PT  - JOURNAL ARTICLE
AU  - Yamamoto, K
AU  - Ishii, E
AU  - Sako, M
AU  - Ohga, S
AU  - Furuno, K
AU  - Suzuki, N
AU  - Ueda, I
AU  - Imayoshi, M
AU  - Yamamoto, S
AU  - Morimoto, A
AU  - Takada, H
AU  - Hara, T
AU  - Imashuku, S
AU  - Sasazuki, T
AU  - Yasukawa, M
TI  - Identification of novel <em>MUNC13-4</em> mutations in familial haemophagocytic lymphohistiocytosis and functional analysis of MUNC13-4-deficient cytotoxic T lymphocytes
AID  - 10.1136/jmg.2004.021121
DP  - 2004 Oct 01
TA  - Journal of Medical Genetics
PG  - 763--767
VI  - 41
IP  - 10
4099  - http://jmg.bmj.com/content/41/10/763.short
4100  - http://jmg.bmj.com/content/41/10/763.full
SO  - J Med Genet2004 Oct 01; 41
AB  - 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.