Loss-of-function germline GATA2 mutations in patients with MDS/AML or MonoMAC syndrome and primary lymphedema reveal a key role for GATA2 in the lymphatic vasculature
Loss-of-function germline GATA2 mutations in patients with MDS/AML or MonoMAC syndrome and primary lymphedema reveal a key role for GATA2 in the lymphatic vasculature
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DOI：
10.1182/blood-2011-08-374363
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发表时间：
2012-02-02
期刊：
影响因子：
20.3
通讯作者：
Harvey, Natasha L.
中科院分区：
文献类型：
--
作者：
Kazenwadel, Jan;Secker, Genevieve A.;Harvey, Natasha L.
最近的研究表明，杂合种系 GATA2 突变使携带者易患家族性骨髓增生异常综合征 (MDS)/急性髓性白血病 (AML)、“MonoMAC”综合征和 DCML 缺陷。在此，我们描述了一个先前未报告的携带错义 GATA2 突变 (p.Thr354Met) 的 MDS 家族，一名携带移码 GATA2 突变 (p.Leu332Thrfs*53) 的 MDS/AML 患者，另一名携带 GATA2 剪接位点突变的 MDS 患者，以及 3 名表现出包含 GATA2 位点大缺失的 MDS 或 MDS/AML 患者。有趣的是，2 名具有 GATA2 缺失的 MDS/AML 或“MonoMAC”综合征患者和一名具有移码突变的患者也患有原发性淋巴水肿。原发性淋巴水肿是由于淋巴管发育和/或功能异常而发生的，这促使我们研究 GATA2 是否在淋巴管系统中发挥作用。我们在此证明，GATA2 蛋白在淋巴管瓣膜中高水平存在，并且 GATA2 控制对淋巴瓣膜发育重要的基因的表达。我们的数据扩展了与种系 GATA2 突变相关的表型，包括原发性淋巴水肿的易感性，并表明 GATA2 的完全单倍体不足或功能丧失，而不是错义突变，是淋巴水肿发作的关键诱发因素。此外，我们揭示了 GATA2 在淋巴管发育中的关键作用。 （血。2012；119(5)：1283-1291）
Recent work has established that heterozygous germline GATA2 mutations predispose carriers to familial myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML), "MonoMAC" syndrome, and DCML deficiency. Here, we describe a previously unreported MDS family carrying a missense GATA2 mutation (p.Thr354Met), one patient with MDS/AML carrying a frameshift GATA2 mutation (p.Leu332Thrfs*53), another with MDS harboring a GATA2 splice site mutation, and 3 patients exhibiting MDS or MDS/AML who have large deletions encompassing the GATA2 locus. Intriguingly, 2 MDS/AML or "MonoMAC" syndrome patients with GATA2 deletions and one with a frameshift mutation also have primary lymphedema. Primary lymphedema occurs as a result of aberrations in the development and/or function of lymphatic vessels, spurring us to investigate whether GATA2 plays a role in the lymphatic vasculature. We demonstrate here that GATA2 protein is present at high levels in lymphatic vessel valves and that GATA2 controls the expression of genes important for programming lymphatic valve development. Our data expand the phenotypes associated with germline GATA2 mutations to include predisposition to primary lymphedema and suggest that complete haploinsufficiency or loss of function of GATA2, rather than missense mutations, is the key predisposing factor for lymphedema onset. Moreover, we reveal a crucial role for GATA2 in lymphatic vascular development. (Blood. 2012;119(5): 1283-1291)