Respiratory failure in a term infant with cis and trans mutations in ABCA3

Jackson, Troy; Wegner, Daniel; White, Frances V.; Hamvas, Aaron; Cole, F. Sessions; Wambach, Jennifer A.

doi:10.1038/jp.2014.236

Cited by 12 publications

(8 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, similar ABCA3 protein processing and colocalization in A549 cells and primary ATII cells suggest biologic relevance of the A549 cell line (Beers et al, 2013; Cheong et al, 2006). In addition, lamellar body phenotypes from patients with ABCA3 deficiency are consistent with our measurements of smaller lamellar body diameter (Citti et al, 2013; Doan et al, 2008; Jackson et al, 2015; Shulenin et al, 2004; Wert, Whitsett, & Nogee, 2009). Finally, quantitative measurements using this A549 cell‐based model permit functional characterization of uncharacterized variants and may be a useful model for drug discovery.…”

Section: Discussionsupporting

confidence: 88%

Functional characterization of four ATP‐binding cassette transporter A3 gene (ABCA3) variants

Yang

Wegner

et al. 2020

Human Mutation

View full text Add to dashboard Cite

ABCA3 transports phospholipids across lamellar body membranes in pulmonary alveolar type II cells and is required for surfactant assembly. Rare, biallelic, pathogenic ABCA3 variants result in lethal neonatal respiratory distress syndrome and childhood interstitial lung disease. Qualitative functional characterization of ABCA3 missense variants suggests two pathogenic classes: disrupted intracellular trafficking (type I mutant) or impaired ATPase‐mediated phospholipid transport into the lamellar bodies (type II mutant). We qualitatively compared wild‐type (WT‐ABCA3) with four uncharacterized ABCA3 variants (c.418A>C;p.Asn140His, c.3609_3611delCTT;p.Phe1203del, c.3784A>G;p.Ser1262Gly, and c.4195G>A;p.Val1399Met) in A549 cells using protein processing, colocalization with intracellular organelles, lamellar body ultrastructure, and ATPase activity. We quantitatively measured lamellar body‐like vesicle diameter and intracellular ABCA3 trafficking using fluorescence‐based colocalization. Three ABCA3 variants (p.Asn140His, p.Ser1262Gly, and p.Val1399Met) were processed and trafficked normally and demonstrated well‐organized lamellar body‐like vesicles, but had reduced ATPase activity consistent with type II mutants. P.Phe1203del was processed normally, had reduced ATPase activity, and well‐organized lamellar body‐like vesicles, but quantitatively colocalized with both endoplasmic reticulum and lysosomal markers, an intermediate phenotype suggesting disruption of both intracellular trafficking and phospholipid transport. All ABCA3 mutants demonstrated mean vesicle diameters smaller than WT‐ABCA3. Qualitative and quantitative functional characterization of ABCA3 variants informs mechanisms of pathogenicity.

show abstract

Section: Discussionsupporting

confidence: 88%

Functional characterization of four ATP‐binding cassette transporter A3 gene (ABCA3) variants

Yang

Wegner

et al. 2020

Human Mutation

View full text Add to dashboard Cite

show abstract

“…This SFTPC variant is located in the last base of exon 4 and results in abnormal splicing with skipping of exon 4 and a truncated protein with abnormal intracellular trafficking 27 . Our results also emphasize the importance of parental DNA samples to phase ABCA3 variants as 5 (~30%) subjects had 3 ABCA3 variants identified consistent with prior studies 5,28 …”

Section: Discussionsupporting

confidence: 84%

Biologic characterization of ABCA3 variants in lung tissue from infants and children with ABCA3 deficiency

Wegner

Geurts

et al. 2022

Pediatric Pulmonology

View full text Add to dashboard Cite

ABCA3 is a phospholipid transporter protein required for surfactant assembly in lamellar bodies of alveolar type II cells. Biallelic pathogenic ABCA3 variants cause severe neonatal respiratory distress syndrome or childhood interstitial lung disease.However, ABCA3 genotype alone does not explain the diversity in disease presentation, severity, and progression. Additionally, monoallelic ABCA3 variants have been reported in infants and children with ABCA3-deficient phenotypes. The effects of most ABCA3 variants identified in patients have not been characterized at the RNA level. ABCA3 allele-specific expression occurs in some cell types due to epigenetic regulation. We obtained lung tissue at transplant or autopsy from 16 infants and children with ABCA3 deficiency due to compound heterozygous ABCA3 variants for biologic characterization of the predicted effects of ABCA3 variants at the RNA level and determination of ABCA3 allele expression. We extracted DNA and RNA from frozen lung tissue and reverse-transcribed cDNA from mRNA. We performed Sanger sequencing to assess allele-specific expression by comparing the heights of variant nucleotide peaks in amplicons from genomic DNA and cDNA. We found similar genomic and cDNA variant nucleotide peak heights and no evidence of allelespecific expression among explant or autopsy samples with biallelic missense ABCA3 variants (n = 6). We observed allele-specific expression of missense alleles in trans with frameshift (n = 4) or nonsense (n = 1) variants, attributable to nonsensemediated decay. The missense variant c.53 A > G;p.Gln18Arg, located near an exonintron junction, encoded abnormal splicing with skipping of exon 4. Biologic characterization of ABCA3 variants can inform discovery of variant-specific disease mechanisms.

show abstract

“…The authors hypothesised that the p.Glu292Val change could in part increase sensitivity to the developmental risk of RDS [25]. Index patient n. 6 presented a single intronic variant in ABCA3 and died at 4 months; ABCA3 was detected at immunohistochemical staining of the lung tissue, however type II pneumocytes hyperplasia, inflammatory cells infiltration and the presence of peripheral dense aggregates in lamellar bodies at electron microscopy may suggest a disorder in surfactant metabolism [26, 27]. (Fig.…”

Section: Discussionmentioning

confidence: 99%

Surfactant proteins gene variants in premature newborn infants with severe respiratory distress syndrome

et al. 2017

View full text Add to dashboard Cite

ObjectiveGenetic surfactant dysfunction causes respiratory failure in term and near-term newborn infants, but little is known of such condition in prematures. We evaluated genetic surfactant dysfunction in premature newborn infants with severe RDS.Patients and methodsA total of 68 preterm newborn infants with gestational age ≤32 weeks affected by unusually severe RDS were analysed for mutations in SFTPB, SFTPC and ABCA3. Therapies included oxygen supplementation, nasal CPAP, different modalities of ventilatory support, administration of exogenous surfactant, inhaled nitric oxide and steroids. Molecular analyses were performed on genomic DNA extracted from peripheral blood and Sanger sequencing of whole gene coding regions and intron junctions. In one case histology and electron microscopy on lung tissue was performed.ResultsHeterozygous previously described rare or novel variants in surfactant proteins genes ABCA3, SFTPB and SFTPC were identified in 24 newborn infants. In total, 11 infants died at age of 2 to 6 months. Ultrastructural analysis of lung tissue of one infant showed features suggesting ABCA3 dysfunction.DiscussionRare or novel genetic variants in genes encoding surfactant proteins were identified in a large proportion (35%) of premature newborn infants with particularly severe RDS. We speculate that interaction of developmental immaturity of surfactant production in association with abnormalities of surfactant metabolism of genetic origin may have a synergic worsening phenotypic effect.

show abstract

Respiratory failure in a term infant with cis and trans mutations in ABCA3

Cited by 12 publications

References 22 publications

Functional characterization of four ATP‐binding cassette transporter A3 gene (ABCA3) variants

Functional characterization of four ATP‐binding cassette transporter A3 gene (ABCA3) variants

Biologic characterization of ABCA3 variants in lung tissue from infants and children with ABCA3 deficiency

Surfactant proteins gene variants in premature newborn infants with severe respiratory distress syndrome

Contact Info

Product

Resources

About