Human Molecular Genetics Advance Access published online on February 9, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi076
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1 Department of Pediatric Hematology and Oncology, Children's Hospital, University of Hamburg, Martinistr. 52, 20246 Hamburg, Germany
* To whom correspondence should be addressed. Familial hemophagocytic lymphohistiocytosis (FHL) is a rare autosomal recessive disorder characterized by hyperactive phagocytes and defects in natural killer (NK) cell function. It has been shown previously that mutations in the perforin 1 gene (PRF1) and in UNC13D are associated with FHL2 and FHL3, respectively, indicating genetic heterogeneity. We performed genome-wide homozygosity mapping in a large consanguineous Kurdish kindred with five children affected with FHL. Linkage to a 10-cM region on chromosome 6q24 between D6S1569 and D6S960 defined a novel FHL locus. By screening positional candidate genes we identified a homozygous deletion of 5 bp in the syntaxin 11 gene (STX11) in this family. We could demonstrate that syntaxin 11 protein was absent in the mononuclear cell fraction of patients with the homozygous 5-bp deletion. In addition to this family we found homozygous mutations in STX11 in 5 consanguineous Turkish/Kurdish FHL kindreds including two families with the 5-bp deletion, one family with a large 19.2-kbp genomic deletion spanning the entire coding region of STX11 (exon 2) and two families with a nonsense mutation that leads to a premature stop codon in the C-terminal end of the protein. Since STX11 and UNC13D both are involved in vesicle trafficking and membrane fusion, we conclude that, besides mutations in perforin 1, defects in the endocytotic or the exocytotic pathway may be a common mechanism in FHL.
Article
Linkage of Familial Hemophagocytic Lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11
2 Gene Mapping Center and Dept. of Molecular Genetics, Max Delbrück Center for Molecular Medicine, Berlin-Buch, Germany
3 Research Center Borstel, Department of Immunology and Cell Biology, Borstel, Germany
4 University of Istanbul, Istanbul Medical Faculty Medical Biology Department and Bone Marrow Bank, Turkey
5 Childhood Cancer Research Unit, Department of Woman and Child Health, Karolinska Institutet, Stockholm, Sweden
6 Gene Mapping Center and Dept. of Molecular Genetics, Max Delbrück Center for Molecular Medicine, Berlin-Buch, Germany; Institute of Medical Genetics, Charité, University Medicine of Berlin, Berlin, Germany
Gritta Janka, E-mail: janka{at}uke.uni-hamburg.de
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