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SFTPC

MIM.178620 8p21

Wednesday 11 February 2004

Surfactant protein C

Pulmonary surfactant protein C (SP-C) is a highly hydrophobic peptide that enhances surface tension and facilitates the recycling of pulmonary surfactant in vitro. It is produced by type-II alveolar cells through the processing of a high-molecular weight precursor (pro-SP-C).

Surfactant protein C is part of the surfactant complex lining up the alveoles and thereby inhibiting collapse of the airways. iT is involved in innate immune responses.

Rare polymorphisms within surfactant protein C have been linked to sporadic paediatric lung diseases, like alveolar proteinosis or interstitial lung diseases.

Surfactant protein C (SP-C), a hydrophobic protein critically involved in surfactant homeostasis,3 is expressed by alveolar type II epithelial cells and encoded by a single gene located on chromosome 8 (8p21.3) called SFTPC. The human SFTPC gene is organised into six exons (I through V coding, VI untranslated).

SP-C is synthesised as a 197 amino acid proprotein (proSP-C) that undergoes multiple processing steps to the mature SP-C peptide of 35 amino acids, to be finally released in the alveoli associated with the other surfactant proteins and phospholipids.

Structure

Pulmonary surfactant protein C (SP-C) has been originally identified as a highly hydrophobic protein of 3.5-kDa purified from broncho-alveolar lavage (BAL) fluid from a patient with pulmonary alveolar proteinosis (PAP), a respiratory distress syndrome in which nonfunctional surfactant is stored in the alveolar space.

The protein is synthesized as a precursor (pro-SP-C) which is then subjected to C- and N-terminal proteolytic cleavage yielding the mature peptide. Two cysteine residues present in the mature peptide are the substrate of post-translational palmitoylation, which confers an extremely hydrophobic nature to the mature protein.

In vitro, SP-C was shown to promote rapid surface film formation by simple mixtures of phospholipids, hence the interest of natural exogenous surfactant preparations containing SP-C.

In addition, SP-C facilitates the reuptake of surfactant phospoholipids in vitro, suggesting a role in surfactant clearance.

The encoding gene, SFTPC (MIM 178620), has been localized to the chromosomal region 8p23.1 It is a relatively small gene spanning 3.5 kb and composed of six exons, and its expression is restricted to the type-II alveolar cells.

The presence of an alternative splice site in the beginning of exon 5 entails two distinct messenger species differing by the insertion or deletion of 18 nucleotides. Two cysteine residues present in the mature peptide are the substrate of post-translational palmitoylation, which confers an extremely hydrophobic nature to the protein.

The meckel-gruber syndrome protein MKS3 is required for ER-associated degradation of surfactant protein C. (19815549)

Pathology

- germline heterozygous mutations in gene SFTPC coding for surfactant proteigenen C (SP-C) in SP-C deficiency (SFTPC deficiency)

  • neonatal alveolar proteinosis (MIM.265120)
  • chronic pneumonitis of infancy
  • familiial pulmonary alveolar proteinosis (MIM.265120)
  • familial interstitial lung disease (Nogee et al. [2001: N Engl J Med 344:573-579]; Thomas et al. [2002: Am J Respir Crit Care Med 165:1322-1328]).
  • familial desquamative interstitial pneumonitis (familial DSIP) (MIM.263000)
  • usual interstitial pneumonitis (UIP)
  • cellualr nonspecific interstitial pneumonitis (NSIP)
  • familial idiopathic pulmonary fibrosis (MIM.178500)
  • unexplained respiratory distress (URD)
  • desquamative interstitial pneumonitis (DIP)
  • dominantly-inherited familial interstitial pneumonitis
  • familial pulmonary fibrosis (FPF)

- SFTPC gene variation in neonatal respiratory disease

  • neonatal cellular pneumonitis or nonspecific interstitial pneumonitis (NSIP)

Mutations

Nogee et al first described an SFTPC mutation in 2001. - 13 SFTPC mutations have been identified. They always occur in one single allele and have been associated with diffuse lung disease in children and adults.

- The mutation, c.435+1G>A, located at the first base of intron 4, alters the normal donor splice site and results in the skipping of exon 4 and the deletion of 37 amino acids in the carboxy terminal domain of proSP-C. This mutation was observed in one allele of a patient suffering from chronic interstitial pneumonitis and was inherited following a dominant pattern.

- The mutation I73T (c.218 T>C) is the more prevalent mutation.

Dominant transmission with variable penetrance has been confirmed in familial cases, but a number of sporadic cases have also been reported with a de novo mutation.

The phenotype associated with SFTPC mutations appears to be very variable.

Indeed, neonatal forms leading to death in the first years of life as well as childhood and adult forms with chronic respiratory disease have been reported.

Single nucleotide polymorphisms (SNPs) have also been detected both in the coding and non-coding sequence, with unclear consequences on proSP-C processing and function.

Physiopathology

- The mutant protein can divert its wild-type counterpart to aggresomes, thus providing a molecular mechanism for the dominant negative effect observed in vivo.

- Electron microscopy performed on patients’ epithelia showed type-II cell atypia with numerous abnormal lamellar bodies.

- aberrant subcellular localization by immunostaining.

- misfolding and trapping of pro-SP-C in or near the endoplasmic reticulum without delivery to distal secretory compartments.

Animal models

To further evaluate the function of the SP-C protein in vivo, the SFTPC gene murine homologue (Sftpc) was targeted by homologous recombination.

When using the D3R strain of embryonic stem (ES) cells and following introduction of the mutation into an outbred NIH Swiss black host strain, homozygotes, maintained in a pathogen-free environment, were normally viable and had normal lung function.

Although Sftpc mRNA was abrogated and no SP-C produced in lung, electron microscopy showed normal lamellar bodies in number and structure, and normal tubular myelin. Other surfactant proteins were normal.

The only noticeable abnormality resided in reduced viscoelasticity of the lungs of homozygotes and decreased stability of surfactant bubbles at small radii only (these abnormalities were thought to reflect the importance of SP-C in vivo at low lung volumes).

However, after 1 year of age, pneumonitis and emphysema developed. Interestingly, when maintained in the congenic 129/Sv strain, the mutation results in SP-C deficient mice that develop severe pneumonitis, emphysema, and remodeling of conducting and peripheral airways within 2 or 3 months after birth.

Thus, unlike the rapidly fatal fate of mice lacking the hydrophobic surfactant protein B (SP-B), the phenotype linked to SP-C deficiency was fully compatible with life at birth, and evolution was highly dependent on the host background, suggesting modifier genes.

See also

- unexplained respiratory distress (URD)
- surfactant protein B (SP-B) deficiency
- SFTPB mutations
- complete SP-C deficiency
- abnormal pro-SP-C processing
- pulmonary alveolar proteinosis (PAP)
- interstitial lung diseases

References

- New surfactant protein C gene mutations associated with diffuse lung disease. Guillot L, Epaud R, Thouvenin G, Jonard L, Mohsni A, Couderc R, Counil F, de Blic J, Taam RA, Le Bourgeois M, Reix P, Flamein F, Clement A, Feldmann D. J Med Genet. 2009 Jul;46(7):490-4. PMID: 19443464 (Free)

- Diffuse lung disease in young children: application of a novel classification scheme. Deutsch GH, Young LR, Deterding RR, Fan LL, Dell SD, Bean JA, Brody AS, Nogee LM, Trapnell BC, Langston C; Pathology Cooperative Group, Albright EA, Askin FB, Baker P, Chou PM, Cool CM, Coventry SC, Cutz E, Davis MM, Dishop MK, Galambos C, Patterson K, Travis WD, Wert SE, White FV; ChILD Research Co-operative. Am J Respir Crit Care Med. 2007 Dec 1;176(11):1120-8. Epub 2007 Sep 20. PMID: 17885266 (Free)

- The meckel-gruber syndrome protein MKS3 is required for ER-associated degradation of surfactant protein C. Wang M, Bridges J, Na CL, Xu Y, Weaver TE. J Biol Chem. 2009 Oct 8. PMID: 19815549

- The meckel-gruber syndrome protein MKS3 is required for ER-associated degradation of surfactant protein C. Wang M, Bridges J, Na CL, Xu Y, Weaver TE. J Biol Chem. 2009 Oct 8. PMID: 19815549

- Markart P, Ruppert C, Wygrecka M, Schmidt R, Korfei M, Harbach H, Theruvath I, Pison U, Seeger W, Guenther A, Witt H. Surfactant protein C mutations in sporadic forms of idiopathic interstitial pneumonias. Eur Respir J. 2007 Jan;29(1):134-7. PMID: 17005585

- Puthothu B, Krueger M, Heinze J, Forster J, Heinzmann A. Haplotypes of surfactant protein C are associated with common paediatric lung diseases. Pediatr Allergy Immunol. 2006 Dec;17(8):572-7. PMID: 17121584

- Nogee LM. Genetics of pediatric interstitial lung disease. Curr Opin Pediatr. 2006 Jun;18(3):287-92. PMID: 16721150

- Bridges JP, Xu Y, Na CL, Wong HR, Weaver TE. Adaptation and increased susceptibility to infection associated with constitutive expression of misfolded SP-C. J Cell Biol. 2006 Jan 30;172(3):395-407. PMID: 16449190

- Soraisham AS, Tierney AJ, Amin HJ. Neonatal respiratory failure associated with mutation in the surfactant protein C gene. J Perinatol. 2006 Jan 1;26(1):67-70. PMID: 16355106

- Tredano M, Griese M, Brasch F, Schumacher S, de Blic J, Marque S, Houdayer C, Elion J, Couderc R, Bahuau M. Mutation of SFTPC in infantile pulmonary alveolar proteinosis with or without fibrosing lung disease. Am J Med Genet A. 2004 Apr 1;126(1):18-26. PMID: 15039969

- Brasch F, Griese M, Tredano M, Johnen G, Ochs M, Rieger C, Mulugeta S, Muller KM, Bahuau M, Beers MF. Interstitial lung disease in a baby with a de novo mutation in the SFTPC gene. Eur Respir J. 2004 Jul;24(1):30-9. PMID: 15293602

- Nogee LM, Dunbar AE 3rd, Wert SE, Askin F, Hamvas A, Whitsett JA. A mutation in the surfactant protein C gene associated with familial interstitial lung disease. N Engl J Med. 2001 Feb 22;344(8):573-9. PMID: 11207353