ABCA3 p.Glu292Lys
| ClinVar: |
c.875A>T
,
p.Glu292Val
D
, Likely pathogenic
|
| Predicted by SNAP2: | A: N (61%), C: N (61%), D: N (72%), F: N (57%), G: N (57%), H: N (61%), I: N (61%), K: D (85%), L: N (57%), M: N (61%), N: N (66%), P: N (61%), Q: N (66%), R: N (57%), S: N (66%), T: N (72%), V: D (66%), W: D (63%), Y: N (61%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Aberrant catalytic cycle and impaired lipid transp... Am J Physiol Lung Cell Mol Physiol. 2008 Oct;295(4):L698-707. Epub 2008 Aug 1. 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 Oct;295(4):L698-707. Epub 2008 Aug 1., [PMID:18676873]
Abstract [show]
The ATP-binding cassette transporter ABCA3 mediates uptake of choline-phospholipids into intracellular vesicles and is essential for surfactant metabolism in lung alveolar type II cells. We have shown previously that ABCA3 mutations in fatal surfactant deficiency impair intracellular localization or ATP hydrolysis of ABCA3 protein. However, the mechanisms underlying the less severe phenotype of patients with ABCA3 mutation are unclear. In this study, we characterized ABCA3 mutant proteins identified in pediatric interstitial lung disease (pILD). E292V (intracellular loop 1), E690K (adjacent to Walker B motif in nucleotide binding domain 1), and T1114M (8th putative transmembrane segment) mutant proteins are localized mainly in intracellular vesicle membranes as wild-type protein. Lipid analysis and sucrose gradient fractionation revealed that the transport function of E292V mutant protein is moderately preserved, whereas those of E690K and T1114M mutant proteins are severely impaired. Vanadate-induced nucleotide trapping and photoaffinity labeling of wild-type and mutant proteins using 8-azido-[(32)P]ATP revealed an aberrant catalytic cycle in these mutant proteins. These results demonstrate the importance of a functional catalytic cycle in lipid transport of ABCA3 and suggest a pathophysiological mechanism of pILD due to ABCA3 mutation.
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No. Sentence Comment
24 On the other hand, patients with the common missense mutation E292V and a second, specific mutation such as E690K or T1114M develop pediatric interstitial lung disease (pILD), the phenotype of which is milder than that of fatal surfactant deficiency, suggesting that the E292V ABCA3 mutation is responsible for the development of pILD (4).
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ABCA3 p.Glu292Lys 18676873:24:257
status: NEW29 The plasmid pEGFPN1-ABCA3 (17), which encodes ABCA3 protein fused with enhanced green fluorescent protein (GFP) at the COOH terminus (ABCA3-GFP), and its mutants containing pILD mutations (E292V, E690K, and T1114M) and other site-directed mutations (E292D, E292K, T1114S, E690D, and E690R) were generated as described previously and used for transient transfection experiment.
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ABCA3 p.Glu292Lys 18676873:29:257
status: NEW176 In E292K mutant protein, it was decreased to 4% of that of wild-type protein (Fig. 4B, lanes 9 and 10, and C).
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ABCA3 p.Glu292Lys 18676873:176:3
status: NEW184 Interaction of E690K mutant ABCA3-GFP protein with nucleotides.
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ABCA3 p.Glu292Lys 18676873:184:295
status: NEW188 The amino acid residues that are conserved in 6 transporters and in 4 or 5 transporters are indicated by asterisks and dots, respectively. B: 20,000-g membrane fraction prepared from HEK-293 cells stably expressing the WT ABCA3-GFP (lanes 3 and 4), E292V (lanes 5 and 6), E292D (lanes 7 and 8), E292K (lanes 9 and 10), or untransfected HEK-293 cells (lanes 1 and 2) was incubated with 10 M 8-azido-[␣-32 P]ATP in the absence or presence of 0.4 mM Vi and 3 mM MgCl2 for 10 min at 37°C. Protein was photoaffinity labeled with UV irradiation after removal of unbound ATP, electrophoresed on SDS-PAGE, and transferred to a PVDF membrane. Membrane was analyzed by autoradiography (top) and IB using anti-GFP antibody (bottom).
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ABCA3 p.Glu292Lys 18676873:188:295
status: NEW172 In E292K mutant protein, it was decreased to 4% of that of wild-type protein (Fig. 4B, lanes 9 and 10, and C).
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ABCA3 p.Glu292Lys 18676873:172:3
status: NEW