ABCMdb

ABCA3 p.Ser1262Gly

Predicted by SNAP2:	A: N (72%), C: N (61%), D: N (57%), E: N (72%), F: D (59%), G: D (66%), H: N (72%), I: N (61%), K: N (78%), L: D (53%), M: D (66%), N: N (82%), P: N (57%), Q: N (66%), R: N (72%), T: N (53%), V: N (57%), W: D (80%), Y: N (53%),
Predicted by PROVEAN:	A: N, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, T: N, V: D, W: D, Y: D,

[switch to compact view]
Comments [show]

None has been submitted yet.

Publications
[hide] Heterozygosity for E292V in ABCA3, lung function a... Respir Res. 2012 Aug 6;13(1):67. Baekvad-Hansen M, Nordestgaard BG, Dahl M
Heterozygosity for E292V in ABCA3, lung function and COPD in 64,000 individuals.
Respir Res. 2012 Aug 6;13(1):67., [PMID:22866751]

Abstract [show]
ABSTRACT: BACKGROUND: Mutations in ATP-binding-cassette-member A3 (ABCA3) are related to severe chronic lung disease in neonates and children, but frequency of chronic lung disease due to ABCA3 mutations in the general population is unknown. We tested the hypothesis that individuals heterozygous for ABCA3 mutations have reduced lung function and increased risk of COPD in the general population. METHODS: We screened 760 individuals with extreme pulmonary phenotypes and identified three novel (H86Y, A320T, A1086D) and four previously described mutations (E292V, P766S, S1262G, R1474W) in the ABCA3 gene. We genotyped the entire Copenhagen City Heart study (n=10,604) to assess the clinical importance of these mutations. To validate our findings we genotyped an additional 54,395 individuals from the Copenhagen General Population Study. RESULTS: In the Copenhagen City Heart Study individuals heterozygous for E292V had 5% reduced FEV1 % predicted compared with noncarriers (t-test: p=0.008), and an increased odds ratio for COPD of 1.9 (95% CI: 1.1-3.1). In contrast, the A1086D mutation was associated with increased FEV1 % predicted (p=0.03). None of the other ABCA3 mutations associated with lung function or COPD risk in the Copenhagen City Heart Study. In the larger Copenhagen General Population Study, and in the two studies combined, E292V heterozygotes did not have reduced lung function or increased risk of COPD (p=0.11-0.98), while this was the case for the positive controls, surfactant protein-B 121ins2 heterozygotes and alpha1-antitrypsin ZZ homozygotes. CONCLUSION: Our results indicate that partially reduced ABCA3 activity due to E292V is not a major risk factor for reduced lung function and COPD in the general population. This is an important finding as 1.3% in the Danish population has partially reduced ABCA3 function due to E292V.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
2 Heterozygosity for E292V in ABCA3, lung function and COPD in 64,000 individuals Respiratory Research 2012, 13:67 doi:10.1186/1465-9921-13-67 Marie Bækvad-Hansen (baekvad@gmail.com}) Børge G Nordestgaard (brno@heh.regionh.dk}) Morten Dahl (dahlos2003@yahoo.dk}) ISSN 1465-9921 Article type Research Submission date 23 March 2012 Acceptance date 27 July 2012 Publication date 6 August 2012 Article URL http://respiratory-research.com/content/13/1/67 This peer-reviewed article was published immediately upon acceptance. Login to comment
10 Methods We screened 760 individuals with extreme pulmonary phenotypes and identified three novel (H86Y, A320T, A1086D) and four previously described mutations (E292V, P766S, S1262G, R1474W) in the ABCA3 gene. Login to comment
77 H86Y, A320T and A1086D were novel variants, whereas E292V, P766S, S1262G and R1474W have been described previously. Login to comment
88 The observed reductions in pulmonary function were almost similar in absolute numbers to those observed for surfactant protein-B 121ins2, a mutation which in the homozygous state associates with a phenotype somewhat similar to that for E292V compound heterozygosity. Login to comment
96 Individuals heterozygous for H86Y, A320T, P766S, S1262G, or R1474W did not differ from wildtypes in FEV1%predicted, FVC%predicted or FEV1/FVC (p≥0.19). Login to comment
98 This individual was compound heterozygous for P766S and S1262G and was not identified among the extreme phenotypes group. Login to comment
105 Due to lack of events among A320T, A1086D and S1262G heterozygotes, we were not able to calculate risk of COPD for these variants. Login to comment
126 Figure 3 Lung function according to ATP binding cassette member 3 (ABCA3) E292V, surfactant protein-B 121ins2, and α1-antitrypsin ZZ genotypes in the Copenhagen City Heart Study and Copenhagen General Population Study combined, stratified for smoking status. Login to comment
135 Numbers of individuals with surfactant protein-B 121ins2 heterozygosity and α1-antitrypsin ZZ homozygosity differ slightly from the number of individuals with an ABCA3 E292V genotype due to different number of study subjects available for analysis within the study period Discussion To test whether individuals heterozygous for ABCA3 variants have reduced lung function and increased risk of COPD in the general population, we screened 760 individuals with extreme lung phenotypes for genetic variations in the ABCA3 gene and identified three novel (H86Y, A320T, A1086D) and four previously described variations (E292V, P766S, S1262G, R1474W). Login to comment
71 H86Y, A320T and A1086D were novel variants, whereas E292V, P766S, S1262G and R1474W have been described previously. Login to comment
90 This individual was compound heterozygous for P766S and S1262G and was not identified among the extreme phenotypes group. Login to comment
97 Due to lack of events among A320T, A1086D and S1262G heterozygotes, we were not able to calculate risk of COPD for these variants. Login to comment
102 Characteristics did not differ between E292V heterozygotes 60 80 100 120 60 80 100 120 0.6 0.8 Genotype N FEV1 % predicted p FVC % predicted p FEV1/FVC p H86Y Wt 9801 Het 15 0.76 0.91 0.39 E292V Wt 9706 Het 110 0.008 0.04 0.03 A320T Wt 9803 Het 13 0.19 0.27 0.74 P766S Wt 9695 Het 121 0.65 0.42 0.55 A1086D Wt 9802 Het 4 0.03 0.008 0.51 S1262G Wt 9802 Het 14 0.47 0.77 0.53 R1474W Wt 9636 Het 180 0.49 0.20 0.48 SP-B121ins2 Wt 10425 Het 21 0.67 0.68 0.10 b1;1-antitrypsin MM 8082 ZZ 6 0.01 0.55 0.0008 Figure 1 Lung function according to ATP binding cassette member 3 (ABCA3) genotype in the Copenhagen City Heart Study. Login to comment

[hide] Surfactant protein C mutations are the basis of a ... Am J Respir Crit Care Med. 2010 Dec 1;182(11):1419-25. Epub 2010 Jul 23. van Moorsel CH, van Oosterhout MF, Barlo NP, de Jong PA, van der Vis JJ, Ruven HJ, van Es HW, van den Bosch JM, Grutters JC
Surfactant protein C mutations are the basis of a significant portion of adult familial pulmonary fibrosis in a dutch cohort.
Am J Respir Crit Care Med. 2010 Dec 1;182(11):1419-25. Epub 2010 Jul 23., [PMID:20656946]

Abstract [show]
RATIONALE: Familial clustering of adult idiopathic interstitial pneumonias (IIP) suggests that genetic factors might play an important role in disease development. Mutations in the gene encoding surfactant protein C (SFTPC) have been found in children and families with idiopathic pneumonias, whereas cocarriage of a mutation in ATP-binding cassette subfamily A member 3 (ABCA3) was postulated to have a disease-modifying effect. OBJECTIVES: To investigate the contribution of SFTPC mutations to adult familial pulmonary fibrosis (FPF) and the disease-modifying effect of mutations in ABCA3 within their families. METHODS: Twenty-two unrelated patients with FPF (10%) were identified within our single-center cohort of 229 patients with IIP. SFTPC was sequenced in 20 patients with FPF and 20 patients with sporadic IIP. In patients with an SFTPC mutation, sequencing of ABCA3 was performed. Discovered variants were typed in more than 100 control subjects and 121 additional patients with sporadic IIP. MEASUREMENTS AND MAIN RESULTS: In 5/20 unrelated patients with FPF (25%; confidence interval, 10-49) a mutation in SFTPC was detected: M71V, IVS4+2, and three times I73T. No mutations were detected in the sporadic or control cohort. Patients with SFTPC mutations presented with a histopathological pattern of usual interstitial pneumonia and nodular septa thickening and multiple lung cysts in combination with ground glass or diffuse lung involvement on chest high-resolution computed tomography. Two variants in ABCA3 were found in adult patients with FPF but not in affected children. CONCLUSIONS: Mutations in SFTPC are a frequent cause of FPF in adult patients in our cohort. Nonclassifiable radiological patterns with cystic changes and histopathological patterns of usual interstitial pneumonia are characteristics of adult SFTPC mutation carriers.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
56 Mutations SFTPC I73T and ABCA3 S1262G were genotyped with an Illumina GoldenGate bead single-nucleotide polymorphism assay (Illumina Inc., San Diego, CA). Login to comment
57 Variations SFTPC M71V, SFTPC IVS412, and ABCA3 R288K were analyzed with high-resolution melting analysis (ABI Fast 7500RT; Applied Biosystems, Foster City, CA). Login to comment
79 ABCA3 Mutation Analysis Sequencing of exonic ABCA3 gene regions in patients with FPF with SFTPC mutations revealed two amino acid substitutions: S1262G and R288K (Table 3, Figure 2). Login to comment
80 In the kindred of FPF9, S1262G did not segregate with disease but was inherited from her healthy father. Login to comment
81 ABCA3-R288K was found in FPF20, whereas a third ABCA3 variant, R280H, was found in one patient with sporadic disease. Login to comment
154 NEWLY IDENTIFIED VARIANTS IN SURFACTANT PROTEIN C AND ATP-BINDING CASSETTE SUBFAMILY A MEMBER 3 Allele Frequency Gene cDNA Position Variant Name Consequence FPF sp.IIP Control Subjects SFTPC c.211 A.G M71V Nonsynonymous FPF7 0 0 c.218 T.C I73T Nonsynonymous FPF9, FPF18, FPF20 0 0 c.43512 T.C IVS412 Splice site FPF10 0 0 ABCA3 c.839G.A R280H Nonsynonymous - 0.004 0.015 c.863G.A R288K Nonsynonymous FPF20 0 0.015 c.3784 A.G S1262G Nonsynonymous FPF9 0 0.005 Definition of abbreviations: ABCA3 5 gene encoding ATP-binding cassette subfamily A member 3; SFTPC 5 gene encoding surfactant protein C; sp.IIP 5 sporadic idiopathic interstitial pneumonia. Login to comment
156 SFTPC I73T and ABCA3 S1262G were genotyped in 511 healthy control subjects. Login to comment
155 NEWLY IDENTIFIED VARIANTS IN SURFACTANT PROTEIN C AND ATP-BINDING CASSETTE SUBFAMILY A MEMBER 3 Allele Frequency Gene cDNA Position Variant Name Consequence FPF sp.IIP Control Subjects SFTPC c.211 A.G M71V Nonsynonymous FPF7 0 0 c.218 T.C I73T Nonsynonymous FPF9, FPF18, FPF20 0 0 c.43512 T.C IVS412 Splice site FPF10 0 0 ABCA3 c.839G.A R280H Nonsynonymous - 0.004 0.015 c.863G.A R288K Nonsynonymous FPF20 0 0.015 c.3784 A.G S1262G Nonsynonymous FPF9 0 0.005 Definition of abbreviations: ABCA3 5 gene encoding ATP-binding cassette subfamily A member 3; SFTPC 5 gene encoding surfactant protein C; sp.IIP 5 sporadic idiopathic interstitial pneumonia. Login to comment
157 SFTPC I73T and ABCA3 S1262G were genotyped in 511 healthy control subjects. Login to comment