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

Respiratory Research - 2014
Ilaria Campo1, Michele Zorzetto1, Francesca Mariani1, Zamir Kadija1, Patrizia Morbini2, Roberto Dore3, Eva Kaltenborn4, Sabrina Frixel4, Ralf Zarbock4, Gerhard Liebisch5, Jan Hegermann6, Christoph Wrede6, Matthias Griese4, Maurizio Luisetti1
1Pneumology Unit, IRCCS San Matteo Foundation Hospital, Piazza Golgi 1, Pavia, 27100, Italy
2Department of Molecular Medicine, Section of Pathology, University of Pavia and Foundation IRCCS Policlinico S. Matteo, Pavia, Italy
3Institute of Radiology, IRCCS San Matteo Foundation Hospital, Pavia, Italy
4Pediatric Pneumology, Dr. von Hauner Children's Hospital, Ludwig-Maximilians University, Member of the German Center for Lung Research (DZL), Munich, Germany
5Institute for Clinical Chemistry and Laboratory Medicine, University of Regensburg, Regensburg, Germany
6Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany and Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover, Germany

Tóm tắt

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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