Spectrum, and clinical and functional implications of UNC13D mutations in familial hemophagocytic lymphohistiocytosis

Eva Rudd ^1*, Yenan T Bryceson ², Chengyun Zheng ¹, Josefine Edner ¹, Stephanie M Wood ³, Kim Ramme ¹, Sofie Gavhed ¹, Aytemiz Gürgey ⁴, Marit Hellebostad ⁵, AnneGrete Bechensteen ⁶, Hans-Gustaf Ljunggren ³, Bengt Fadeel ⁷, Magnus Nordenskjold ⁸ and Jan-Inge Henter ¹

¹ Childhood Cancer Research Unit, Dept of Woman & Child Health, Karolinska Institutet, Karolinska Hosp, Sweden
² Center for Infectious Medicine, Dept of Medicine, Karolinska Institutet, Huddinge Hospital, Sweden
³ Center for Infectious Medicine, Dept of Medicine, Karolinska Institutet, Karolinska Hospital, Sweden
⁴ Department of Pediatric Hematology, Hacettepe University, Ankara, Turkey
⁵ Department of Pediatrics, Rikshospitalet University Hospital, Oslo, Norway
⁶ Department of Pediatrics, Ullevål University Hospital, Oslo, Norway
⁷ Division of Biochemical Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Sweden
⁸ Clinical Genetics Unit, Dept of Molecular Medicine & Surgery, Karolinska Inst, Karolinska Hospital, Sweden

^* To whom correspondence should be addressed. E-mail: eva.rudd{at}ki.se.

Accepted 15 October 2007

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.

Keywords: Munc13-4, familial hemophagocytic lymphohistiocytosis, lymphocyte cytotoxicity, mutations, natural killer cells

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