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

Identification of Novel MUNC13-4 Mutations in Familial Haemophagocytic Lymphohistiocytosis and Functional Analysis of MUNC13-4-deficient Cytotoxic T Lymphocytes

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Free PMC article

Identification of Novel MUNC13-4 Mutations in Familial Haemophagocytic Lymphohistiocytosis and Functional Analysis of MUNC13-4-deficient Cytotoxic T Lymphocytes

K Yamamoto et al. J Med Genet. .
Free PMC article

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.

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