An Intronic ABCA3 Mutation That is Responsible for Respiratory Disease

Overview

Journal Pediatr Res

Specialties Biology
Pediatrics

Date 2012 Feb 17

PMID 22337229

Citations 28

Authors

Amit Agrawal

Aaron Hamvas

F Sessions Cole

Jennifer A Wambach

Daniel Wegner

Carl Coghill

Keith Harrison

Lawrence M Nogee

Affiliations

Soon will be listed here.

Abstract

Introduction: Member A3 of the ATP-binding cassette family of transporters (ABCA3) is essential for surfactant metabolism. Nonsense, missense, frameshift, and splice-site mutations in the ABCA3 gene (ABCA3) have been reported as causes of neonatal respiratory failure (NRF) and interstitial lung disease. We tested the hypothesis that mutations in noncoding regions of ABCA3 may cause lung disease.

Methods: ABCA3-specific cDNA was generated and sequenced from frozen lung tissue from a child with fatal lung disease with only one identified ABCA3 mutation. ABCA3 was sequenced from genomic DNA prepared from blood samples obtained from the proband, parents, and other children with NRF.

Results: ABCA3 cDNA from the proband contained sequences derived from intron 25 that would be predicted to alter the structure and function of the ABCA3 protein. Genomic DNA sequencing revealed a heterozygous C>T transition in intron 25 trans to the known mutation, creating a new donor splice site. Seven additional infants with an ABCA3-deficient phenotype and inconclusive genetic findings had this same variant, which was not found in 2,132 control chromosomes.

Discussion: These findings support that this variant is a disease-causing mutation that may account for additional cases of ABCA3 deficiency with negative genetic studies.

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References

Garmany T, Moxley M, White F, Dean M, Hull W, Whitsett J . Surfactant composition and function in patients with ABCA3 mutations. Pediatr Res. 2006; 59(6):801-5. DOI: 10.1203/01.pdr.0000219311.14291.df. View

Bullard J, Wert S, Whitsett J, Dean M, Nogee L . ABCA3 mutations associated with pediatric interstitial lung disease. Am J Respir Crit Care Med. 2005; 172(8):1026-31. PMC: 1403838. DOI: 10.1164/rccm.200503-504OC. View

Costantino L, Claut L, Paracchini V, Coviello D, Colombo C, Porcaro L . A novel donor splice site characterized by CFTR mRNA analysis induces a new pseudo-exon in CF patients. J Cyst Fibros. 2010; 9(6):411-8. DOI: 10.1016/j.jcf.2010.08.009. View

Gower W, Wert S, Ginsberg J, Golan A, Whitsett J, Nogee L . Fatal familial lung disease caused by ABCA3 deficiency without identified ABCA3 mutations. J Pediatr. 2010; 157(1):62-8. DOI: 10.1016/j.jpeds.2010.01.010. View

Stahlman M, Besnard V, Wert S, Weaver T, Dingle S, Xu Y . Expression of ABCA3 in developing lung and other tissues. J Histochem Cytochem. 2006; 55(1):71-83. DOI: 10.1369/jhc.6A6962.2006. View

Somaschini M, Nogee L, Sassi I, Danhaive O, Presi S, Boldrini R . Unexplained neonatal respiratory distress due to congenital surfactant deficiency. J Pediatr. 2007; 150(6):649-53, 653.e1. DOI: 10.1016/j.jpeds.2007.03.008. View

Hamvas A, Nogee L, Wegner D, DePass K, Christodoulou J, Bennetts B . Inherited surfactant deficiency caused by uniparental disomy of rare mutations in the surfactant protein-B and ATP binding cassette, subfamily a, member 3 genes. J Pediatr. 2009; 155(6):854-859.e1. PMC: 2794197. DOI: 10.1016/j.jpeds.2009.06.006. View

Mulugeta S, Gray J, Notarfrancesco K, Gonzales L, Koval M, Feinstein S . Identification of LBM180, a lamellar body limiting membrane protein of alveolar type II cells, as the ABC transporter protein ABCA3. J Biol Chem. 2002; 277(25):22147-55. DOI: 10.1074/jbc.M201812200. View

Batenburg J . Surfactant phospholipids: synthesis and storage. Am J Physiol. 1992; 262(4 Pt 1):L367-85. DOI: 10.1152/ajplung.1992.262.4.L367. View

10.

Nogee L, Dunbar 3rd A, Wert S, Askin F, Hamvas A, Whitsett J . A mutation in the surfactant protein C gene associated with familial interstitial lung disease. N Engl J Med. 2001; 344(8):573-9. DOI: 10.1056/NEJM200102223440805. View

11.

Nogee L, Wert S, Proffit S, HULL W, Whitsett J . Allelic heterogeneity in hereditary surfactant protein B (SP-B) deficiency. Am J Respir Crit Care Med. 2000; 161(3 Pt 1):973-81. DOI: 10.1164/ajrccm.161.3.9903153. View

12.

Matsumura Y, Ban N, Inagaki N . Aberrant catalytic cycle and impaired lipid transport into intracellular vesicles in ABCA3 mutants associated with nonfatal pediatric interstitial lung disease. Am J Physiol Lung Cell Mol Physiol. 2008; 295(4):L698-707. DOI: 10.1152/ajplung.90352.2008. View

13.

Yamano G, Funahashi H, Kawanami O, Zhao L, Ban N, Uchida Y . ABCA3 is a lamellar body membrane protein in human lung alveolar type II cells. FEBS Lett. 2001; 508(2):221-5. DOI: 10.1016/s0014-5793(01)03056-3. View

14.

Langston C, Patterson K, Dishop M, Askin F, Baker P, Chou P . A protocol for the handling of tissue obtained by operative lung biopsy: recommendations of the chILD pathology co-operative group. Pediatr Dev Pathol. 2006; 9(3):173-80. DOI: 10.2350/06-03-0065.1. View

15.

Lin Z, Wang G, deMello D, Floros J . An alternatively spliced surfactant protein B mRNA in normal human lung: disease implication. Biochem J. 1999; 343 Pt 1:145-9. PMC: 1220535. View

16.

Brasch F, Schimanski S, Muhlfeld C, Barlage S, Langmann T, Aslanidis C . Alteration of the pulmonary surfactant system in full-term infants with hereditary ABCA3 deficiency. Am J Respir Crit Care Med. 2006; 174(5):571-80. DOI: 10.1164/rccm.200509-1535OC. View

17.

Nagata K, Yamamoto A, Ban N, Tanaka A, Matsuo M, Kioka N . 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. 2004; 324(1):262-8. DOI: 10.1016/j.bbrc.2004.09.043. View

18.

Nogee L, de Mello D, Dehner L, Colten H . Brief report: deficiency of pulmonary surfactant protein B in congenital alveolar proteinosis. N Engl J Med. 1993; 328(6):406-10. DOI: 10.1056/NEJM199302113280606. View

19.

Ban N, Matsumura Y, Sakai H, Takanezawa Y, Sasaki M, Arai H . ABCA3 as a lipid transporter in pulmonary surfactant biogenesis. J Biol Chem. 2007; 282(13):9628-9634. DOI: 10.1074/jbc.M611767200. View

20.

Nogee L, Garnier G, Dietz H, Singer L, Murphy A, deMello D . A mutation in the surfactant protein B gene responsible for fatal neonatal respiratory disease in multiple kindreds. J Clin Invest. 1994; 93(4):1860-3. PMC: 294267. DOI: 10.1172/JCI117173. View