Interstitial lung disease in a baby with a de novo mutation in the SFTPC gene.
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 (173T) 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 173T 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.
Institute of Pathology, University Hospital Bergmannsheil, Bochum, Germany. Frank.E.Brasch@ruhr-uni-bochum.de
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Brasch
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Griese
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Tredano
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Johnen
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Ochs
C
C
Rieger
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Mulugeta
K M
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Müller
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Bahuau
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Beers
D001483:Base Sequence; D001707:Biopsy, Needle; D015153:Blotting, Western; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006801:Humans; D007150:Immunohistochemistry; D007231:Infant, Newborn; D017563:Lung Diseases, Interstitial / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011486:Protein C / Q000235:genetics*; D012680:Sensitivity and Specificity
D011486:Protein C