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Spectrum, and clinical and functional implications of UNC13D mutations in familial hemophagocytic lymphohistiocytosis
  1. Eva Rudd (eva.rudd{at}ki.se)
  1. Childhood Cancer Research Unit, Dept of Woman & Child Health, Karolinska Institutet, Karolinska Hosp, Sweden
    1. Yenan T Bryceson (ybryceson{at}niaid.nih.gov)
    1. Center for Infectious Medicine, Dept of Medicine, Karolinska Institutet, Huddinge Hospital, Sweden
      1. Chengyun Zheng (chengyun.zheng{at}ki.se)
      1. Childhood Cancer Research Unit, Dept of Woman & Child Health, Karolinska Institutet, Karolinska Hosp, Sweden
        1. Josefine Edner (josefine.edner{at}ki.se)
        1. Childhood Cancer Research Unit, Dept of Woman & Child Health, Karolinska Institutet, Karolinska Hosp, Sweden
          1. Stephanie M Wood (stephanie.wood{at}ki.se)
          1. Center for Infectious Medicine, Dept of Medicine, Karolinska Institutet, Karolinska Hospital, Sweden
            1. Kim Ramme (kim.ericson{at}ki.se)
            1. Childhood Cancer Research Unit, Dept of Woman & Child Health, Karolinska Institutet, Karolinska Hosp, Sweden
              1. Sofie Gavhed (sofie.gavhed{at}ki.se)
              1. Childhood Cancer Research Unit, Dept of Woman & Child Health, Karolinska Institutet, Karolinska Hosp, Sweden
                1. Aytemiz Gürgey (agurgey{at}hacettepe.edu.tr)
                1. Department of Pediatric Hematology, Hacettepe University, Ankara, Turkey
                  1. Marit Hellebostad (marit.hellebostad{at}rikshospitalet.no)
                  1. Department of Pediatrics, Rikshospitalet University Hospital, Oslo, Norway
                    1. AnneGrete Bechensteen (annegrete.bechensteen{at}ulleval.no)
                    1. Department of Pediatrics, Ullevål University Hospital, Oslo, Norway
                      1. Hans-Gustaf Ljunggren (hans-gustaf.ljunggren{at}ki.se)
                      1. Center for Infectious Medicine, Dept of Medicine, Karolinska Institutet, Karolinska Hospital, Sweden
                        1. Bengt Fadeel (bengt.fadeel{at}ki.se)
                        1. Division of Biochemical Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Sweden
                          1. Magnus Nordenskjold (magnus.nordenskjold{at}ki.se)
                          1. Clinical Genetics Unit, Dept of Molecular Medicine & Surgery, Karolinska Inst, Karolinska Hospital, Sweden
                            1. Jan-Inge Henter (jan-inge.henter{at}ki.se)
                            1. Childhood Cancer Research Unit, Dept of Woman & Child Health, Karolinska Institutet, Karolinska Hosp, Sweden

                              Abstract

                              Objective: Familial hemophagocytic 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 families where mutations in the PRF1 and STX11 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 CNS symptoms. NK cell activity was impaired in all four patients studied. Defective cytotoxic lymphocyte degranulation was evident in the two patients investigated, more pronounced in a patient with onset during infancy than in one 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, hyperferritinemia, and/or CNS symptoms.

                              • Munc13-4
                              • familial hemophagocytic lymphohistiocytosis
                              • lymphocyte cytotoxicity
                              • mutations
                              • natural killer cells

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