Mutations in the 5′ UTR of ANKRD26, the Ankirin Repeat Domain 26 Gene, Cause an Autosomal-Dominant Form of Inherited Thrombocytopenia, THC2
Mutations in the 5′ UTR of ANKRD26, the Ankirin Repeat Domain 26 Gene, Cause an Autosomal-Dominant Form of Inherited Thrombocytopenia, THC2
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DOI：
10.1016/j.ajhg.2010.12.006
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发表时间：
2011-01-07
影响因子：
9.8
通讯作者：
Balduini, Carlo L.
中科院分区：
文献类型：
--
作者：
Pippucci, Tommaso;Savoia, Anna;Balduini, Carlo L.
THC2 是一种常染色体显性血小板减少症，迄今为止仅在两个家族中发生过描述，被归因于 MASTL 或 ACBD5 的突变。在这里，我们表明 THC2 基因座内的另一个基因 ANKRD26（MASTL 和 ACBD5 都不是）在 8 个不相关的家族中发生突变。在之前报道的 ACBD5 突变家族中也发现了 ANKRD26 突变。我们鉴定了六种不同的 ANKRD26 突变，它们聚集在位于 5' 非翻译区的高度保守的 19 bp 序列中。 500 个对照中未检测到突变，1000 个基因组数据库中也不存在突变。来自动物模型和 Watson 博士基因组的现有数据提供了证据，证明单倍体不足是 ANKRD26 介导的血小板减少症的发病机制。荧光素酶报告基因检测表明这些 5' UTR 突变可能会增强 ANKRD26 的表达。 ANKRD26 是称为 POTE 的灵长类特异性基因家族的祖先，该基因最近被鉴定为促凋亡蛋白家族。因此，细胞凋亡失调可能是发病机制，正如另一种血小板减少症 THC4 所证明的那样。需要进一步调查来提供支持这一假设的证据。
THC2, an autosomal-dominant thrombocytopenia described so far in only two families, has been ascribed to mutations in MASTL or ACBD5. Here, we show that ANKRD26, another gene within the THC2 locus, and neither MASTL nor ACBD5, is mutated in eight unrelated families. ANKRD26 was also found to be mutated in the family previously reported to have an ACBD5 mutation. We identified six different ANKRD26 mutations, which were clustered in a highly conserved 19 bp sequence located in the 5' untranslated region. Mutations were not detected in 500 controls and are absent from the 1000 Genomes database. Available data from an animal model and Dr. Watson's genome give evidence against haploinsufficiency as the pathogenetic mechanism for ANKRD26-mediated thrombocytopenia. The luciferase reporter assay suggests that these 5' UTR mutations might enhance ANKRD26 expression. ANKRD26 is the ancestor of a family of primate-specific genes termed POTE, which have been recently identified as a family of proapoptotic proteins. Dysregulation of apoptosis might therefore be the pathogenetic mechanism, as demonstrated for another thrombocytopenia, THC4. Further investigation is needed to provide evidence supporting this hypothesis.