Molecular and cellular characteristics of ABCA3 mutations associated with diffuse parenchymal lung diseases in children
Molecular and cellular characteristics of ABCA3 mutations associated with diffuse parenchymal lung diseases in children
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DOI：
10.1093/hmg/ddr508
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发表时间：
2012-02-15
影响因子：
3.5
通讯作者：
Guillot, Loic
中科院分区：
文献类型：
--
作者：
Flamein, Florence;Riffault, Laure;Guillot, Loic
ABCA 3（ATP结合盒亚家族A，成员3）在肺泡II型细胞的板层体中表达，对肺表面活性物质的储存和体内平衡至关重要。ABCA 3基因突变与新生儿呼吸窘迫（NRD）和儿科间质性肺病（ILD）相关。本研究的目的是在重度NRD和/或ILD患者中寻找ABCA 3基因突变。在47例重度NRD和/或ILD患者中筛选了30个ABCA 3编码外显子。47例患者中有10例发现ABCA 3突变，其中纯合子2例，复合杂合子5例，杂合子3例。SP-B和SP-C表达模式因患者而异。在ABCA 3突变患者中，5例出生后不久死亡，5例发生ILD（包括1例无NRD）。p.D253H和p.T1173R突变的功能研究表明，p.D253H和p.T1173R诱导异常板层体。此外，p.T1173R在体外增加了IL-8的分泌。总之，我们在危及生命的NRD和/或ILD患者中发现了新的ABCA 3突变。尽管临床表型相似，但与ILD相关的两种突变通过不同的病理生理机制起作用。
ABCA3 (ATP-binding cassette subfamily A, member 3) is expressed in the lamellar bodies of alveolar type II cells and is crucial to pulmonary surfactant storage and homeostasis. ABCA3 gene mutations have been associated with neonatal respiratory distress (NRD) and pediatric interstitial lung disease (ILD). The objective of this study was to look for ABCA3 gene mutations in patients with severe NRD and/or ILD. The 30 ABCA3 coding exons were screened in 47 patients with severe NRD and/or ILD. ABCA3 mutations were identified in 10 out of 47 patients, including 2 homozygous, 5 compound heterozygous and 3 heterozygous patients. SP-B and SP-C expression patterns varied across patients. Among patients with ABCA3 mutations, five died shortly after birth and five developed ILD (including one without NRD). Functional studies of p.D253H and p.T1173R mutations revealed that p.D253H and p.T1173R induced abnormal lamellar bodies. Additionally, p.T1173R increased IL-8 secretion in vitro. In conclusion, we identified new ABCA3 mutations in patients with life-threatening NRD and/or ILD. Two mutations associated with ILD acted via different pathophysiological mechanisms despite similar clinical phenotypes.