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Eur Respir J 2004; 24:30-39
Copyright ©ERS Journals Ltd 2004

Interstitial lung disease in a baby with a de novo mutation in the SFTPC gene

F. Brasch1,2, M. Griese1,3, M. Tredano4, G. Johnen2, M. Ochs5, C. Rieger6, S. Mulugeta7, K.M. Müller2, M. Bahuau4 and M.F. Beers7

1 , 2 Institute of Pathology, University Hospital "Bergmannsheil", and 6 Children's Hospital, Ruhr-University, Bochum, 3 Dr. von Haunersches Children's Hospital, Ludwig-Maximilians-University, Munich, and 5 Division of Electron Microscopy, Dept of Anatomy, University of Göttingen, Göttingen, Germany. 4 Service de Biochimie et Biologie Moléculaire, Hôpital d'Enfants Armand-Trousseau (AP-HP), Paris, France. 7 Lung Epithelial Cell Biology Laboratories, Pulmonary and Critical Care Division, Dept of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

CORRESPONDENCE: F. Brasch, Institute of Pathology, University Hospital "Bergmannsheil", Bürkle-de-la-Camp Platz 1, D-44789 Bochum, Germany. Fax: 49 234/3026671. E-mail: Frank.E.Brasch@ruhr-uni-bochum.de

Keywords: Interstitial lung disease, nonspecific interstitial pneumonia, pulmonary alveolar proteinosis, surfactant protein C, surfactant protein C gene

Received: January 1, 2004
Accepted March 23, 2004

Major funding was provided as a gift from M. Pressac, Pharm.D. Additional support came from NIH HL-19737, NIH HL-074064, and P50-HL-56401 (M.F. Beers) and DFG Gr 970/7-1 (M. Griese). *These authors contributed equally to this work.

Mutations in the surfactant protein C gene (SFTPC) were recently reported in patients with interstitial lung disease.

In a 13-month-old infant with severe respiratory insufficiency, a lung biopsy elicited combined histological patterns of nonspecific interstitial pneumonia and pulmonary alveolar proteinosis. Immunohistochemical and biochemical analyses showed an intra-alveolar accumulation of surfactant protein (SP)-A, precursors of SP-B, mature SP-B, aberrantly processed proSP-C, as well as mono- and dimeric SP-C.

Sequencing of genomic DNA detected a de novo heterozygous missense mutation of the SFTPC gene (g.1286T>C) resulting in a substitution of threonine for isoleucine (I73T) in the C-terminal propeptide. At the ultrastructural level, abnormal transport vesicles were detected in type-II pneumocytes. Fusion proteins, consisting of enhanced green fluorescent protein and wild-type or mutant proSP-C, were used to evaluate protein trafficking in vitro. In contrast to wild-type proSP-C, mutant proSP-C was routed to early endosomes when transfected into A549 epithelial cells.

In contrast to previously reported mutations, the I73T represents a new class of surfactant protein C gene mutations, which is marked by a distinct trafficking, processing, palmitoylation, and secretion of the mutant and wild-type surfactant protein C. This report heralds the emerging diversity of phenotypes associated with the expression of mutant surfactant C proteins.




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