Abstract
Familial Hemophagocytic Lymphohistiocytosis (HLH) is a rare, autosomal recessive, if untreated, fatal disorder of early childhood characterized mainly by persistent fever, hepatocyplenomegaly, cytopenia, hypertriglyceridemia, hyperferritinemia, defective natural killer cell activity and hemophagocytosis in bone marrow, lymph nodes, liver and spleen. Familial HLH is a genetically heterogeneous disease; at least four sub-types (I–IV) associated with three genes and one chromosomal locus (9q21.3-q22) have been reported in the disease to date. A number of mutations in both Perforin and Munc13– 4 genes have been described in different populations whereas only 3 different types of mutations in Syntaxin 11 gene have, thus far, been described in a few families solely from Turkish population. Therefore, elucidation of the mutation spectrum of the Syntaxin 11 gene mostly depends on the identification of its genetic defects in this population. In this communication, we present our findings on Syntaxin 11 gene which is responsible for the familial HLH type IV. A total of 84 potentially primary HLH patients selected on the basis of consanguinity and/or family history and/or relapse were included in the study. Patients and family members were studied by linkage analysis for all 4 described gene loci and homozygosity for Syntaxin 11 gene was observed in 20 patients from consanguineous families. Sequencing of these patients for the complete coding and flanking sequences of Syntaxin 11 gene revealed molecular defects in only 5 patients (2M/3F) with the ages ranging from 2 months to 3 years. Contrary to the heterogeneity in the mutation spectrum of hereditary disorders generally observed in Turkish population, a single type of homozygous mutation (c369–370delAG, c374–376delCGC) was identified in these 5 unrelated patients who had a family history of at least one deceased sibling except one. Screening of the family members revealed that the obligate carriers and some of the siblings were heterozygous for the mutation. This 2 plus 3 nucleotide deletion in exon 2 leads to frameshift and premature termination of translation 59 altered aminoacids downstream (Val124fsX60). Haplotype analysis indicated that these patients who were coming from different parts of Turkey may have a common ancestor (founder effect). Besides confirmation of the “Turkish population endemic” profile of the Syntaxin 11 gene mutations, the findings provided here elucidate the single/common mutation characteristic of the gene which is extremely important in the molecular diagnosis of the disease. This study was supported by TUBITAK (Project No: 105S386; SBAG-3193).
A Novel Syntaxin 11 Gene (STX11) Mutation c.650T>C, p.Leu217Pro, in a Korean Child With Familial Hemophagocytic Lymphohistiocytosis
