ABCA3 p.Trp1148*
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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
178 Recently, we identified a novel compound heterozygous mutation (maternal T1114A and paternal W1148X) from a Japanese boy with respiratory distress from age 18 mo (37).
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ABCA3 p.Trp1148* 18676873:178:93
status: NEW232 Accordingly, E292V, E690K, and T1114M are type II mutations.
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ABCA3 p.Trp1148* 18676873:232:102
status: NEW235 Although an exception has been identified in a Japanese patient with a type I/type II ABCA3 mutation (W1148X/T1114A) (37), the moderately preserved lipid transport function of the E292V mutant protein may underlie the generally milder phenotype of pILD patients.
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ABCA3 p.Trp1148* 18676873:235:102
status: NEW252 Genotype-phenotype correlation for ABCA3 mutation ABCA3 Mutation Age of Symptoms Phenotype Ref. W1142X W1142X Neonate FSD 27 L101P L101P Neonate FSD 27 L1553P L1553P Neonate FSD 27 Ins1518 L1580P Neonate FSD 27 L982P G1221S Neonate FSD 27 E292V T1114M Neonate pILD 4 E292V E690K 5 or 7 yr pILD 4 W1148X T1114A 12 mo pILD 37 Type I and type II ATP binding cassette A3 (ABCA3) mutations are shown in italics and roman, respectively.
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ABCA3 p.Trp1148* 18676873:252:296
status: NEW174 Recently, we identified a novel compound heterozygous mutation (maternal T1114A and paternal W1148X) from a Japanese boy with respiratory distress from age 18 mo (37).
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ABCA3 p.Trp1148* 18676873:174:93
status: NEW249 Genotype-phenotype correlation for ABCA3 mutation ABCA3 Mutation Age of Symptoms Phenotype Ref. W1142X W1142X Neonate FSD 27 L101P L101P Neonate FSD 27 L1553P L1553P Neonate FSD 27 Ins1518 L1580P Neonate FSD 27 L982P G1221S Neonate FSD 27 E292V T1114M Neonate pILD 4 E292V E690K 5 or 7 yr pILD 4 W1148X T1114A 12 mo pILD 37 Type I and type II ATP binding cassette A3 (ABCA3) mutations are shown in italics and roman, respectively.
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ABCA3 p.Trp1148* 18676873:249:296
status: NEW[hide] Heterozygous ABCA3 mutation associated with non-fa... Eur J Pediatr. 2008 Jun;167(6):691-3. Epub 2007 Jul 6. Yokota T, Matsumura Y, Ban N, Matsubayashi T, Inagaki N
Heterozygous ABCA3 mutation associated with non-fatal evolution of respiratory distress.
Eur J Pediatr. 2008 Jun;167(6):691-3. Epub 2007 Jul 6., [PMID:17618459]
Abstract [show]
A boy without symptoms up to 12 months of age started with persisting cough followed by respiratory failure at 18 months of age, resulting in mechanical ventilation because of alveolar proteinosis. Lung biopsy showed PAS-positive material. PCR was negative for CMV, Pneumocystis jiroveci and adenovirus. BALF showed mature SP-B. Analysis of the ATP-binding cassette transporter A3 (ABCA3; OMIM 601615) gene showed a compound heterozygous mutation from paternal W1148X and maternal T1114A. Alveolar lavage with 720 mg of bovine surfactant allowed weaning from ventilator support. Heterozygous mutation in the ABCA3 gene could be associated with a milder evolution as compared to the homozygous frequently lethal evolution.
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No. Sentence Comment
4 Analysis of the ATP-binding cassette transporter A3 (ABCA3; OMIM 601615) gene showed a compound heterozygous mutation from paternal W1148X and maternal T1114A.
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ABCA3 p.Trp1148* 17618459:4:132
status: NEW27 Direct sequence analysis of ABCA3 in the patient revealed a compound heterozygous mutation, W1148X on the paternal allele and T1114A on the maternal allele.
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ABCA3 p.Trp1148* 17618459:27:92
status: NEW28 In vitro study showed that the T1114A mutant had moderately preserved ATP-hydrolysis activity (51% of wild type) with normal intracellular localization, while the W1148X mutant had impaired intracellular localization.
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ABCA3 p.Trp1148* 17618459:28:163
status: NEW29 W1148X is a type I, loss-of-function mutation (abnormal intracellular localization) and T1114A is a type II mutation (normal intracellular localization with decreased ATP-hydrolysis activity) [2].
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ABCA3 p.Trp1148* 17618459:29:0
status: NEW