Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11.
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.
zur Stadt
Udo
U
Department of Pediatric Hematology and Oncology, Children's Hospital, University of Hamburg, Germany.
Schmidt
Susanne
S
Kasper
Brigitte
B
Beutel
Karin
K
Diler
A Sarper
AS
Henter
Jan-Inge
JI
Kabisch
Hartmut
H
Schneppenheim
Reinhard
R
Nürnberg
Peter
P
Janka
Gritta
G
Hennies
Hans Christian
HC
D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D018389:Codon, Nonsense; D008040:Genetic Linkage; D015616:Histiocytosis, Non-Langerhans-Cell / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D050765:Qa-SNARE Proteins; D017384:Sequence Deletion
D018389:Codon, Nonsense; D008565:Membrane Proteins; D050765:Qa-SNARE Proteins