Familial hemophagocytic lymphohistiocytosis type 3 (FHL3) caused by deep intronic mutation and inversion in UNC13D
Familial hemophagocytic lymphohistiocytosis type 3 (FHL3) caused by deep intronic mutation and inversion in UNC13D
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DOI：
10.1182/blood-2011-07-369090
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发表时间：
2011-11-24
期刊：
影响因子：
20.3
通讯作者：
Bryceson, Yenan T.
中科院分区：
文献类型：
--
作者：
Meeths, Marie;Chiang, Samuel C. C.;Bryceson, Yenan T.
家族性噬血细胞性淋巴组织细胞增多症 (FHL) 是一种常染色体隐性遗传、常致命的高炎症性疾病。 PRF1、UNC13D、STX11 和 STXBP2 的突变分别导致 FHL2、3、4 和 5。在大多数来自北欧的疑似 FHL 患者中，对淋巴细胞细胞毒性所需的此类基因的外显子和剪接位点进行测序，结果显示没有或仅有单等位基因 UNC13D 突变。在这里，我们在 21 名患者中描述了 UNC13D 的 2 种致病性非编码畸变。第一个是位于内含子 1 进化保守区域的点突变。这种突变选择性损害淋巴细胞中的 UNC13D 转录，消除 Munc13-4 的表达。第二个是跨 UNC13D 的 253 kb 倒置，影响转录本的 3' 末端，并同样废除 Munc13-4 表达。在欧洲各地的患者中都发现了内含子 1 突变的携带情况，而倒位突变的携带情况仅限于北欧。值得注意的是，后一种畸变代表了对由倒位引起的常染色体隐性人类疾病的首次描述。这些发现暗示了 Munc13-4 细胞类型特异性表达中的内含子序列，并表明外显子和剪接位点之外的变异是 FHL3 的常见原因。基于这些数据，我们提出了一种对进化保守非编码区进行靶向测序以诊断原发性免疫缺陷的策略。 （血。2011；118(22):5783-5793）
Familial hemophagocytic lymphohistiocytosis (FHL) is an autosomal recessive, often-fatal hyperinflammatory disorder. Mutations in PRF1, UNC13D, STX11, and STXBP2 are causative of FHL2, 3, 4, and 5, respectively. In a majority of suspected FHL patients from Northern Europe, sequencing of exons and splice sites of such genes required for lymphocyte cytotoxicity revealed no or only monoallelic UNC13D mutations. Here, in 21 patients, we describe 2 pathogenic, noncoding aberrations of UNC13D. The first is a point mutation localized in an evolutionarily conserved region of intron 1. This mutation selectively impairs UNC13D transcription in lymphocytes, abolishing Munc13-4 expression. The second is a 253-kb inversion straddling UNC13D, affecting the 3'-end of the transcript and likewise abolishing Munc13-4 expression. Carriership of the intron 1 mutation was found in patients across Europe, whereas carriership of the inversion was limited to Northern Europe. Notably, the latter aberration represents the first description of an autosomal recessive human disease caused by an inversion. These findings implicate an intronic sequence in cell-type specific expression of Munc13-4 and signify variations outside exons and splice sites as a common cause of FHL3. Based on these data, we propose a strategy for targeted sequencing of evolutionary conserved noncoding regions for the diagnosis of primary immunodeficiencies. (Blood. 2011;118(22):5783-5793)