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  • Identification of novel MUNC13-4 mutations in familial haemophagocytic lymphohistiocytosis and functional analysis of MUNC13-4-deficient cytotoxic T lymphocytes

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Identification of novel MUNC13-4 mutations in familial haemophagocytic lymphohistiocytosis and functional analysis of MUNC13-4-deficient cytotoxic T lymphocytes
  1. K Yamamoto1,
  2. E Ishii2,
  3. M Sako3,
  4. S Ohga4,
  5. K Furuno1,
  6. N Suzuki5,
  7. I Ueda6,
  8. M Imayoshi2,
  9. S Yamamoto2,
  10. A Morimoto6,
  11. H Takada4,
  12. T Hara4,
  13. S Imashuku6,
  14. T Sasazuki7,
  15. M Yasukawa8
  1. 1Division of Molecular Population Genetics, Department of Molecular Genetics, Medical Institute of Bioregulation, and Kyushu University COE Programme on Lifestyle-Related Diseases, Kyushu University
  2. 2Department of Paediatrics, Faculty of Medicine, Saga University, Saga, Japan
  3. 3Division of Paediatrics, Osaka City General Hospital, Osaka, Japan
  4. 4Department of Paediatrics, Graduate School of Medical Sciences, Kyushu University, Kyushu, Japan
  5. 5Department of Paediatrics, Sapporo Medical University, Sapporo, Japan
  6. 6Department of Paediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan
  7. 7Research Institute, International Medical Centre of Japan, Tokyo, Japan
  8. 8Department of 1st Internal Medicine, Ehime University, Ehime, Japan
  1. Correspondence to:
 Dr Eiichi Ishii
 Department of Paediatrics, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan; ishieimed.saga-u.ac.jp

Abstract

Background: Familial haemophagocytic lymphohistiocytosis (FHL) has an autosomal recessive mode of inheritance and consists of at least three subtypes. FHL2 subtype with perforin (PRF1) mutation accounts for 30% of all FHL cases, while FHL with MUNC13-4 mutation was recently identified and designated as FHL3 subtype.

Objective: To examine MUNC13-4 mutations and the cytotoxic function of MUNC13-4 deficient T lymphocytes in Japanese FHL patients

Methods: Mutations of MUNC13-4 and the cytotoxicity of MUNC13-4-deficient cytotoxic T lymphocytes (CTL) were analysed in 16 Japanese families with non-FHL2 subtype.

Results: Five new mutations of the MUNC13-4 gene were identified in six families. The mutations were in the introns 4, 9, and 18, and exons 8 and 19. Two families had homozygous mutations, while the remaining four had compound heterozygous mutations. Cytotoxicity of MUNC13-4 deficient CTL was low compared with control CTL, but was still present. Clinically, the onset of disease tended to occur late; moreover, natural killer cell activity was not deficient in some FHL3 patients.

Conclusions:MUNC13-4 mutations play a role in the development of FHL3 through a defective cytotoxic pathway.

  • B-LCL, B lymphoblastoid cell line
  • CTL, cytotoxic T lymphocytes
  • FHL, familial haemophagocytic lymphohistiocytosis
  • HLA, human leucocyte antigen
  • familial haemophagocytic lymphohistiocytosis
  • perforin
  • MUNC13-4
  • cytotoxicity

https://doi.org/10.1136/jmg.2004.021121

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    Footnotes

    • Conflicts of interest: none declared