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.