Skip to main content
Biochemical Journal logoLink to Biochemical Journal
. 1999 Oct 1;343(Pt 1):145–149.

An alternatively spliced surfactant protein B mRNA in normal human lung: disease implication.

Z Lin 1, G Wang 1, D E Demello 1, J Floros 1
PMCID: PMC1220535  PMID: 10493923

Abstract

We identified an alternatively-spliced surfactant protein B (SP-B) mRNA from normal human lung with a 12 nt deletion at the beginning of exon 8. This deletion causes a loss of four amino acids in the SP-B precursor protein. Sequence comparison of the 3' splice sites reveals only one difference in the frequency of U/C in the 11 predominantly-pyrimidine nucleotide tract, 73% for the normal and 45% for the alternatively-spliced SP-B mRNA (77-99% for the consensus sequence). Analysis of SP-B mRNA in lung indicates that the abundance of the alternatively-spliced form is very low and varies among individuals. Although the relative abundance of the deletion form of SP-B mRNA remains constant among normal lungs, it is found with relatively higher abundance in the lungs of some individuals with diseases such as congenital alveolar proteinosis, respiratory distress syndrome, bronchopulmonary dysplasia, alveolar capillary dysplasia and hypophosphatasia. This observation points to the possibility that the alternative splicing is a potential regulatory mechanism of SP-B and may play a role in the pathogenesis of disease under certain circumstances.

Full Text

The Full Text of this article is available as a PDF (131.9 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Akinbi H. T., Breslin J. S., Ikegami M., Iwamoto H. S., Clark J. C., Whitsett J. A., Jobe A. H., Weaver T. E. Rescue of SP-B knockout mice with a truncated SP-B proprotein. Function of the C-terminal propeptide. J Biol Chem. 1997 Apr 11;272(15):9640–9647. doi: 10.1074/jbc.272.15.9640. [DOI] [PubMed] [Google Scholar]
  2. Burrows N. P., Nicholls A. C., Richards A. J., Luccarini C., Harrison J. B., Yates J. R., Pope F. M. A point mutation in an intronic branch site results in aberrant splicing of COL5A1 and in Ehlers-Danlos syndrome type II in two British families. Am J Hum Genet. 1998 Aug;63(2):390–398. doi: 10.1086/301948. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Chambliss K. L., Hinson D. D., Trettel F., Malaspina P., Novelletto A., Jakobs C., Gibson K. M. Two exon-skipping mutations as the molecular basis of succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria). Am J Hum Genet. 1998 Aug;63(2):399–408. doi: 10.1086/301964. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chi X., Garnier G., Hawgood S., Colten H. R. Identification of a novel alternatively spliced mRNA of murine pulmonary surfactant protein B. Am J Respir Cell Mol Biol. 1998 Jul;19(1):107–113. doi: 10.1165/ajrcmb.19.1.2900. [DOI] [PubMed] [Google Scholar]
  5. Clark J. C., Weaver T. E., Iwamoto H. S., Ikegami M., Jobe A. H., Hull W. M., Whitsett J. A. Decreased lung compliance and air trapping in heterozygous SP-B-deficient mice. Am J Respir Cell Mol Biol. 1997 Jan;16(1):46–52. doi: 10.1165/ajrcmb.16.1.8998078. [DOI] [PubMed] [Google Scholar]
  6. Clark J. C., Wert S. E., Bachurski C. J., Stahlman M. T., Stripp B. R., Weaver T. E., Whitsett J. A. Targeted disruption of the surfactant protein B gene disrupts surfactant homeostasis, causing respiratory failure in newborn mice. Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7794–7798. doi: 10.1073/pnas.92.17.7794. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Ferlini A., Galié N., Merlini L., Sewry C., Branzi A., Muntoni F. A novel Alu-like element rearranged in the dystrophin gene causes a splicing mutation in a family with X-linked dilated cardiomyopathy. Am J Hum Genet. 1998 Aug;63(2):436–446. doi: 10.1086/301952. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Floros J., Kala P. Surfactant proteins: molecular genetics of neonatal pulmonary diseases. Annu Rev Physiol. 1998;60:365–384. doi: 10.1146/annurev.physiol.60.1.365. [DOI] [PubMed] [Google Scholar]
  9. Floros J., Phelps D. S., Harding H. P., Church S., Ware J. Postnatal stimulation of rat surfactant protein A synthesis by dexamethasone. Am J Physiol. 1989 Aug;257(2 Pt 1):L137–L143. doi: 10.1152/ajplung.1989.257.2.L137. [DOI] [PubMed] [Google Scholar]
  10. Floros J., Steinbrink R., Jacobs K., Phelps D., Kriz R., Recny M., Sultzman L., Jones S., Taeusch H. W., Frank H. A. Isolation and characterization of cDNA clones for the 35-kDa pulmonary surfactant-associated protein. J Biol Chem. 1986 Jul 5;261(19):9029–9033. [PubMed] [Google Scholar]
  11. Gantla S., Bakker C. T., Deocharan B., Thummala N. R., Zweiner J., Sinaasappel M., Roy Chowdhury J., Bosma P. J., Roy Chowdhury N. Splice-site mutations: a novel genetic mechanism of Crigler-Najjar syndrome type 1. Am J Hum Genet. 1998 Mar;62(3):585–592. doi: 10.1086/301756. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Guttentag S. H., Beers M. F., Bieler B. M., Ballard P. L. Surfactant protein B processing in human fetal lung. Am J Physiol. 1998 Sep;275(3 Pt 1):L559–L566. doi: 10.1152/ajplung.1998.275.3.L559. [DOI] [PubMed] [Google Scholar]
  13. Harteveld K. L., Losekoot M., Fodde R., Giordano P. C., Bernini L. F. The involvement of Alu repeats in recombination events at the alpha-globin gene cluster: characterization of two alphazero-thalassaemia deletion breakpoints. Hum Genet. 1997 Apr;99(4):528–534. doi: 10.1007/s004390050401. [DOI] [PubMed] [Google Scholar]
  14. Jacobs K. A., Phelps D. S., Steinbrink R., Fisch J., Kriz R., Mitsock L., Dougherty J. P., Taeusch H. W., Floros J. Isolation of a cDNA clone encoding a high molecular weight precursor to a 6-kDa pulmonary surfactant-associated protein. J Biol Chem. 1987 Jul 15;262(20):9808–9811. [PubMed] [Google Scholar]
  15. Kala P., Ten Have T., Nielsen H., Dunn M., Floros J. Association of pulmonary surfactant protein A (SP-A) gene and respiratory distress syndrome: interaction with SP-B. Pediatr Res. 1998 Feb;43(2):169–177. doi: 10.1203/00006450-199802000-00003. [DOI] [PubMed] [Google Scholar]
  16. Karinch A. M., Floros J. Translation in vivo of 5' untranslated-region splice variants of human surfactant protein-A. Biochem J. 1995 Apr 15;307(Pt 2):327–330. doi: 10.1042/bj3070327. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Krawczak M., Reiss J., Cooper D. N. The mutational spectrum of single base-pair substitutions in mRNA splice junctions of human genes: causes and consequences. Hum Genet. 1992 Sep-Oct;90(1-2):41–54. doi: 10.1007/BF00210743. [DOI] [PubMed] [Google Scholar]
  18. Levran O., Doggett N. A., Auerbach A. D. Identification of Alu-mediated deletions in the Fanconi anemia gene FAA. Hum Mutat. 1998;12(3):145–152. doi: 10.1002/(SICI)1098-1004(1998)12:3<145::AID-HUMU2>3.0.CO;2-G. [DOI] [PubMed] [Google Scholar]
  19. Lin S., Akinbi H. T., Breslin J. S., Weaver T. E. Structural requirements for targeting of surfactant protein B (SP-B) to secretory granules in vitro and in vivo. J Biol Chem. 1996 Aug 16;271(33):19689–19695. doi: 10.1074/jbc.271.33.19689. [DOI] [PubMed] [Google Scholar]
  20. Lin Z., deMello D. E., Wallot M., Floros J. An SP-B gene mutation responsible for SP-B deficiency in fatal congenital alveolar proteinosis: evidence for a mutation hotspot in exon 4. Mol Genet Metab. 1998 May;64(1):25–35. doi: 10.1006/mgme.1998.2702. [DOI] [PubMed] [Google Scholar]
  21. Liu W., Qian C., Francke U. Silent mutation induces exon skipping of fibrillin-1 gene in Marfan syndrome. Nat Genet. 1997 Aug;16(4):328–329. doi: 10.1038/ng0897-328. [DOI] [PubMed] [Google Scholar]
  22. Nogee L. M., Garnier G., Dietz H. C., Singer L., Murphy A. M., deMello D. E., Colten H. R. A mutation in the surfactant protein B gene responsible for fatal neonatal respiratory disease in multiple kindreds. J Clin Invest. 1994 Apr;93(4):1860–1863. doi: 10.1172/JCI117173. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Padgett R. A., Grabowski P. J., Konarska M. M., Seiler S., Sharp P. A. Splicing of messenger RNA precursors. Annu Rev Biochem. 1986;55:1119–1150. doi: 10.1146/annurev.bi.55.070186.005351. [DOI] [PubMed] [Google Scholar]
  24. Pilot-Matias T. J., Kister S. E., Fox J. L., Kropp K., Glasser S. W., Whitsett J. A. Structure and organization of the gene encoding human pulmonary surfactant proteolipid SP-B. DNA. 1989 Mar;8(2):75–86. doi: 10.1089/dna.1.1989.8.75. [DOI] [PubMed] [Google Scholar]
  25. Pousi B., Hautala T., Heikkinen J., Pajunen L., Kivirikko K. I., Myllylä R. Alu-Alu recombination results in a duplication of seven exons in the lysyl hydroxylase gene in a patient with the type VI variant of Ehlers-Danlos syndrome. Am J Hum Genet. 1994 Nov;55(5):899–906. [PMC free article] [PubMed] [Google Scholar]
  26. Puget N., Torchard D., Serova-Sinilnikova O. M., Lynch H. T., Feunteun J., Lenoir G. M., Mazoyer S. A 1-kb Alu-mediated germ-line deletion removing BRCA1 exon 17. Cancer Res. 1997 Mar 1;57(5):828–831. [PubMed] [Google Scholar]
  27. Rogan P. K., Faux B. M., Schneider T. D. Information analysis of human splice site mutations. Hum Mutat. 1998;12(3):153–171. doi: 10.1002/(SICI)1098-1004(1998)12:3<153::AID-HUMU3>3.0.CO;2-I. [DOI] [PubMed] [Google Scholar]
  28. So C. W., Ma Z. G., Price C. M., Dong S., Chen S. J., Gu L. J., So C. K., Wiedemann L. M., Chan L. C. MLL self fusion mediated by Alu repeat homologous recombination and prognosis of AML-M4/M5 subtypes. Cancer Res. 1997 Jan 1;57(1):117–122. [PubMed] [Google Scholar]
  29. Vamvakopoulos N. C., Modi W. S., Floros J. Mapping the human pulmonary surfactant-associated protein B gene (SFTP3) to chromosome 2p12-->p11.2. Cytogenet Cell Genet. 1995;68(1-2):8–10. doi: 10.1159/000133878. [DOI] [PubMed] [Google Scholar]
  30. Weaver T. E. Synthesis, processing and secretion of surfactant proteins B and C. Biochim Biophys Acta. 1998 Nov 19;1408(2-3):173–179. doi: 10.1016/s0925-4439(98)00066-0. [DOI] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES