ABCA3 Mutations Associated with Pediatric Interstitial Lung Disease

Abstract

Rationale: ABCA3 is a member of the ATP-binding cassette family of proteins that mediate the translocation of a wide variety of substrates, including lipids, across cellular membranes. Mutations in the gene encoding ABCA3 were recently identified in full-term neonates with fatal surfactant deficiency. Objective: To test the hypothesis that ABCA3 mutations are not always associated with fatal neonatal lung disease but are a cause of pediatric interstitial lung disease. Methods: DNA samples were obtained from 195 children with chronic lung disease of unknown etiology. The 30 coding exons of the ABCA3 gene were sequenced in four unrelated children with a referring diagnosis of desquamative interstitial pneumonitis and who were older than 10 years at the time of enrollment. Results: Three of four patients (ages 16, 23, and 11 years) with desquamative interstitial pneumonitis had ABCA3 mutations identified on both alleles. All three had the same missense mutation (E292V) and a second unique mutation. The E292V mutation was not found on 200 control alleles from adults without lung disease, but seven additional patients of the remaining study patients had the E292V mutation on one allele. Immunohistochemical analysis of surfactant protein expression in three patients revealed a specific staining pattern for surfactant protein-B, which was the same pattern observed in several infants with fatal lung disease due to ABCA3 mutations. Conclusion: ABCA3 mutations cause some types of interstitial lung disease in pediatric patients. Keywords: desquamative interstitial pneumonitis; pulmonary alveolar proteinosis; surfactantPulmonary surfactant is a mixture of lipids and specific proteins needed to reduce alveolar surface tension. Surfactant is produced and stored by alveolar type II cells, is secreted by exocytosis, and forms a lipid-rich monolayer at the air-liquid interphase, which lowers surface tension and prevents end-expiratory atelectasis. Deficiency of surfactant due to prematurity is the primary cause of respiratory distress syndrome in some infants (1). Lung disease in some full-term infants and older children with interstitial lung disease (ILD) has a genetic basis related to surfactant metabolism. Single-gene defects that encode the hydrophobic surfactant proteins, SP-B and SP-C, result in severe neonatal and chronic ILD, respectively (2-4). Recently, mutations in the gene encoding the ATP-binding cassette protein A3 (ABCA3) were identified in full-term neonates with fatal surfactant defi-

Clinical and ultrastructural spectrum of diffuse lung disease associated with surfactant protein C mutations

“…These alterations are distinct from those observed in SP-B or ABCA3 deficiency 3,6 and appear specific in both our observations and the literature. 15,28 In SP-C-deficient mice, LBs and extracellular surfactant are similar to controls, 35 suggesting that the human disease is not primarily caused by SP-C haploinsufficiency itself.…”

“…Prevalence in pDLD series, as in ours, varies from 8 to 17%. 1, 3,6,7,19,26 SP-C mutations have been described in term 15,27 or late preterm infants with severe RDS, although this presentation is more typical of SP-B and ABCA3 biallelic mutations. 2 The typical presentation of SP-C defects consists of dyspnea, cough or wheezing with an onset between 2 and 12 months of age, gradual cyanosis and failure to thrive.…”

“…The N terminus domain is involved in cell trafficking and the C terminus domain harbors the BRICHOS domain, a chaperone preventing aggregation of the hydrophobic mature peptide during posttranscriptional processes. SP-B and ABCA3 deficiencies are autosomal recessive diseases presenting as neonatal respiratory distress syndrome (RDS) typically fatal within the first months of age (although certain ABCA3 mutations may lead to later onset disease 6 ). SP-C mutations are mostly mono-allelic, either sporadic or inherited, and are expressed in a dominant fashion in~50% of cases.…”

Aberrant catalytic cycle and impaired lipid transport into intracellular vesicles in ABCA3 mutants associated with nonfatal pediatric interstitial lung disease

“…For example, patients with type I homozygous ABCA3 mutations such as W1142X/W1142X or type I/type II compound heterozygous ABCA3 mutations such as L982P/G1221S die of surfactant deficiency within the neonatal period (27). On the other hand, patients with the common missense mutation E292V and a second, specific mutation such as E690K or T1114M develop pediatric interstitial lung disease (pILD), the phenotype of which is milder than that of fatal surfactant deficiency, suggesting that the E292V ABCA3 mutation is responsible for the development of pILD (4). However, the mechanism underlying the phenotypic heterogeneity of lung disease associated with ABCA3 mutation remains unknown.…”

The ABCA subfamily—gene and protein structures, functions and associated hereditary diseases

“…Electron micrograph images revealed abnormally small and dense lamellar bodies and peripheral inclusions in this organelle. More recently [10], it has been shown that mutations in ABCA3 are not always associated with fatal neonatal surfactant deficiency, but can be the cause of other nonlethal lung diseases.…”