-Herlenius
    • , Gabor G Illei
    • , Torsten Witte
    • , Roland Jonsson
    • , Maureen Rischmueller
    • , Lars Rönnblom
    • , Gunnel Nordmark
    • , Wan-Fai Ng
    • , Xavier Mariette
    • , Juan-Manuel Anaya
    • , Nelson L Rhodus
    • , Barbara M Segal
    • , R Hal Scofield
    • , Courtney G Montgomery
    • , John B Harley
    •  & Kathy L Sivils

    Nature Genetics (2013)

  • Bare lymphocyte syndrome: An opportunity to discover our immune system

    • Dilip Shrestha
    • , János Szöllősi
    •  & Attila Jenei

    Immunology Letters (2012)