Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11

Udo zur Stadt, Susanne Schmidt, Brigitte Kasper, Karin Beutel, A. Sarper Diler, Jan Inge Henter, Hartmut Kabisch, Reinhard Schneppenheim, Peter Nürnberg, Gritta Janka, Hans Christian Hennies

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Abstract

Familial hemophagocytic lymphohistiocytosis (FHL) is a rare autosomal recessive disorder characterized by hyperactive phagocytes and defects in natural killer 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 five consanguineous Turkish/Kurdish FHL kindreds including two families with the 5 bp deletion, one family with a large 19.2 kb 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. As both STX11 and UNC13D 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.

LanguageEnglish
Pages827-834
Number of pages8
JournalHuman Molecular Genetics
Volume14
Issue number6
DOIs
Publication statusPublished - 15 Mar 2005
Externally publishedYes

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Qa-SNARE Proteins
Hemophagocytic Lymphohistiocytosis
Chromosomes
Mutation
Genes
Perforin
Nonsense Codon
Membrane Fusion
Genetic Heterogeneity
Phagocytes
Natural Killer Cells
Hemophagocytic lymphohistiocytosis, familial, 4
Exons
Genome

Cite this

zur Stadt, Udo ; Schmidt, Susanne ; Kasper, Brigitte ; Beutel, Karin ; Diler, A. Sarper ; Henter, Jan Inge ; Kabisch, Hartmut ; Schneppenheim, Reinhard ; Nürnberg, Peter ; Janka, Gritta ; Hennies, Hans Christian. / Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11. In: Human Molecular Genetics. 2005 ; Vol. 14, No. 6. pp. 827-834.
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abstract = "Familial hemophagocytic lymphohistiocytosis (FHL) is a rare autosomal recessive disorder characterized by hyperactive phagocytes and defects in natural killer 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 five consanguineous Turkish/Kurdish FHL kindreds including two families with the 5 bp deletion, one family with a large 19.2 kb 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. As both STX11 and UNC13D 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.",
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zur Stadt, U, Schmidt, S, Kasper, B, Beutel, K, Diler, AS, Henter, JI, Kabisch, H, Schneppenheim, R, Nürnberg, P, Janka, G & Hennies, HC 2005, 'Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11', Human Molecular Genetics, vol. 14, no. 6, pp. 827-834. https://doi.org/10.1093/hmg/ddi076

Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11. / zur Stadt, Udo; Schmidt, Susanne; Kasper, Brigitte; Beutel, Karin; Diler, A. Sarper; Henter, Jan Inge; Kabisch, Hartmut; Schneppenheim, Reinhard; Nürnberg, Peter; Janka, Gritta; Hennies, Hans Christian.

In: Human Molecular Genetics, Vol. 14, No. 6, 15.03.2005, p. 827-834.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11

AU - zur Stadt, Udo

AU - Schmidt, Susanne

AU - Kasper, Brigitte

AU - Beutel, Karin

AU - Diler, A. Sarper

AU - Henter, Jan Inge

AU - Kabisch, Hartmut

AU - Schneppenheim, Reinhard

AU - Nürnberg, Peter

AU - Janka, Gritta

AU - Hennies, Hans Christian

PY - 2005/3/15

Y1 - 2005/3/15

N2 - Familial hemophagocytic lymphohistiocytosis (FHL) is a rare autosomal recessive disorder characterized by hyperactive phagocytes and defects in natural killer 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 five consanguineous Turkish/Kurdish FHL kindreds including two families with the 5 bp deletion, one family with a large 19.2 kb 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. As both STX11 and UNC13D 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.

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DO - 10.1093/hmg/ddi076

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