Abstract
Heterozygous SFTPC mutations have been associated with adult and pediatric interstitial lung disease (pILD). Inheritance is autosomal dominant, but de novo mutations may cause sporadic disease. SFTPC mutations have been associated with variable onset of symptoms, ranging from early infancy to late adulthood. The underlying mechanisms for this variability are unknown. Recently, mutations in ABCA3 (encoding member A3 of the adenosine triphosphate–binding cassette family of transporters) were identified as a cause of pILD. To test the hypothesis that ABCA3 mutations modify the severity of lung disease in individuals with SFTPC mutations, we sequenced ABCA3 from four symptomatic infants with the same SFTPC mutation, a substitution of isoleucine by threonine in codon 73 (I73T). Each infant developed respiratory symptoms by 2 mo of age and inherited the mutation from an asymptomatic parent. Three of the four infants were also heterozygous for an ABCA3 mutation, which was inherited from the parent without SFTPC I73T. The finding of heterozygosity for ABCA3 mutations in severely affected infants with SFTPC I73T, and independent inheritance from disease-free parents supports that ABCA3 acts as a modifier gene for the phenotype associated with an SFTPC mutation.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- ABCA3:
-
adenosine triphosphate–binding cassette protein group A3 gene
- pILD:
-
pediatric interstitial lung disease
- SFTPC:
-
surfactant protein C gene
References
Weaver TE, Conkright JJ 2001 Function of surfactant proteins B and C. Annu Rev Physiol 63: 555–578
Tredano M, Griese M, Brasch F, Schumacher S, de Blic J, Marque S, Houdayer C, Elion J, Couderc R, Bahuau M 2004 Mutation of SFTPC in infantile pulmonary alveolar proteinosis with or without fibrosing lung disease. Am J Med Genet A 126: 18–26
Nogee LM, Dunbar AE 3rd, Wert SE, Askin F, Hamvas A, Whitsett JA 2001 A mutation in the surfactant protein C gene associated with familial interstitial lung disease. N Engl J Med 344: 573–579
Amin RS, Wert SE, Baughman RP, Tomashefski JF Jr, Nogee LM, Brody AS, Hull WM, Whitsett JA 2001 Surfactant protein deficiency in familial interstitial lung disease. J Pediatr 139: 85–92
Beers MF, Mulugeta S 2005 Surfactant protein C biosynthesis and its emerging role in conformational lung disease. Annu Rev Physiol 67: 663–696
Hamvas A, Nogee LM, White FV, Schuler P, Hackett BP, Huddleston CB, Mendeloff EN, Hsu FF, Wert SE, Gonzales LW, Beers MF, Ballard PL 2004 Progressive lung disease and surfactant dysfunction with a deletion in surfactant protein C gene. Am J Respir Cell Mol Biol 30: 771–776
Thomas AQ, Lane K, Phillips J 3rd, Prince M, Markin C, Speer M, Schwartz DA, Gaddipati R, Marney A, Johnson J, Roberts R, Haines J, Stahlman M, Loyd JE 2002 Heterozygosity for a surfactant protein C gene mutation associated with usual interstitial pneumonitis and cellular nonspecific interstitial pneumonitis in one kindred. Am J Respir Crit Care Med 165: 1322–1328
Stevens PA, Pettenazzo A, Brasch F, Mulugeta S, Baritussio A, Ochs M, Morrison L, Russo SJ, Beers MF 2005 Nonspecific interstitial pneumonia, alveolar proteinosis, and abnormal proprotein trafficking resulting from a spontaneous mutation in the surfactant protein C gene. Pediatr Res 57: 89–98
Lawson WE, Grant SW, Ambrosini V, Womble KE, Dawson EP, Lane KB, Markin C, Renzoni E, Lympany P, Thomas AQ, Roldan J, Scott TA, Blackwell TS, Phillips JA 3rd, Loyd JE, du Bois RM 2004 Genetic mutations in surfactant protein C are a rare cause of sporadic cases of IPF. Thorax 59: 977–980
Cameron HS, Somaschini M, Carrera P, Hamvas A, Whitsett JA, Wert SE, Deutsch G, Nogee LM 2005 A common mutation in the surfactant protein C gene associated with lung disease. J Pediatr 146: 370–375
Brasch F, Griese M, Tredano M, Johnen G, Ochs M, Rieger C, Mulugeta S, Muller KM, Bahuau M, Beers MF 2004 Interstitial lung disease in a baby with a de novo mutation in the SFTPC gene. Eur Respir J 24: 30–39
Percopo S, Cameron HS, Nogee LM, Pettinato G, Montella S, Santamaria F 2004 Variable phenotype associated with SP-C gene mutations: fatal case with the I73T mutation. Eur Respir J 24: 1072–1073
Glasser SW, Burhans MS, Korfhagen TR, Na CL, Sly PD, Ross GF, Ikegami M, Whitsett JA 2001 Altered stability of pulmonary surfactant in SP-C-deficient mice. Proc Natl Acad Sci U S A 98: 6366–6371
Glasser SW, Detmer EA, Ikegami M, Na CL, Stahlman MT, Whitsett JA 2003 Pneumonitis and emphysema in sp-C gene targeted mice. J Biol Chem 278: 14291–14298
Connors TD, Van Raay TJ, Petry LR, Klinger KW, Landes GM, Burn TC 1997 The cloning of a human ABC gene (ABC3) mapping to chromosome 16p13.3. Genomics 39: 231–234
Yamano G, Funahashi H, Kawanami O, Zhao LX, Ban N, Uchida Y, Morohoshi T, Ogawa J, Shioda S, Inagaki N 2001 ABCA3 is a lamellar body membrane protein in human lung alveolar type II cells. FEBS Lett 508: 221–225
Mulugeta S, Gray JM, Notarfrancesco KL, Gonzales LW, Koval M, Feinstein SI, Ballard PL, Fisher AB, Shuman H 2002 Identification of LBM180, a lamellar body limiting membrane protein of alveolar type II cells, as the ABC transporter protein ABCA3. J Biol Chem 277: 22147–22155
Zen K, Notarfrancesco K, Oorschot V, Slot JW, Fisher AB, Shuman H 1998 Generation and characterization of monoclonal antibodies to alveolar type II cell lamellar body membrane. Am J Physiol 275: L172–L183
Cheong N, Madesh M, Gonzales LW, Zhao M, Yu K, Ballard PL, Shuman H 2006 Functional and trafficking defects in ATP binding cassette A3 mutants associated with respiratory distress syndrome. J Biol Chem 281: 9791–9800
Nagata K, Yamamoto A, Ban N, Tanaka AR, Matsuo M, Kioka N, Inagaki N, Ueda K 2004 Human ABCA3, a product of a responsible gene for abca3 for fatal surfactant deficiency in newborns, exhibits unique ATP hydrolysis activity and generates intracellular multilamellar vesicles. Biochem Biophys Res Commun 324: 262–268
Garmany TH, Moxley MA, White FV, Dean M, Hull WM, Whitsett JA, Nogee LM, Hamvas A 2006 Surfactant composition and function in patients with ABCA3 mutations. Pediatr Res 59: 801–805
Shulenin S, Nogee LM, Annilo T, Wert SE, Whitsett JA, Dean M 2004 ABCA3 gene mutations in newborns with fatal surfactant deficiency. N Engl J Med 350: 1296–1303
Bullard JE, Wert SE, Whitsett JA, Dean M, Nogee LM 2005 ABCA3 mutations associated with pediatric interstitial lung disease. Am J Respir Crit Care Med 172: 1026–1031
Nogee LM, Dunbar AE 3rd, Wert S, Askin F, Hamvas A, Whitsett JA 2002 Mutations in the surfactant protein C gene associated with interstitial lung disease. Chest 121: 20S–21S
Warr RG, Hawgood S, Buckley DI, Crisp TM, Schilling J, Benson BJ, Ballard PL, Clements JA, White RT 1987 Low molecular weight human pulmonary surfactant protein (SP5): isolation, characterization, and cDNA and amino acid sequences. Proc Natl Acad Sci U S A 84: 7915–7919
Chui DH, Dover GJ 2001 Sickle cell disease: no longer a single gene disorder. Curr Opin Pediatr 13: 22–27
Bridges JP, Xu Y, Na CL, Wong HR, Weaver TE 2006 Adaptation and increased susceptibility to infection associated with constitutive expression of misfolded SP-C. J Cell Biol 172: 395–407
Conkright JJ, Bridges JP, Na CL, Voorhout WF, Trapnell B, Glasser SW, Weaver TE 2001 Secretion of surfactant protein C, an integral membrane protein, requires the N-terminal propeptide. J Biol Chem 276: 14658–14664
Bridges JP, Wert SE, Nogee LM, Weaver TE 2003 Expression of a human surfactant protein C mutation associated with interstitial lung disease disrupts lung development in transgenic mice. J Biol Chem 278: 52739–52746
Nogee LM 2002 Abnormal expression of surfactant protein C and lung disease. Am J Respir Cell Mol Biol 26: 641–644
Brasch F, Schimanski S, Muhlfeld C, Barlage S, Langmann T, Aslanidis C, Boettcher A, Dada A, Schroten H, Mildenberger E, Prueter E, Ballmann M, Ochs M, Johnen G, Griese M, Schmitz G 2006 Alteration of the pulmonary surfactant system in full-term infants with hereditary ABCA3 deficiency. Am J Respir Crit Care Med 174: 571–580
Beers MF, Lomax CA, Russo SJ 1998 Synthetic processing of surfactant protein C by alveolar epithelial cells. The COOH terminus of proSP-C is required for post-translational targeting and proteolysis. J Biol Chem 273: 15287–15293
Kabore AF, Wang WJ, Russo SJ, Beers MF 2001 Biosynthesis of surfactant protein C: characterization of aggresome formation by EGFP chimeras containing propeptide mutants lacking conserved cysteine residues. J Cell Sci 114: 293–302
Mulugeta S, Nguyen V, Russo SJ, Muniswamy M, Beers MF 2005 A surfactant protein C precursor protein BRICHOS domain mutation causes endoplasmic reticulum stress, proteasome dysfunction, and caspase 3 activation. Am J Respir Cell Mol Biol 32: 521–530
Author information
Authors and Affiliations
Corresponding author
Additional information
Supported by the National Institutes of Health (HL-54703 to L.M.N.) and the Eudowood Foundation.
Rights and permissions
About this article
Cite this article
Bullard, J., Nogee, L. Heterozygosity for ABCA3 Mutations Modifies the Severity of Lung Disease Associated with a Surfactant Protein C Gene (SFTPC) Mutation. Pediatr Res 62, 176–179 (2007). https://doi.org/10.1203/PDR.0b013e3180a72588
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1203/PDR.0b013e3180a72588
This article is cited by
-
Correlating SFTPC gene variants to interstitial lung disease in Egyptian children
Journal of Genetic Engineering and Biotechnology (2022)
-
Child Interstitial Lung Disease in an Infant with Surfactant Protein C Dysfunction due to c.202G>T Variant (p.V68F)
Lung (2022)
-
Surfactant protein disorders in childhood interstitial lung disease
European Journal of Pediatrics (2021)
-
Clinical and genetic spectrum of interstitial lung disease in Chinese children associated with surfactant protein C mutations
Italian Journal of Pediatrics (2019)
-
The biology of the ABCA3 lipid transporter in lung health and disease
Cell and Tissue Research (2017)
