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

Wambach, Jennifer A.; Yang, Ping; Wegner, Daniel; Heins, Hillary B.; Kaliberova, Lyudmila N.; Kaliberov, Sergey A.; Curiel, David T.; White, Frances V.; Hamvas, Aaron; Hackett, Brian P.; Cole, F. Sessions

doi:10.1165/rcmb.2016-0008oc

Cited by 51 publications

(73 citation statements)

References 29 publications

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“…). Among the other novel or very rare variants, three ABCA3 missense (p.Pro249Thr; p.Ile703Thr, p.Arg661Gln) were found, predicted as benign; interestingly the variant p.Ile703Thr as well as the p.Arg661Gln are located in the ATPase AAA + domain, suggesting that they could determine a functional change in the ATPase activity, as it was showed for the p.Arg288Lys [13]. …”

Section: Resultsmentioning

confidence: 99%

“…(Tyr1390 = )8F26650Oxygen, CPAP, surfactant, CMV, NIV, HFOV, SteroidsAlive at 2 yearswtwtp. (Arg288Lys) [13, 15]9M26881Oxygen, CPAP, surfactant, CMV, HFOV, SteroidsAlive at 4 yearswtwtp. (Arg661Gln)10M301900Oxygen, CPAP, surfactant, CMVAlive at 10 yearswtwtp.…”

Section: Resultsmentioning

confidence: 99%

“…(Pro249Thr)Novel000Benign (0.063)Deleterious (0.03)38C0–c.863 G > Ap. (Arg288Lys) [13, 25]rs1176039310.0020.005910Benign (0.002)Tolerated (1)26C0–c.1502 C > Ap. (Ala501Glu) [12]rs1416219690.00340.003817Benign (0.001)Tolerated (1)107C0–c.1982G > Ap.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2017

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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

et al. 2017

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“…Autosomal recessive mutations in ABCA3 cause severe lung disease in infants and children, and they represent the most common genetic cause of respiratory failure in newborns (1,(7)(8)(9). ABCA3-related lung disease in infants is accompanied by lung injury and extensive tissue remodeling, leading to loss of alveolar structures that is generally fatal despite intensive care and ventilatory support (7,10,11). At present, lung transplantation is the only effective treatment for infants with severe ABCA3-related lung disease (12,13).…”

Section: Introductionmentioning

confidence: 99%

Alveolar injury and regeneration following deletion of ABCA3

Rindler¹,

Stockman²,

Filuta³

et al. 2017

JCI Insight

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“…15 In order to classify the ABCA3 mutations, published functional analyses were used to define functional effects of mutations. 4,[16][17][18] Of the 233 unique mutations collated, 14 had been experimentally classified. If only DNA mutations were reported, we attempted to find the protein mutation using MutationTaster.…”

Section: Classification Criteriamentioning

confidence: 99%

The classification of ATP‐binding cassette subfamily A member 3 mutations using the cystic fibrosis transmembrane conductance regulator classification system

Denman

Yonker

Kinane

2018

Pediatric Investigation

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Importance: The ATP-binding cassette subfamily A member 3 (ABCA3) protein plays a vital role in surfactant homeostasis. Mutations in the ABCA3 gene lead to the development of interstitial lung disease. In the most severe manifestation, mutations can lead to a fatal respiratory distress syndrome in neonates. ABCA3 belongs to the same ATP-binding cassette transporter superfamily as the cystic fibrosis transmembrane conductance regulator (CFTR), the gene that causes cystic fibrosis. Objective: To classify ABCA3 mutations in a manner similar to CFTR mutations in order to take advantage of recent advances in therapeutics. Methods: Sequence homology between the CFTR protein and the ABCA3 protein was established. The region of CFTR that is a target for the new potentiator class of drugs was of particular interest. We performed a literature search to obtain all published mutations that were thought to be disease causing. We classified these mutations using the established CFTR classification system. When possible, we drew on previous experimental classification of ABCA3 mutations. Results: Although the proteins share the same overall structure, only a 19% identity was established between CFTR and ABCA3. The CFTR therapeutic target region has a 22% homology with the corresponding ABCA3 region. Totally 233 unique protein mutations were identified. All protein mutations were classified and mapped to a schematic diagram of the ABCA3 protein.Interpretation: This new classification system for ABCA3, based on CFTR classification, will likely aid further research of clinical outcomes and identification of mutation-tailored therapeutics, with the aim for improving clinical care for patients with ABCA3 mutations.

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

Cited by 51 publications

References 29 publications

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

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

Alveolar injury and regeneration following deletion of ABCA3

The classification of ATP‐binding cassette subfamily A member 3 mutations using the cystic fibrosis transmembrane conductance regulator classification system

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