Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11
Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11
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DOI：
10.1093/hmg/ddi076
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发表时间：
2005-03-15
影响因子：
3.5
通讯作者：
Hennies, HC
中科院分区：
文献类型：
--
作者：
zur Stadt, U;Schmidt, S;Hennies, HC
家族性噬血细胞性淋巴组织细胞增多症（FHL）是一种罕见的常染色体隐性遗传疾病，其特征是吞噬细胞过度活跃和自然杀伤细胞功能缺陷。先前已表明，穿孔素 1 基因 (PRF1) 和 UNC13D 中的突变分别与 FHL2 和 FHL3 相关，表明遗传异质性。我们对一个有 5 名患有 FHL 的儿童的大型库尔德近亲亲属进行了全基因组纯合性作图。与 D6S1569 和 D6S960 之间染色体 6q24 上 10 cM 区域的连锁定义了一个新的 FHL 基因座。通过筛选位置候选基因，我们在该家族的突触蛋白 11 基因（STX11）中发现了 5 bp 的纯合缺失。我们可以证明，在纯合 5 bp 缺失患者的单核细胞部分中不存在突触融合蛋白 11 蛋白。除了这个家族之外，我们还在五个土耳其/库尔德 FHL 近亲家族中发现了 STX11 纯合突变，其中包括两个具有 5 bp 缺失的家族、一个具有横跨 STX11 整个编码区（外显子 2）的 19.2 kb 大基因组缺失的家族，以及两个具有无义突变的家族，该无义突变导致蛋白质 C 末端出现过早终止密码子。由于STX11和UNC13D都参与囊泡运输和膜融合，我们得出的结论是，除了穿孔素1的突变之外，内吞或胞吐途径的缺陷可能是FHL的常见机制。
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.