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Journal of Molecular Medicine

, Volume 85, Issue 5, pp 531–537 | Cite as

A mutation in TREX1 that impairs susceptibility to granzyme A-mediated cell death underlies familial chilblain lupus

  • Min Ae Lee-Kirsch
  • Dipanjan Chowdhury
  • Scott Harvey
  • Maoliang Gong
  • Lydia Senenko
  • Kerstin Engel
  • Christiane Pfeiffer
  • Thomas Hollis
  • Manfred Gahr
  • Fred W. Perrino
  • Judy Lieberman
  • Norbert Hubner
Rapid Communications

Abstract

We recently described a novel autosomal-dominant genodermatosis, termed familial chilblain lupus, and mapped its genetic locus to chromosome 3p21. Familial chilblain lupus manifests in early childhood with ulcerating acral skin lesions and is associated with arthralgias and circulating antinuclear antibodies. In this study, we report the identification of a heterozygous missense mutation (D18N) in TREX1 encoding the 3′-5′repair exonuclease 1 in affected individuals of the family with chilblain lupus. The homodimeric TREX1 is the most abundant intracellular DNase in mammalian cells. We have recently shown that TREX1 plays a role in apoptotic single-stranded DNA damage induced by the killer lymphocyte protease granzyme A. D18N affects a highly conserved amino acid residue critical for catalytic activity. Recombinant mutant TREX1 homodimers are enzymatically inactive, while wild type/mutant heterodimers show residual exonucleolytic activity, suggesting a heterozygous loss of function. Lymphoblastoid cells carrying the D18N mutation are significantly less sensitive to granzyme A-mediated cell death, suggesting a novel role for this caspase-independent form of apoptosis in the pathogenesis of familial chilblain lupus. Our findings also warrant further investigation of TREX1 in common forms of lupus erythematosus.

Keywords

Familial chilblain lupus Systemic lupus erythematosus TREX1 Genetics Apoptosis Autoimmune disease 

Notes

Acknowledgment

We thank the members of the family for their participation in this study. We thank Maja Linné for clinical assistance and Angela Rösen-Wolff and Joachim Rösler for helpful discussions. This work was supported by a Marie Curie Development Host Fellowship from the European Commission to M.L.-K., US grant GM069962 from the NIH to F.W.P., US grant AI45587 from the NIH to J.L., and a grant-in-aid from the National Genome Research Network (NGFN2) of the German Ministry of Science and Education (BMBF) to N.H.

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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Min Ae Lee-Kirsch
    • 1
  • Dipanjan Chowdhury
    • 2
  • Scott Harvey
    • 3
  • Maoliang Gong
    • 4
  • Lydia Senenko
    • 1
  • Kerstin Engel
    • 1
  • Christiane Pfeiffer
    • 5
  • Thomas Hollis
    • 3
  • Manfred Gahr
    • 1
  • Fred W. Perrino
    • 3
  • Judy Lieberman
    • 2
  • Norbert Hubner
    • 4
  1. 1.Klinik für Kinder-und JugendmedizinTechnische Universität DresdenDresdenGermany
  2. 2.CBR Institute for Biomedical Research, Department of PediatricsHarvard Medical SchoolBostonUSA
  3. 3.Department of BiochemistryWake Forest University Health SciencesWinston-SalemUSA
  4. 4.Max-Delbrück-Center for Molecular MedicineBerlin-BuchGermany
  5. 5.Klinik für DermatologieTechnische Universität DresdenDresdenGermany

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