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J Med Genet. 2004 Oct;41(10):763-7.

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

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  • 1Division of Molecular Population Genetics, Department of Molecular Genetics, Medical Institute of Bioregulation, and Kyushu University COE Programme on Lifestyle-Related Diseases, Kyushu University, Japan.

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.

PMID:
15466010
PMCID:
PMC1735600
DOI:
10.1136/jmg.2004.021121
[PubMed - indexed for MEDLINE]
Free PMC Article
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