Abstract
Human pulmonary surfactant protein A (SP-A) is encoded by two genes, SP-A1 and SP-A2, that exhibit coding sequence (allelic) and 5' splicing variability. In this report we determine the effect of the genetic variability within the SP-A1 and SP-A2 genes on the level of SP-A mRNAs and on the SP-A2 splicing variants in different individuals. We analysed mRNA specimens from 23 unrelated adults using genotype analysis, Northern analysis and primer extension, and made the following observations. (1) The level of SP-A mRNA varies among individuals (coefficient of variation = 0.49). One SP-A genotype (6A(2)6A(2)1A(0)1A0) appears to be associated with a low to moderate level of SP-A mRNA. (2) The SP-A1/SP-A2 mRNA ratio varies among individuals, from 0.94 (lowest) to 6.80 (highest) within the study population. One genotype appears to be associated with a moderate to high SP-A1/SP-A2 mRNA ratio and another with a low to moderate ratio. (3) There is no correlation between the level of SP-A mRNA and the SP-A1/SP-A2 mRNA ratio. (4) Variability in the ratio of the major SP-A2 splice variants among individuals results from nucleotide differences in the splice-recognition sequence of specific SP-A2 alleles. The SP-A mRNA levels, the SP-A1/SP-A2 mRNA ratio, and the ratio of the major SP-A2 splice variants have a genetic basis in that they vary depending upon the specific SP-A alleles present.
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- Ballard P. L., Hawgood S., Liley H., Wellenstein G., Gonzales L. W., Benson B., Cordell B., White R. T. Regulation of pulmonary surfactant apoprotein SP 28-36 gene in fetal human lung. Proc Natl Acad Sci U S A. 1986 Dec;83(24):9527–9531. doi: 10.1073/pnas.83.24.9527. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ballard P. L., Liley H. G., Gonzales L. W., Odom M. W., Ammann A. J., Benson B., White R. T., Williams M. C. Interferon-gamma and synthesis of surfactant components by cultured human fetal lung. Am J Respir Cell Mol Biol. 1990 Feb;2(2):137–143. doi: 10.1165/ajrcmb/2.2.137. [DOI] [PubMed] [Google Scholar]
- Boggaram V., Smith M. E., Mendelson C. R. Regulation of expression of the gene encoding the major surfactant protein (SP-A) in human fetal lung in vitro. Disparate effects of glucocorticoids on transcription and on mRNA stability. J Biol Chem. 1989 Jul 5;264(19):11421–11427. [PubMed] [Google Scholar]
- Dekowski S. A., Snyder J. M. Insulin regulation of messenger ribonucleic acid for the surfactant-associated proteins in human fetal lung in vitro. Endocrinology. 1992 Aug;131(2):669–676. doi: 10.1210/endo.131.2.1639013. [DOI] [PubMed] [Google Scholar]
- Dobbs L. G., Wright J. R., Hawgood S., Gonzalez R., Venstrom K., Nellenbogen J. Pulmonary surfactant and its components inhibit secretion of phosphatidylcholine from cultured rat alveolar type II cells. Proc Natl Acad Sci U S A. 1987 Feb;84(4):1010–1014. doi: 10.1073/pnas.84.4.1010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Floros J., DiAngelo S., Koptides M., Karinch A. M., Rogan P. K., Nielsen H., Spragg R. G., Watterberg K., Deiter G. Human SP-A locus: allele frequencies and linkage disequilibrium between the two surfactant protein A genes. Am J Respir Cell Mol Biol. 1996 Oct;15(4):489–498. doi: 10.1165/ajrcmb.15.4.8879183. [DOI] [PubMed] [Google Scholar]
- Floros J., Karinch A. M. Human SP-A: then and now. Am J Physiol. 1995 Feb;268(2 Pt 1):L162–L165. doi: 10.1152/ajplung.1995.268.2.L162. [DOI] [PubMed] [Google Scholar]
- 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]
- Floros J., Phelps D. S., deMello D. E., Longmate J., Harding H., Benson B., White T. The utility of postmortem lung for RNA studies; variability and correlation of the expression of surfactant proteins in human lung. Exp Lung Res. 1991 Jan-Feb;17(1):91–104. doi: 10.3109/01902149109063284. [DOI] [PubMed] [Google Scholar]
- 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]
- Gregory T. J., Longmore W. J., Moxley M. A., Whitsett J. A., Reed C. R., Fowler A. A., 3rd, Hudson L. D., Maunder R. J., Crim C., Hyers T. M. Surfactant chemical composition and biophysical activity in acute respiratory distress syndrome. J Clin Invest. 1991 Dec;88(6):1976–1981. doi: 10.1172/JCI115523. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hallman M., Merritt T. A., Akino T., Bry K. Surfactant protein A, phosphatidylcholine, and surfactant inhibitors in epithelial lining fluid. Correlation with surface activity, severity of respiratory distress syndrome, and outcome in small premature infants. Am Rev Respir Dis. 1991 Dec;144(6):1376–1384. doi: 10.1164/ajrccm/144.6.1376. [DOI] [PubMed] [Google Scholar]
- Hamm H., Lührs J., Guzman y Rotaeche J., Costabel U., Fabel H., Bartsch W. Elevated surfactant protein A in bronchoalveolar lavage fluids from sarcoidosis and hypersensitivity pneumonitis patients. Chest. 1994 Dec;106(6):1766–1770. doi: 10.1378/chest.106.6.1766. [DOI] [PubMed] [Google Scholar]
- Hatzis D., Deiter G., deMello D. E., Floros J. Human surfactant protein-C: genetic homogeneity and expression in RDS; comparison with other species. Exp Lung Res. 1994 Jan-Feb;20(1):57–72. doi: 10.3109/01902149409064373. [DOI] [PubMed] [Google Scholar]
- Honda Y., Takahashi H., Shijubo N., Kuroki Y., Akino T. Surfactant protein-A concentration in bronchoalveolar lavage fluids of patients with pulmonary alveolar proteinosis. Chest. 1993 Feb;103(2):496–499. doi: 10.1378/chest.103.2.496. [DOI] [PubMed] [Google Scholar]
- Karinch A. M., Floros J. 5' splicing and allelic variants of the human pulmonary surfactant protein A genes. Am J Respir Cell Mol Biol. 1995 Jan;12(1):77–88. doi: 10.1165/ajrcmb.12.1.7811473. [DOI] [PubMed] [Google Scholar]
- 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]
- Katyal S. L., Singh G., Locker J. Characterization of a second human pulmonary surfactant-associated protein SP-A gene. Am J Respir Cell Mol Biol. 1992 Apr;6(4):446–452. doi: 10.1165/ajrcmb/6.4.446. [DOI] [PubMed] [Google Scholar]
- King R. J., Simon D., Horowitz P. M. Aspects of secondary and quaternary structure of surfactant protein A from canine lung. Biochim Biophys Acta. 1989 Feb 20;1001(3):294–301. doi: 10.1016/0005-2760(89)90114-8. [DOI] [PubMed] [Google Scholar]
- Krizkova L., Sakthivel R., Olowe S. A., Rogan P. K., Floros J. Human SP-A: genotype and single-strand conformation polymorphism analysis. Am J Physiol. 1994 May;266(5 Pt 1):L519–L527. doi: 10.1152/ajplung.1994.266.5.L519. [DOI] [PubMed] [Google Scholar]
- Liley H. G., White R. T., Benson B. J., Ballard P. L. Glucocorticoids both stimulate and inhibit production of pulmonary surfactant protein A in fetal human lung. Proc Natl Acad Sci U S A. 1988 Dec;85(23):9096–9100. doi: 10.1073/pnas.85.23.9096. [DOI] [PMC free article] [PubMed] [Google Scholar]
- McCormack F. X., King T. E., Jr, Voelker D. R., Robinson P. C., Mason R. J. Idiopathic pulmonary fibrosis. Abnormalities in the bronchoalveolar lavage content of surfactant protein A. Am Rev Respir Dis. 1991 Jul;144(1):160–166. doi: 10.1164/ajrccm/144.1.160. [DOI] [PubMed] [Google Scholar]
- McCormick S. M., Boggaram V., Mendelson C. R. Characterization of mRNA transcripts and organization of human SP-A1 and SP-A2 genes. Am J Physiol. 1994 Apr;266(4 Pt 1):L354–L366. doi: 10.1152/ajplung.1994.266.4.L354. [DOI] [PubMed] [Google Scholar]
- McCormick S. M., Mendelson C. R. Human SP-A1 and SP-A2 genes are differentially regulated during development and by cAMP and glucocorticoids. Am J Physiol. 1994 Apr;266(4 Pt 1):L367–L374. doi: 10.1152/ajplung.1994.266.4.L367. [DOI] [PubMed] [Google Scholar]
- Metzler M. D., Snyder J. M. Retinoic acid differentially regulates expression of surfactant-associated proteins in human fetal lung. Endocrinology. 1993 Nov;133(5):1990–1998. doi: 10.1210/endo.133.5.8404646. [DOI] [PubMed] [Google Scholar]
- Odom M. J., Snyder J. M., Mendelson C. R. Adenosine 3',5'-monophosphate analogs and beta-adrenergic agonists induce the synthesis of the major surfactant apoprotein in human fetal lung in vitro. Endocrinology. 1987 Sep;121(3):1155–1163. doi: 10.1210/endo-121-3-1155. [DOI] [PubMed] [Google Scholar]
- 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]
- Pryhuber G. S., O'Reilly M. A., Clark J. C., Hull W. M., Fink I., Whitsett J. A. Phorbol ester inhibits surfactant protein SP-A and SP-B expression. J Biol Chem. 1990 Dec 5;265(34):20822–20828. [PubMed] [Google Scholar]
- Rishi A., Hatzis D., McAlmon K., Floros J. An allelic variant of the 6A gene for human surfactant protein A. Am J Physiol. 1992 May;262(5 Pt 1):L566–L573. doi: 10.1152/ajplung.1992.262.5.L566. [DOI] [PubMed] [Google Scholar]
- Romeo G., McKusick V. A. Phenotypic diversity, allelic series and modifier genes. Nat Genet. 1994 Aug;7(4):451–453. doi: 10.1038/ng0894-451. [DOI] [PubMed] [Google Scholar]
- Suzuki Y., Fujita Y., Kogishi K. Reconstitution of tubular myelin from synthetic lipids and proteins associated with pig pulmonary surfactant. Am Rev Respir Dis. 1989 Jul;140(1):75–81. doi: 10.1164/ajrccm/140.1.75. [DOI] [PubMed] [Google Scholar]
- Voss T., Eistetter H., Schäfer K. P., Engel J. Macromolecular organization of natural and recombinant lung surfactant protein SP 28-36. Structural homology with the complement factor C1q. J Mol Biol. 1988 May 5;201(1):219–227. doi: 10.1016/0022-2836(88)90448-2. [DOI] [PubMed] [Google Scholar]
- Voss T., Melchers K., Scheirle G., Schäfer K. P. Structural comparison of recombinant pulmonary surfactant protein SP-A derived from two human coding sequences: implications for the chain composition of natural human SP-A. Am J Respir Cell Mol Biol. 1991 Jan;4(1):88–94. doi: 10.1165/ajrcmb/4.1.88. [DOI] [PubMed] [Google Scholar]
- Weaver T. E., Whitsett J. A. Function and regulation of expression of pulmonary surfactant-associated proteins. Biochem J. 1991 Jan 15;273(Pt 2):249–264. doi: 10.1042/bj2730249. [DOI] [PMC free article] [PubMed] [Google Scholar]
- White R. T., Damm D., Miller J., Spratt K., Schilling J., Hawgood S., Benson B., Cordell B. Isolation and characterization of the human pulmonary surfactant apoprotein gene. 1985 Sep 26-Oct 2Nature. 317(6035):361–363. doi: 10.1038/317361a0. [DOI] [PubMed] [Google Scholar]
- Whitsett J. A., Weaver T. E., Lieberman M. A., Clark J. C., Daugherty C. Differential effects of epidermal growth factor and transforming growth factor-beta on synthesis of Mr = 35,000 surfactant-associated protein in fetal lung. J Biol Chem. 1987 Jun 5;262(16):7908–7913. [PubMed] [Google Scholar]
- Williams M. C., Hawgood S., Hamilton R. L. Changes in lipid structure produced by surfactant proteins SP-A, SP-B, and SP-C. Am J Respir Cell Mol Biol. 1991 Jul;5(1):41–50. doi: 10.1165/ajrcmb/5.1.41. [DOI] [PubMed] [Google Scholar]
- deMello D. E., Heyman S., Phelps D. S., Floros J. Immunogold localization of SP-A in lungs of infants dying from respiratory distress syndrome. Am J Pathol. 1993 May;142(5):1631–1640. [PMC free article] [PubMed] [Google Scholar]
- deMello D. E., Phelps D. S., Patel G., Floros J., Lagunoff D. Expression of the 35kDa and low molecular weight surfactant-associated proteins in the lungs of infants dying with respiratory distress syndrome. Am J Pathol. 1989 Jun;134(6):1285–1293. [PMC free article] [PubMed] [Google Scholar]