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STX11 mutations and clinical phenotypes of familial hemophagocytic lymphohistiocytosis in North America
Author(s) -
Marsh Rebecca A.,
Satake Noriko,
Biroschak Jennifer,
Jacobs Thedia,
Johnson Judith,
Jordan Michael B.,
Bleesing Jack J.,
Filipovich Alexandra H.,
Zhang Kejian
Publication year - 2010
Publication title -
pediatric blood and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.116
H-Index - 105
eISSN - 1545-5017
pISSN - 1545-5009
DOI - 10.1002/pbc.22499
Subject(s) - missense mutation , nonsense mutation , hemophagocytic lymphohistiocytosis , compound heterozygosity , medicine , mutation , phenotype , genetics , immunology , disease , biology , gene
Background Mutations in STX11 are responsible for Familial Hemophagocytic Lymphohistiocytosis (FHLH) type 4, a rare primary immunodeficiency which has previously been observed only in patients of Kurdish, Turkish, and Lebanese ethnic background. Methods We reviewed our experience with STX11 mutations among North American patients and studied the impact of patient mutations upon syntaxin 11 expression and NK cell function. Results Between 2007 and 2008, 243 patients with HLH (lacking disease‐causing mutations in PRF1 and UNC13D ) were referred for STX11 mutational analysis. We observed 1 novel homozygous nonsense mutation, 73 G > T (E25X), occurring in Hispanic siblings, and 2 novel biallelic heterozygous missense mutations, 106G > C (E36Q) and 616G > A (E206K), occurring in 1 Caucasian patient. The N‐terminal nonsense mutation resulted in absence of detectable syntaxin 11 and abrogation of in vitro NK cell degranulation and function, while the biallelic heterozygous missense mutations resulted in detectable mutated syntaxin 11 and preservation of in vitro NK cell degranulation and cytotoxicity. The two sibling patients with the nonsense mutations presented with HLH during infancy, whereas the patient with biallelic heterozygous missense mutations presented at 5 years of age. Conclusion We conclude that mutations in STX11 are responsible for HLH in approximately 1% of North American patients and can cause variable defects in syntaxin 11 expression and function with resultant impact on clinical phenotype. Pediatr Blood Cancer 2010;55:134–140. © 2010 Wiley‐Liss, Inc.