Novel mutations in the gene encoding ATP binding cassette protein member A3 (ABCA3) resulting in fatal neonatal lung disease

Saugstad, Ola Didrik; Hansen, Thor Willy Ruud; Rønnestad, Arild; Nakstad, Britt; Tølløfsrud, Per Arne; Reinholt, Finn P.; Hamvas, Aaron; Cole, F. Sessions; Dean, Michael; Wert, Susan E.; Whitsett, Jeffrey A.; Nogee, Lawrence M.

doi:10.1111/j.1651-2227.2007.00016.x

Cited by 32 publications

(22 citation statements)

References 25 publications

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“…Among the different genes involved in these processes, the ABCA3 gene encodes a 1704 amino acid protein of the ATP binding cassette transporter family. It is mainly expressed in the lungs at the limiting membrane of the lamellar bodies of alveolar type II cells; loss of normal ABCA3 function is associated with lung disease [20,21]. …”

Section: Discussionmentioning

confidence: 99%

A large kindred of pulmonary fibrosis associated with a novel ABCA3 gene variant

et al. 2014

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BackgroundInterstitial lung disease occurring in children is a condition characterized by high frequency of cases due to genetic aberrations of pulmonary surfactant homeostasis, that are also believed to be responsible of a fraction of familial pulmonary fibrosis. To our knowledge, ABCA3 gene was not previously reported as causative agent of fibrosis affecting both children and adults in the same kindred.MethodsWe investigated a large kindred in which two members, a girl whose interstitial lung disease was first recognized at age of 13, and an adult, showed a diffuse pulmonary fibrosis with marked differences in terms of morphology and imaging. An additional, asymptomatic family member was detected by genetic analysis. Surfactant abnormalities were investigated at biochemical, and genetic level, as well as by cell transfection experiments.ResultsBronchoalveolar lavage fluid analysis of the patients revealed absence of surfactant protein C, whereas the gene sequence was normal. By contrast, sequence of the ABCA3 gene showed a novel homozygous G > A transition at nucleotide 2891, localized within exon 21, resulting in a glycine to aspartic acid change at codon 964. Interestingly, the lung specimens from the girl displayed a morphologic usual interstitial pneumonitis-like pattern, whereas the specimens from one of the two adult patients showed rather a non specific interstitial pneumonitis-like pattern.ConclusionsWe have detected a large kindred with a novel ABCA3 mutation likely causing interstitial lung fibrosis affecting either young and adult family members. We suggest that ABCA3 gene should be considered in genetic testing in the occurrence of familial pulmonary fibrosis.

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Section: Discussionmentioning

confidence: 99%

A large kindred of pulmonary fibrosis associated with a novel ABCA3 gene variant

et al. 2014

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“…P.V1399M is rare and has been previously reported in symptomatic infants. 8, 15 Neither p.V1399M nor p.Q1589X is identified among individuals in the ESP database. P.Q1589X is predicted to result in a truncated protein.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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A full-term female neonate presented with persistent respiratory failure and radiologic studies consistent with surfactant deficiency. Sequencing of the ATP-binding cassette transporter A3 gene (ABCA3) revealed 3 mutations: R280C, V1399M, and Q1589X. The infant underwent bilateral lung transplantation at 9 months of age and is alive at 3 years of age. Parental sequencing demonstrated that 2 of the mutations (R280C and Q1589X) were oriented on the same allele (cis) while V1399M was oriented on the opposite allele (trans). As more than one mutation in ABCA3 can be present on the same allele, parental studies are needed to determine allelic orientation to inform clinical decision making and future reproductive counseling.

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“…Abnormal ultrastructure of lamellar bodies, the surfactant storage organelle, was observed in Stat-3 ⌬/⌬ mice previously (26). Abca3 is present in the limiting membranes of the lamellar bodies; mutations in the Abca3 gene cause respiratory distress in newborn infants associated with altered surfactant metabolism and abnormal ultrastructure of lamellar bodies (38,41).…”

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confidence: 99%

STAT-3 regulates surfactant phospholipid homeostasis in normal lung and during endotoxin-mediated lung injury

Ikegami¹,

Falcone²,

Whitsett³

2008

Journal of Applied Physiology

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Novel mutations in the gene encoding ATP binding cassette protein member A3 (ABCA3) resulting in fatal neonatal lung disease

Abstract: ABCA3 mutations were the basis for lung disease in all three patients. Children with lung disease due to ABCA3 deficiency may not have symptoms at birth. The finding of five novel mutations indicates allelic heterogeneity for ABCA3 mutations within the Norwegian population.

Cited by 32 publications

References 25 publications

A large kindred of pulmonary fibrosis associated with a novel ABCA3 gene variant

A large kindred of pulmonary fibrosis associated with a novel ABCA3 gene variant

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

STAT-3 regulates surfactant phospholipid homeostasis in normal lung and during endotoxin-mediated lung injury

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