title: STXBP2 mutations in children with familial haemophagocytic lymphohistiocytosis type 5.
abstract: BACKGROUND
  Familial haemophagocytic lymphohistiocytosis (FHL) is a rare immune deficiency with uncontrolled inflammation; the clinical course usually starts within the first years of life, and is usually fatal unless promptly treated and then cured with haematopoietic stem cell transplant. FHL is caused by genetic mutations resulting in defective cell cytotoxicity; three disease related genes have been identified to date: perforin, Munc13-4 and syntaxin-11. A fourth gene, STXBP2, has been identified very recently as responsible for a defect in Munc18-2 in FHL-5.
  
  
  OBJECTIVE
  To describe the result of the screening of families with HLH and previously unassigned genetic defects.
  
  
  METHODS
  Patients with HLH diagnosed according to current diagnostic criteria, and who lacked mutations in the PRF1, Munc13-4, and STX11 genes were sequenced for mutations in STXBP2. Functional study was performed when material was available.
  
  
  RESULTS
  Among the 28 families investigated, 4 (14%) with biallelic STXBP2 mutations were identified. They originated from Italy, England, Kuwait and Pakistan. The p.Pro477Leu resulting from c.1430C>T, and p.Arg405Gln resulting from the single c.1214G>A nucleotide change are known, while we contribute two novel mutations: p.Glu132Ala resulting from c.395A>C, and p.Gly541Ser, resulting from c.1621G>A. The detrimental effect of the p.Gly541Ser mutation was documented biochemically and functionally in NK and CD8 cells. Additional polymorphisms are also described.
  
  
  CONCLUSIONS
  These data expand current knowledge on the genetic heterogeneity of FHL and suggest that patients with FHL5 may have different results in degranulation assays under different conditions.
authors.affiliation: Department Pediatric Hematology Oncology, Azienda Ospedaliero-Universitaria Meyer, Florence, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Cetica
authors.forename: Alessandra
authors.initials: A
authors.lastname: Santoro
authors.forename: Kimberly C
authors.initials: KC
authors.lastname: Gilmour
authors.forename: Elena
authors.initials: E
authors.lastname: Sieni
authors.forename: Karin
authors.initials: K
authors.lastname: Beutel
authors.forename: Daniela
authors.initials: D
authors.lastname: Pende
authors.forename: Stefania
authors.initials: S
authors.lastname: Marcenaro
authors.forename: Florian
authors.initials: F
authors.lastname: Koch
authors.forename: Samantha
authors.initials: S
authors.lastname: Grieve
authors.forename: Rachel
authors.initials: R
authors.lastname: Wheeler
authors.forename: Fang
authors.initials: F
authors.lastname: Zhao
authors.forename: Udo
authors.initials: U
authors.lastname: zur Stadt
authors.forename: Gillian M
authors.initials: GM
authors.lastname: Griffiths
authors.forename: Maurizio
authors.initials: M
authors.lastname: Aricò
mesh_terms: D000483:Alleles; D015550:Cell Degranulation; D002648:Child; D002675:Child, Preschool; D003602:Cytotoxicity, Immunologic; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D047468:Immunoprecipitation; D007223:Infant; D051359:Lymphohistiocytosis, Hemophagocytic / Q000145:classification* / Q000235:genetics* / Q000276:immunology; D052118:Lysosomal-Associated Membrane Protein 1 / Q000378:metabolism; D008297:Male; D051938:Munc18 Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology
chemical_list: D052118:Lysosomal-Associated Membrane Protein 1; D051938:Munc18 Proteins; C497940:STXBP2 protein, human
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