Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Pediatr Res. 2012 Jun;71(6):633-7. doi: 10.1038/pr.2012.21. Epub 2012 Feb 15.
Member A3 of the ATP-binding cassette family of transporters (ABCA3) is essential for surfactant metabolism. Nonsense, missense, frameshift, and splice-site mutations in the ABCA3 gene (ABCA3) have been reported as causes of neonatal respiratory failure (NRF) and interstitial lung disease. We tested the hypothesis that mutations in noncoding regions of ABCA3 may cause lung disease.
ABCA3-specific cDNA was generated and sequenced from frozen lung tissue from a child with fatal lung disease with only one identified ABCA3 mutation. ABCA3 was sequenced from genomic DNA prepared from blood samples obtained from the proband, parents, and other children with NRF.
ABCA3 cDNA from the proband contained sequences derived from intron 25 that would be predicted to alter the structure and function of the ABCA3 protein. Genomic DNA sequencing revealed a heterozygous C>T transition in intron 25 trans to the known mutation, creating a new donor splice site. Seven additional infants with an ABCA3-deficient phenotype and inconclusive genetic findings had this same variant, which was not found in 2,132 control chromosomes.
These findings support that this variant is a disease-causing mutation that may account for additional cases of ABCA3 deficiency with negative genetic studies.
三磷酸腺苷结合盒转运蛋白家族成员 A3（ABCA3）是表面活性剂代谢所必需的。ABCA3 基因（ABCA3）中的无义突变、错义突变、移码突变和剪接位点突变已被报道为新生儿呼吸衰竭（NRF）和间质性肺病的原因。我们检验了这样一个假说，即 ABCA3 非编码区的突变可能导致肺部疾病。
从一名患有致命性肺部疾病的儿童的冷冻肺组织中生成并测序 ABCA3 特异性 cDNA，该儿童仅有一个已确定的 ABCA3 突变。从先证者、父母和其他患有 NRF 的儿童的血液样本中提取的基因组 DNA 中对 ABCA3 进行测序。
来自先证者的 ABCA3 cDNA 包含源自内含子 25 的序列，这些序列预计会改变 ABCA3 蛋白的结构和功能。基因组 DNA 测序显示内含子 25 中转录的杂合性 C>T 转换，创建了一个新的供体位点。另外 7 名具有 ABCA3 缺乏表型和不确定遗传发现的婴儿也存在这种相同的变异，而在 2132 个对照染色体中未发现该变异。
这些发现支持该变体是一种致病突变，可能导致额外的 ABCA3 缺乏症病例出现阴性遗传研究。
