{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T11:15:12Z","timestamp":1784546112333,"version":"3.55.0"},"reference-count":30,"publisher":"BMJ","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Med Genet"],"published-print":{"date-parts":[[2008,3]]},"abstract":"<jats:sec>\n                  <jats:title>Objective:<\/jats:title>\n                  <jats:p>Familial haemophagocytic lymphohistiocytosis (FHL) is a fatal disorder of immune dysregulation with defective cytotoxic lymphocyte function. Disease-causing mutations have been identified in the genes encoding perforin (<jats:italic>PRF1<\/jats:italic>), syntaxin-11 (<jats:italic>STX11<\/jats:italic>), and Munc13-4 (<jats:italic>UNC13D<\/jats:italic>). We screened for <jats:italic>UNC13D<\/jats:italic> mutations and studied clinical and functional implications of such mutations in a well defined patient cohort.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods:<\/jats:title>\n                  <jats:p>Sequencing of <jats:italic>UNC13D<\/jats:italic> was performed in 38 FHL patients from 34 FHL families in which <jats:italic>PRF1<\/jats:italic> and <jats:italic>STX11<\/jats:italic> mutations had been excluded.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results:<\/jats:title>\n                  <jats:p>We identified six different mutations affecting altogether 9\/38 individuals (24%) in 6\/34 (18%) unrelated <jats:italic>PRF1\/STX11<\/jats:italic>-negative families. Four novel mutations were revealed; two homozygous nonsense mutations (R83X and W382X), one splice mutation (exon 28), and one missense mutation (R928P). In addition, two known mutations were identified (R214X and a deletion resulting in a frame-shift starting at codon 782). There was considerable variation in the age at diagnosis, ranging from time of birth to 14 years (median 69 days). Three of nine patients (33%) developed central nervous system (CNS) symptoms. Natural killer (NK) cell activity was impaired in all four patients studied. Defective cytotoxic lymphocyte degranulation was evident in the two patients investigated, more pronounced in the patient with onset during infancy than in the patient with adolescent onset.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions:<\/jats:title>\n                  <jats:p>Biallelic <jats:italic>UNC13D<\/jats:italic> mutations were found in 18% of the <jats:italic>PRF1\/STX11<\/jats:italic>-negative FHL families. Impairment of NK cell degranulation was less pronounced in a patient with adolescent onset. FHL should be considered not only in infants but also in adolescents, and possibly young adults, presenting with fever, splenomegaly, cytopenia, hyperferritinaemia, and\/or CNS symptoms.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jmg.2007.054288","type":"journal-article","created":{"date-parts":[[2007,11,9]],"date-time":"2007-11-09T20:34:11Z","timestamp":1194640451000},"page":"134-141","source":"Crossref","is-referenced-by-count":52,"title":["Spectrum, and clinical and functional implications of <i>UNC13D<\/i> mutations in familial haemophagocytic lymphohistiocytosis"],"prefix":"10.1136","volume":"45","author":[{"given":"E","family":"Rudd","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y T","family":"Bryceson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Edner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S 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AC Trottestam H Aric\u00c3\u00b3 M Egeler RM Filipovich AH Gadner H Imashuku S Ladisch S Webb D Janka G Henter J-I . Frequency and spectrum of CNS involvement in 193 children with hemophagocytic lymphohistiocytosis. Br J Haematol (in press)."},{"key":"2025100511214491000_45.3.134.28","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-08-3296"},{"key":"2025100511214491000_45.3.134.29","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20062447"},{"key":"2025100511214491000_45.3.134.30","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V99.1.61"}],"container-title":["Journal of Medical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jmg.2007.054288","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,5]],"date-time":"2025-10-05T18:21:53Z","timestamp":1759688513000},"score":1,"resource":{"primary":{"URL":"https:\/\/jmg.bmj.com\/lookup\/doi\/10.1136\/jmg.2007.054288"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2007,11,9]]},"references-count":30,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2008,2,29]]},"published-print":{"date-parts":[[2008,3]]}},"alternative-id":["10.1136\/jmg.2007.054288"],"URL":"https:\/\/doi.org\/10.1136\/jmg.2007.054288","relation":{},"ISSN":["0022-2593","1468-6244"],"issn-type":[{"value":"0022-2593","type":"print"},{"value":"1468-6244","type":"electronic"}],"subject":[],"published":{"date-parts":[[2007,11,9]]}}}