RT Journal Article
SR Electronic
T1 Identification of novel <em>MUNC13-4</em> mutations in familial haemophagocytic lymphohistiocytosis and functional analysis of MUNC13-4-deficient cytotoxic T lymphocytes
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 763
OP 767
DO 10.1136/jmg.2004.021121
VO 41
IS 10
A1 Yamamoto, K
A1 Ishii, E
A1 Sako, M
A1 Ohga, S
A1 Furuno, K
A1 Suzuki, N
A1 Ueda, I
A1 Imayoshi, M
A1 Yamamoto, S
A1 Morimoto, A
A1 Takada, H
A1 Hara, T
A1 Imashuku, S
A1 Sasazuki, T
A1 Yasukawa, M
YR 2004
UL http://jmg.bmj.com/content/41/10/763.abstract
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.