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

J Med Genet. 2004 Oct;41(10):763-7. doi: 10.1136/jmg.2004.021121.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age of Onset
  • DNA Mutational Analysis
  • Exons / genetics
  • Female
  • Histiocytosis, Non-Langerhans-Cell / genetics*
  • Histiocytosis, Non-Langerhans-Cell / immunology
  • Histiocytosis, Non-Langerhans-Cell / physiopathology
  • Humans
  • Infant
  • Introns / genetics
  • Japan
  • Male
  • Molecular Sequence Data
  • Mutation / genetics*
  • Nerve Tissue Proteins / deficiency*
  • Nerve Tissue Proteins / genetics*
  • Pedigree
  • T-Lymphocytes, Cytotoxic / immunology*
  • T-Lymphocytes, Cytotoxic / metabolism*


  • Nerve Tissue Proteins
  • UNC13B protein, human

Associated data

  • OMIM/603552
  • OMIM/603553
  • RefSeq/XM_113950