Genetics of pediatric interstitial lung disease

Nogee, Lawrence M.

doi:10.1097/01.mop.0000193310.22462.1f

Cited by 51 publications

(31 citation statements)

References 59 publications

(38 reference statements)

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“…These findings also suggest that, in A549 cells, reduced ATP hydrolysis activity of ABCA3 does not disrupt biogenesis of lamellar body-like vesicles. The ExAC frequencies of p.R288K (0.6%) and p.R1474W (0.5%) are similar to that of p.E292V (0.2%), the most common ABCA3 mutation associated with chILD (5,23,25,26). Five individuals homozygous for p.R288K and five individuals homozygous for p.R1474W are reported in ExAC; however, their phenotypes are not described.…”

Section: Discussionmentioning

confidence: 80%

Functional Characterization of ATP-Binding Cassette Transporter A3 Mutations from Infants with Respiratory Distress Syndrome

Wambach

Yang

Wegner

et al. 2016

Am J Respir Cell Mol Biol

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Mutations in the ATP-binding cassette transporter A3 gene (ABCA3) result in severe neonatal respiratory distress syndrome and childhood interstitial lung disease. As most ABCA3 mutations are rare or private, determination of mutation pathogenicity is often based on results from in silico prediction tools, identification in unrelated diseased individuals, statistical association studies, or expert opinion. Functional biologic studies of ABCA3 mutations are needed to confirm mutation pathogenicity and inform clinical decision making. Our objective was to functionally characterize two ABCA3 mutations (p.R288K and p.R1474W) identified among term and latepreterm infants with respiratory distress syndrome with unclear pathogenicity in a genetically versatile model system. We performed transient transfection of HEK293T cells with wild-type or mutant ABCA3 alleles to assess protein processing with immunoblotting. We used transduction of A549 cells with adenoviral vectors, which concurrently silenced endogenous ABCA3 and expressed either wildtype or mutant ABCA3 alleles (p.R288K and p.R1474W) to assess immunofluorescent localization, ATPase activity, and organelle ultrastructure. Both ABCA3 mutations (p.R288K and p.R1474W) encoded proteins with reduced ATPase activity but with normal intracellular localization and protein processing. Ultrastructural phenotypes of lamellar body-like vesicles in A549 cells transduced with mutant alleles were similar to wild type. Mutant proteins encoded by ABCA3 mutations p.R288K and p.R1474W had reduced ATPase activity, a biologically plausible explanation for disruption of surfactant metabolism by impaired phospholipid transport into the lamellar body. These results also demonstrate the usefulness of a genetically versatile, human model system for functional characterization of ABCA3 mutations with unclear pathogenicity.Keywords: surfactant; childhood interstitial lung disease; neonatal respiratory distress; respiratory distress syndrome ATP-binding cassette transporter A3 (ABCA3), a member of a large family of proteins that hydrolyze ATP to transport substances across biologic membranes, is encoded by an 80-kb gene (ABCA3; NM_001089.2, Gene ID 21) and consists of 1,704 amino acids with two membranespanning domains and two nucleotide binding domains. ABCA3 is expressed in alveolar type II cells, localizes to the membranes of lamellar bodies, and transports phospholipids into the lamellar body, where surfactant, a complex protein-phospholipid mixture that reduces surface tension and prevents alveolar collapse at end expiration, is assembled and stored (1-3). ABCA3 is also required for lamellar body biogenesis (4).Biallelic loss-of-function (nonsense, frameshift) mutations in ABCA3 result in severe, progressive neonatal respiratory distress syndrome (RDS) that is lethal by 1 year of age without lung transplantation (5). However, for individuals with missense, T.C., F.V.W., A.H., B.P.H., and F.S.C.; drafting and revising the manuscript for important intellectual content-J.A.W., P.Y....

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Section: Discussionmentioning

confidence: 80%

Functional Characterization of ATP-Binding Cassette Transporter A3 Mutations from Infants with Respiratory Distress Syndrome

Wambach

Yang

Wegner

et al. 2016

Am J Respir Cell Mol Biol

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“…T, (4) F1203del, and (5) c.3997_3998delAG. p.E292V is the most common ABCA3 mutation associated with childhood interstitial lung disease (13,15,21) and was identified among 16 subjects (Subjects 53, 129-143; see Table E2). One infant was homozygous for p.E292V, presented with neonatal respiratory failure, and died shortly after birth (Subject 129; see Table E2).…”

Section: Resultsmentioning

confidence: 99%

Genotype–Phenotype Correlations for Infants and Children with ABCA3 Deficiency

Wambach

Casey

Fishman

et al. 2014

Am J Respir Crit Care Med

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184

223

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Rationale: Recessive mutations in the ATP-binding cassette transporter A3 (ABCA3) cause lethal neonatal respiratory failure and childhood interstitial lung disease. Most ABCA3 mutations are private.Objectives: To determine genotype-phenotype correlations for recessive ABCA3 mutations.Methods: We reviewed all published and unpublished ABCA3 sequence and phenotype data from our prospective genetic studies of symptomatic infants and children at Washington and Johns Hopkins Universities. Mutations were classified based on their predicted disruption of protein function: frameshift and nonsense mutations were classified as "null," whereas missense, predicted splice site mutations, and insertion/deletions were classified as "other." We compared age of presentation and outcomes for the three genotypes: null/null, null/other, and other/other. Measurements and Main Results:We identified 185 infants and children with homozygous or compound heterozygous ABCA3 mutations and lung disease. All of the null/null infants presented with respiratory failure at birth compared with 75% of infants with null/ other or other/other genotypes (P = 0.00011). By 1 year of age, all of the null/null infants had died or undergone lung transplantation compared with 62% of the null/other and other/other children (P , 0.0001).Conclusions: Genotype-phenotype correlations exist for homozygous or compound heterozygous mutations in ABCA3. Frameshift or nonsense ABCA3 mutations are predictive of neonatal presentation and poor outcome, whereas missense, splice site, and insertion/deletions are less reliably associated with age of presentation and prognosis. Counseling and clinical decision making should acknowledge these correlations.

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“…7 The classic lung pathology findings include desquamative interstitial pneumonia-like picture with or without alveolar proteinosis and abnormal lamellar bodies with dense inclusion bodies observed on electron microscopy, which were not evident in our case. 8 Lung disease caused by ABCA3 mutations requires mutations in both alleles as it is inherited as an autosomal recessive disorder. 9 The ABCA3 sequence variants in our patient were likely not disease-causing, as his unaffected father was shown to carry the same variants.…”

Section: Discussionmentioning

confidence: 99%

Tachypnea of Infancy as the First Sign of Sanfilippo Syndrome

Chiang¹,

Raiman²,

Cutz

et al. 2014

Pediatrics

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This report describes the first known case of Mucopolysaccharidosis type IIIA presenting with respiratory symptoms and characteristic lung pathology. This case highlights under-recognized areas of systemic involvement and earlier modes of presentation in lysosomal storage disorders as well as the importance of investigating infants who have persistent tachypnea. Pediatrics 2014;134:e884-e888 AUTHORS:

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Genetics of pediatric interstitial lung disease

Cited by 51 publications

References 59 publications

Functional Characterization of ATP-Binding Cassette Transporter A3 Mutations from Infants with Respiratory Distress Syndrome

Functional Characterization of ATP-Binding Cassette Transporter A3 Mutations from Infants with Respiratory Distress Syndrome

Genotype–Phenotype Correlations for Infants and Children with ABCA3 Deficiency

Tachypnea of Infancy as the First Sign of Sanfilippo Syndrome

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