{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T01:36:59Z","timestamp":1774057019863,"version":"3.50.1"},"reference-count":16,"publisher":"BMJ","issue":"10","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Med Genet"],"published-print":{"date-parts":[[2004,10]]},"abstract":"<jats:p>\n                  <jats:bold>Background:<\/jats:bold> Familial haemophagocytic lymphohistiocytosis (FHL) has an autosomal recessive mode of inheritance and consists of at least three subtypes. FHL2 subtype with <jats:italic>perforin<\/jats:italic> (<jats:italic>PRF1<\/jats:italic>) mutation accounts for 30% of all FHL cases, while FHL with <jats:italic>MUNC13-4<\/jats:italic> mutation was recently identified and designated as FHL3 subtype.<\/jats:p>\n               <jats:p>\n                  <jats:bold>Objective:<\/jats:bold> To examine <jats:italic>MUNC13-4<\/jats:italic> mutations and the cytotoxic function of MUNC13-4 deficient T lymphocytes in Japanese FHL patients<\/jats:p>\n               <jats:p>\n                  <jats:bold>Methods:<\/jats:bold> Mutations of <jats:italic>MUNC13-4<\/jats:italic> and the cytotoxicity of MUNC13-4-deficient cytotoxic T lymphocytes (CTL) were analysed in 16 Japanese families with non-FHL2 subtype.<\/jats:p>\n               <jats:p>\n                  <jats:bold>Results:<\/jats:bold> Five new mutations of the <jats:italic>MUNC13-4<\/jats:italic> 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.<\/jats:p>\n               <jats:p>\n                  <jats:bold>Conclusions:<\/jats:bold>\n                  <jats:italic>MUNC13-4<\/jats:italic> mutations play a role in the development of FHL3 through a defective cytotoxic pathway.<\/jats:p>","DOI":"10.1136\/jmg.2004.021121","type":"journal-article","created":{"date-parts":[[2004,10,1]],"date-time":"2004-10-01T12:24:04Z","timestamp":1096633444000},"page":"763-767","source":"Crossref","is-referenced-by-count":54,"title":["Identification of novel <i>MUNC13-4<\/i> mutations in familial haemophagocytic lymphohistiocytosis and functional analysis of MUNC13-4-deficient cytotoxic T lymphocytes"],"prefix":"10.1136","volume":"41","author":[{"given":"K","family":"Yamamoto","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"E","family":"Ishii","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M","family":"Sako","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S","family":"Ohga","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"K","family":"Furuno","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"N","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"I","family":"Ueda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M","family":"Imayoshi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S","family":"Yamamoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A","family":"Morimoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H","family":"Takada","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"T","family":"Hara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S","family":"Imashuku","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"T","family":"Sasazuki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M","family":"Yasukawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2004,10,1]]},"reference":[{"key":"2025101801174119000_41.10.763.1","first-page":"34","volume":"18","year":"1991","journal-title":"Semin 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