ABCA3 gene mutations in newborns with fatal surfactant deficiency
ABCA3 gene mutations in newborns with fatal surfactant deficiency
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DOI：
10.1056/nejmoa032178
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发表时间：
2004-03-25
影响因子：
158.5
通讯作者：
Dean, M
中科院分区：
文献类型：
--
作者：
Shulenin, S;Nogee, LM;Dean, M
背景：肺表面活性物质形成一层富含脂质的单层，覆盖在肺的气道上，对肺的适当充气和功能至关重要。表面活性剂由肺泡II型细胞产生，储存在细胞内称为板层体的细胞器中，并通过胞吐分泌。ATP结合盒转运体A3（ABCA3）的基因在肺泡II型细胞中表达，蛋白质定位于板层体，这表明它在表面活性剂metabolism.METHODS中具有重要作用：我们测序了21个种族和民族不同的婴儿血液DNA中ABCA3基因的编码外显子，严重的新生儿表面活性剂缺乏症的病因过程是未知的。肺组织从四个病人进行了检查，通过高分辨率的光和电子microscopic.Results：无义和移码突变，以及突变的高度保守的残基和剪接位点的ABCA 3基因被确定在16的21例（76%）。在5个有突变的近亲家系中，每对同胞都是同一突变的纯合子，并且每个突变只在一个家系中发现。显着异常板层小体观察肺组织的超微结构检查，从4例不同的ABCA3突变，包括无义，剪接位点，错义mutations.Conclusions：ABCA3基因突变导致致命的表面活性物质缺乏症的新生儿。ABCA 3对于板层体的适当形成和表面活性剂功能至关重要，并且对于其他肺部疾病中的肺功能也可能是重要的。由于它与ABCA 1和ABCA 4密切相关，ABCA 1和ABCA 4是在巨噬细胞和感光细胞中转运磷脂的蛋白质，因此它可能在表面活性剂磷脂代谢中发挥作用。
BACKGROUND:Pulmonary surfactant forms a lipid-rich monolayer that coats the airways of the lung and is essential for proper inflation and function of the lung. Surfactant is produced by alveolar type II cells, stored intracellularly in organelles known as lamellar bodies, and secreted by exocytosis. The gene for ATP-binding cassette transporter A3 (ABCA3) is expressed in alveolar type II cells, and the protein is localized to lamellar bodies, suggesting that it has an important role in surfactant metabolism.METHODS:We sequenced each of the coding exons of the ABCA3 gene in blood DNA from 21 racially and ethnically diverse infants with severe neonatal surfactant deficiency for which the etiologic process was unknown. Lung tissue from four patients was examined by high-resolution light and electron microscopy.RESULTS:Nonsense and frameshift mutations, as well as mutations in highly conserved residues and in splice sites of the ABCA3 gene were identified in 16 of the 21 patients (76 percent). In five consanguineous families with mutations, each pair of siblings was homozygous for the same mutation and each mutation was found in only one family. Markedly abnormal lamellar bodies were observed by ultrastructural examination of lung tissue from four patients with different ABCA3 mutations, including nonsense, splice-site, and missense mutations.CONCLUSIONS:Mutation of the ABCA3 gene causes fatal surfactant deficiency in newborns. ABCA3 is critical for the proper formation of lamellar bodies and surfactant function and may also be important for lung function in other pulmonary diseases. Since it is closely related to ABCA1 and ABCA4, proteins that transport phospholipids in macrophages and photoreceptor cells, it may have a role in surfactant phospholipid metabolism.