title: Spectrum, and clinical and functional implications of UNC13D mutations in familial haemophagocytic lymphohistiocytosis.
abstract: OBJECTIVE
  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 (PRF1), syntaxin-11 (STX11), and Munc13-4 (UNC13D). We screened for UNC13D mutations and studied clinical and functional implications of such mutations in a well defined patient cohort.
  
  
  METHODS
  Sequencing of UNC13D was performed in 38 FHL patients from 34 FHL families in which PRF1 and STX11 mutations had been excluded.
  
  
  RESULTS
  We identified six different mutations affecting altogether 9/38 individuals (24%) in 6/34 (18%) unrelated PRF1/STX11-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.
  
  
  CONCLUSIONS
  Biallelic UNC13D mutations were found in 18% of the PRF1/STX11-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.
authors.affiliation: Childhood Cancer Research Unit, Department of Woman and Child Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. Eva.Rudd@ki.se
authors.forename: E
authors.initials: E
authors.lastname: Rudd
authors.forename: Y T
authors.initials: YT
authors.lastname: Bryceson
authors.forename: C
authors.initials: C
authors.lastname: Zheng
authors.forename: J
authors.initials: J
authors.lastname: Edner
authors.forename: S M
authors.initials: SM
authors.lastname: Wood
authors.forename: K
authors.initials: K
authors.lastname: Ramme
authors.forename: S
authors.initials: S
authors.lastname: Gavhed
authors.forename: A
authors.initials: A
authors.lastname: Gürgey
authors.forename: M
authors.initials: M
authors.lastname: Hellebostad
authors.forename: A G
authors.initials: AG
authors.lastname: Bechensteen
authors.forename: H-G
authors.initials: HG
authors.lastname: Ljunggren
authors.forename: B
authors.initials: B
authors.lastname: Fadeel
authors.forename: M
authors.initials: M
authors.lastname: Nordenskjöld
authors.forename: J-I
authors.initials: JI
authors.lastname: Henter
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D015550:Cell Degranulation; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007694:Killer Cells, Natural / Q000276:immunology; D051359:Lymphohistiocytosis, Hemophagocytic / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000276:immunology; D009154:Mutation; D020125:Mutation, Missense; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000235:genetics; D050765:Qa-SNARE Proteins / Q000235:genetics; D017384:Sequence Deletion
chemical_list: D018389:Codon, Nonsense; D008565:Membrane Proteins; C510468:PRF1 protein, human; D052899:Pore Forming Cytotoxic Proteins; D050765:Qa-SNARE Proteins; C507969:UNC13D protein, human; D054353:Perforin