Identification of novel MUNC13-4 mutations in familial haemophagocytic lymphohistiocytosis and functional analysis of MUNC13-4-deficient cytotoxic T lymphocytes.
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.
Division of Molecular Population Genetics, Department of Molecular Genetics, Medical Institute of Bioregulation, and Kyushu University COE Programme on Lifestyle-Related Diseases, Kyushu University, Japan.
K
K
Yamamoto
E
E
Ishii
M
M
Sako
S
S
Ohga
K
K
Furuno
N
N
Suzuki
I
I
Ueda
M
M
Imayoshi
S
S
Yamamoto
A
A
Morimoto
H
H
Takada
T
T
Hara
S
S
Imashuku
T
T
Sasazuki
M
M
Yasukawa
D017668:Age of Onset; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D015616:Histiocytosis, Non-Langerhans-Cell / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology; D006801:Humans; D007223:Infant; D007438:Introns / Q000235:genetics; D007564:Japan; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics*; D010375:Pedigree; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism*
D009419:Nerve Tissue Proteins; C485548:UNC13B protein, human