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01.12.2014 | Research | Ausgabe 1/2014 Open Access

Respiratory Research 1/2014

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

Zeitschrift:
Respiratory Research > Ausgabe 1/2014
Autoren:
Ilaria Campo, Michele Zorzetto, Francesca Mariani, Zamir Kadija, Patrizia Morbini, Roberto Dore, Eva Kaltenborn, Sabrina Frixel, Ralf Zarbock, Gerhard Liebisch, Jan Hegermann, Christoph Wrede, Matthias Griese, Maurizio Luisetti
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1465-9921-15-43) contains supplementary material, which is available to authorized users.

Competing interests

The authors declare that they have no competing interests.

Authors’ contribution

IC performed the gene and gene expression analysis and drafted the manuscript, MZ performed the bioinformatic analysis, FM and ZK coordinated clinical diagnosis, PM performed the histochemistry analysis, RD performed the radiology investigation, EK and SF and RZ performed the Western Blot analysis and the cell transfection experiments, GL performed lipid analysis ofthe cells, JH and CW prepared electron micrographs and analyzed them. MG coordinated Western Blot lipidomic analysis and the cell transfection experiments and drafted and supervised the manuscript, ML drafted and critically revised the manuscript and supervised the research. All authors read and approved the final manuscript.

Abstract

Background

Interstitial 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.

Methods

We 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.

Results

Bronchoalveolar 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.

Conclusions

We 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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