Disease relevance of SFTPC

• The goal of this study was to determine whether a disease-linked mutation in SFTPC causes lung disease in transgenic mice [1].
• Using a candidate gene approach, we found a heterozygous exon 5 + 128 T-->A transversion of SFTPC in a large familial pulmonary fibrosis kindred, including adults with usual interstitial pneumonitis and children with cellular nonspecific interstitial pneumonitis [2].
• We show that an SFTPC mutation segregates with the pulmonary fibrosis phenotype in this kindred and may cause type II cellular injury [2].
• Mouse lung epithelial cells transfected with the SFTPC mutation were notable for similar electron microscopy findings and for exaggerated cellular toxicity [2].
• Mapping of the pulmonary surfactant SP5 (SFTP2) locus to 8p21 and characterization of a microsatellite repeat marker that shows frequent loss of heterozygosity in human carcinomas [3].

High impact information on SFTPC

• Lesions consisted of fibrous tissue that included groups of epithelial cells expressing endogenous SP-C mRNA, consistent with their identification as distal respiratory epithelial cells [4].
• Adult mice bearing the SP-C-TGF-alpha transgene developed severe pulmonary fibrosis [4].
• To test whether TGF-alpha mediates pulmonary fibrotic responses, we have generated transgenic mice expressing human TGF-alpha under control of regulatory regions of the human surfactant protein C (SP-C) gene [4].
• Both stimulation and its reversal on removal of hormone were more rapid for SP-B than for SP-C [5].
• Thus, the genes for SP-B and SP-C are expressed in vivo before synthesis of both SP-A (28,000-36,000 D) and surfactant lipids [5].

Chemical compound and disease context of SFTPC

• RECENT FINDINGS: Mutations in the genes encoding surfactant protein C, SFTPC, and a member of the adenosine triphosphate-binding cassette family of proteins, ABCA3, have been shown to result in pediatric interstitial lung diseases inherited in autosomal-dominant and autosomal-recessive patterns, respectively [6].
• We describe a full-term infant with respiratory insufficiency associated with a spontaneous heterozygous mutation resulting in a substitution of lysine for glutamic acid at position 66 (= E66K) of the proximal hSP-C COOH flanking propeptide [7].

Biological context of SFTPC

• 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 [8].
• Adaptation to chronic ER stress imposed by misfolded SP-C was associated with increased susceptibility to viral-induced cell death [9].
• Low molecular weight human pulmonary surfactant protein (SP5): isolation, characterization, and cDNA and amino acid sequences [10].
• We have derived the full amino acid sequence of human SP5 from the nucleotide sequence of cDNAs identified with oligonucleotide probes based on the NH2-terminal sequence of SP5 [10].
• SP-C genes were encoded by approximately 3.0 kilobase pairs of DNA containing six exons and five introns [11].

Anatomical context of SFTPC

• The SFTPC mutation, designated g.1728 G --> A, results in the deletion of exon4, generating a truncated form of SP-C (SP-C(Deltaexon4)). cDNA encoding SP-C(Deltaexon4) was constitutively expressed in type II epithelial cells of transgenic mice [1].
• We have determined the entire nucleotide sequence of two distinct genes encoding SP-C from a genomic library prepared from human leukocytes [11].
• Although its solubility in organic solvents and avidity for lipid membranes impart properties important for its biophysical activity, SP-C represents a structurally and functionally challenging protein for the alveolar type II cell that must synthesize and traffic the peptide through the regulated secretory pathway [12].
• SP-A, SP-C, and/or SP-D transcripts were detected in 11 (84.6%) of 13 lymph nodes with histologically identifiable metastases of pulmonary adenocarcinomas and in 10 (55.5%) of 18 lymph nodes that were tumor free on routine histological examination [13].
• Surfactant protein C (SP-C) is synthesized by alveolar type II cells as a 21-kDa propeptide (proSP-C21) which is proteolytically processed in subcellular compartments distal to the trans-Golgi network to yield a 35-residue mature form [14].

Associations of SFTPC with chemical compounds

• These results prove that native SP-C is a lipopeptide with two palmitoyl groups covalently linked to the polypeptide chain [15].
• Hydrophobic surfactant-associated polypeptides: SP-C is a lipopeptide with two palmitoylated cysteine residues, whereas SP-B lacks covalently linked fatty acyl groups [15].
• Treatment of SP-C with KOH releases fatty acids (palmitic acid to more than 85%) in molar ratios of 1.8-2.0 relative to the polypeptide [15].
• The mutation is predicted to substitute a glutamine for a conserved leucine residue and may hinder processing of SP-C precursor protein [2].
• However, unlike SP-C, SP-C(i) exhibited a very poor ability to promote phospholipid adsorption, gave high surface tension during cyclic film compression, and did not bind lipopolysaccharide in vitro [16].

Physical interactions of SFTPC

• The TTF-1/TAP26 complex differentially modulates surfactant protein-B (SP-B) and -C (SP-C) promoters in lung cells [17].

Enzymatic interactions of SFTPC

• Furthermore, addition of control SP-B can improve samples containing oxidized SP-C, but not vice versa [18].

Regulatory relationships of SFTPC

• To test the role of this bridge in SP-B function in vivo, a construct was generated in which cysteine residues 235 and 246 of the human SP-B proprotein were mutated to serine and cloned under the control of the 3.7-kilobase hSP-C promoter (hSP-B(C235S/C246S)) [19].

Other interactions of SFTPC

• Mutations in the gene encoding SP-B result in severe, fatal neonatal lung disease, and mutations in the gene encoding SP-C are associated with chronic interstitial lung diseases in newborns, older children, and adults [20].
• Although human carboxypeptidase-M is known as a marker of type I cells, the expression of this rat protein was detected in columnar epithelial cells expressing type II cell markers, SP-C and a lamellar body protein ABCA3, in developing lung [21].
• Mutation of SFTPC in infantile pulmonary alveolar proteinosis with or without fibrosing lung disease [22].
• The SP-C and SP-D SNPs and SP-B-linked microsatellite markers studied did not associate with IPF [23].
• VEGF-treated explants also demonstrated increased surfactant protein (SP) A mRNA, SP-C mRNA, and SP-A protein levels compared with controls [24].

Analytical, diagnostic and therapeutic context of SFTPC

• Of the 10 patients with abnormal pro-SP-C processing, as suggested from analysis of broncho-alveolar lavage (BAL) fluid, two distinct heterozygous SFTPC missense mutations were identified [22].
• We have purified a hydrophobic surfactant protein of approximately 5 kDa that we term SP5 from bronchopulmonary lavage fluid from a patient with alveolar proteinosis and shown that it promotes rapid surface film formation by simple mixtures of phospholipids [10].
• Northern blot studies showed lung-specific expression of the full-length SFTPC transcript, appearing in 50-day-old fetus and increasing during lung development [25].
• Both SFTPC transcripts were detected mainly in lung by real-time RT-PCR and they were significantly down-regulated in necrotic lungs of pigs infected with Actinobacillus pleuropneumoniae [25].
• By Western blot analysis, all of these recognized a low molecular weight surfactant species (9 kd) that could be either SP-B or SP-C [26].

References