ABCA3 p.Asp253His
| Predicted by SNAP2: | A: D (71%), C: D (75%), E: N (57%), F: D (85%), G: D (66%), H: D (75%), I: D (80%), K: D (63%), L: D (80%), M: D (80%), N: D (66%), P: D (71%), Q: D (66%), R: D (71%), S: D (63%), T: D (53%), V: D (75%), W: D (91%), Y: D (80%), |
| Predicted by PROVEAN: | A: D, C: 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, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Molecular and cellular characteristics of ABCA3 mu... Hum Mol Genet. 2012 Feb 15;21(4):765-75. Epub 2011 Nov 7. Flamein F, Riffault L, Muselet-Charlier C, Pernelle J, Feldmann D, Jonard L, Durand-Schneider AM, Coulomb A, Maurice M, Nogee LM, Inagaki N, Amselem S, Dubus JC, Rigourd V, Bremont F, Marguet C, Brouard J, de Blic J, Clement A, Epaud R, Guillot L
Molecular and cellular characteristics of ABCA3 mutations associated with diffuse parenchymal lung diseases in children.
Hum Mol Genet. 2012 Feb 15;21(4):765-75. Epub 2011 Nov 7., [PMID:22068586]
Abstract [show]
ABCA3 (ATP-binding cassette subfamily A, member 3) is expressed in the lamellar bodies of alveolar type II cells and is crucial to pulmonary surfactant storage and homeostasis. ABCA3 gene mutations have been associated with neonatal respiratory distress (NRD) and pediatric interstitial lung disease (ILD). The objective of this study was to look for ABCA3 gene mutations in patients with severe NRD and/or ILD. The 30 ABCA3 coding exons were screened in 47 patients with severe NRD and/or ILD. ABCA3 mutations were identified in 10 out of 47 patients, including 2 homozygous, 5 compound heterozygous and 3 heterozygous patients. SP-B and SP-C expression patterns varied across patients. Among patients with ABCA3 mutations, five died shortly after birth and five developed ILD (including one without NRD). Functional studies of p.D253H and p.T1173R mutations revealed that p.D253H and p.T1173R induced abnormal lamellar bodies. Additionally, p.T1173R increased IL-8 secretion in vitro. In conclusion, we identified new ABCA3 mutations in patients with life-threatening NRD and/or ILD. Two mutations associated with ILD acted via different pathophysiological mechanisms despite similar clinical phenotypes.
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No. Sentence Comment
7 Functional studies of p.D253H and p.T1173R mutations revealed that p.D253H and p.T1173R induced abnormal lamellar bodies.
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ABCA3 p.Asp253His 22068586:7:24
status: NEWX
ABCA3 p.Asp253His 22068586:7:69
status: NEW41 Analysis of genomic DNA from the parents and kindred showed that the compound heterozygous p.R1583W/ p.S128Rfs (Fig. 1A) and p.R208W/p.R1521W (Fig. 1B) mutations were inherited, as well as the homozygous mutations p.T1173R (Fig. 1C) and p.D253H (Fig. 1D).
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ABCA3 p.Asp253His 22068586:41:239
status: NEW54 Genetic analysis results in the 10 children harboring homozygous and compound heterozygous (shaded) or heterozygous ABCA3 mutations Patient NRD Clinical outcome ABCA3 mutation ABCA3 SNPs ABCA3 variants cDNA level Protein level dbSNPs rs# cluster id Missense variants in conserved amino acid 1 Yes ILD c.[3518C.G] + [3518C.G] p.[T1173R] + [T1173R] rs149532, rs13332514 2 Yes ILD c.[757G.C] + [757G.C] p.[D253H] + [D253H] 3 Yes Death c.[1385T.G] + [2890G.A] p.[L462R] + [G964S] rs149532 4 Yes Death c.[4747C.T] + c.[384delC] p.[R1583W] + p.[S128Rfs] rs149532 c.[450G.A] (het) 5 No Death c.[629G.T] + [3079G.C] p.[G210V] + [A1027P] rs149532 6 Yes ILD c.[622C.T] + [4561C.T] p.[R208W] + [R1521W] rs149532, rs323043 7 Yes Death c.[604G.C] + [907C.G] p.[G202R] + [L303V] rs149532, rs323043 (het), rs13332514 8 Yes Death c.[2888A.G] + [?]
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ABCA3 p.Asp253His 22068586:54:403
status: NEWX
ABCA3 p.Asp253His 22068586:54:413
status: NEW68 Pedigree of the families with the ABCA3 mutations p.R1583W/p.S128Rfs (A), p.R1521W/R208W (B), p.T1173R/p.T1173R (C) and p.D253H/ p.T1173R (D).
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ABCA3 p.Asp253His 22068586:68:122
status: NEW78 Electron microscopy was performed on a lung biopsy from the patient harboring the p.D253H mutation and showed abnormal lamellar bodies with dense inclusions (Fig. 3C).
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ABCA3 p.Asp253His 22068586:78:84
status: NEW79 BALF analysis Western blot analysis of surfactant proteins (Fig. 4) was performed in seven patients, who had the following ABCA3 mutations: p.D253H (patient 2), p.T1173R (patient 1), p.L462R/ p.G964S (patient 3), p.G202R/p.L303V (patient 7), p.Y963C (patient 8), p.R1583W/p.S128Rfs (patient 4) and p.S872G (patient 10), respectively.
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ABCA3 p.Asp253His 22068586:79:142
status: NEW80 SP-C (Fig. 4A) and SP-B (Fig. 4B) were detected at a size of 3.7 and 8 kDa in variable amounts, the smallest amount being found in the patient with the p.G202R/p.L303V ABCA3 mutation (patient 7) in whom SP-C and SP-B are only faintly visible.
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ABCA3 p.Asp253His 22068586:80:84
status: NEW84 Characterization of ABCA3 mutations The two mutations p.T1173R and p.D253H were deliberately chosen for subsequent functional studies because they were homozygous.
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ABCA3 p.Asp253His 22068586:84:69
status: NEW89 (A) HRCT scan, (B) hematoxylin and eosin (HE) staining of lung tissue and (C) electron microscopy of type-II cells from the patient (patient 2) harboring the ABCA3 homozygous mutation p.D253H.
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ABCA3 p.Asp253His 22068586:89:186
status: NEW97 Thus, p.D253H and p.T1173R mutants were not associated with a localization defect.
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ABCA3 p.Asp253His 22068586:97:8
status: NEW99 In WT, p.T1173R and p.D253H cells, anti-GFP antibody revealed two bands of 180 kDa (150 kDa ABCA3 + 30 kDa GFP) and 220 kDa (190 + 30 kDa GFP), respectively (Fig. 6).
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ABCA3 p.Asp253His 22068586:99:8
status: NEWX
ABCA3 p.Asp253His 22068586:99:22
status: NEW101 Lamellar bodies in ABCA3 WT, p.D253H and p.T1173R cells.
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ABCA3 p.Asp253His 22068586:101:22
status: NEWX
ABCA3 p.Asp253His 22068586:101:31
status: NEW104 The p.D253H mutation induced abnormal lamellar bodies with electron-dense inclusions (Fig. 7, dashed arrows), consistent with the results of the patient`s lung biopsy (Fig. 3C).
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ABCA3 p.Asp253His 22068586:104:6
status: NEW106 Cytokine production by ABCA3 WT, p.D253H and p.T1173R cells.
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ABCA3 p.Asp253His 22068586:106:6
status: NEWX
ABCA3 p.Asp253His 22068586:106:35
status: NEW110 A significant, faint increase in IL-8 mRNA expression was also observed between WT and p.D253H cells.
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ABCA3 p.Asp253His 22068586:110:89
status: NEW112 At the protein level, ELISA results confirmed that A549 cells expressing the p.T1173R mutant produced more IL-8 than did WT cells (Fig. 8A).
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ABCA3 p.Asp253His 22068586:112:89
status: NEW113 In contrast, IL-8 production by p.D253H cells was similar to that of WT cells (Fig. 8B).
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ABCA3 p.Asp253His 22068586:113:34
status: NEW123 Human Molecular Genetics, 2012, Vol. 21, No. 4 769 ERK1/2 inhibitor treatment, IL-8 production by p.T1173R cells remained increased compared with WT and p.D253H cells.
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ABCA3 p.Asp253His 22068586:123:156
status: NEW125 Western blot and relative quantification of ERK1/2 phosphorylation confirmed that the observed IL-8 overproduction in p.T1173R cells was independent of ERK1/2 signaling.
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ABCA3 p.Asp253His 22068586:125:104
status: NEW137 Intracellular localization of wild-type ABCA3 and of the p.D253H and p.T1173R mutants.
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ABCA3 p.Asp253His 22068586:137:59
status: NEW138 A549 cells either non-transfected or transfected with mock vector, wild-type protein ABCA3-WT (A) or mutated proteins p.D253H (B) and p.T1173R (C) were analyzed using confocal microscopy.
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ABCA3 p.Asp253His 22068586:138:120
status: NEW141 Western blot analysis of ABCA3 in cells transiently transfected with ABCA3-WT or the p.D253H or p.T1173R mutation.
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ABCA3 p.Asp253His 22068586:141:87
status: NEW155 To confirm the hypothesis, it would have been interesting to compare the patterns of siblings harboring the p.D253H mutation.
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ABCA3 p.Asp253His 22068586:155:110
status: NEW161 The presence of abnormal lamellar bodies in the patient harboring the p.D253H mutation supports a pathogenic effect of this mutation.
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ABCA3 p.Asp253His 22068586:161:72
status: NEW162 These abnormalities were also observed in vitro in p.D253H- and p.T1173R-transfected cells, suggesting that ABCA3 abnormalities may consistently induce abnormal lamellar bodies.
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ABCA3 p.Asp253His 22068586:162:53
status: NEW163 However, since we do not have the corresponding biopsy from the patient harboring the p.T1173R, we cannot draw a firm conclusion on this point.
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ABCA3 p.Asp253His 22068586:163:72
status: NEW166 A549 cells transfected with mock vector (pEGFP-N1), ABCA3-WT (A), or mutated ABCA3-D253H (B) or ABCA3-T1173R-GFP were analyzed using electron microscopy.
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ABCA3 p.Asp253His 22068586:166:83
status: NEW167 Human Molecular Genetics, 2012, Vol. 21, No. 4 771 We performed in vitro experiments to elucidate the pathophysiological effects of two mutations associated with progression towards ILD, p.D253H and T1173R.
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ABCA3 p.Asp253His 22068586:167:190
status: NEW172 The p.D253H and p.T1173R mutations induced abnormal lamellar bodies.
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ABCA3 p.Asp253His 22068586:172:6
status: NEW192 (B) Role for MAPK and NF-kB-dependent signaling in IL-8 secretion by ABCA3-WT, D253H and T1173R cells.
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ABCA3 p.Asp253His 22068586:192:79
status: NEW227 Mutagenesis primers (Sigma) were as follows: D253H-For-5' -ACCCGCCGTTCATCGCACACCCCTTCC-3' , D253H-Rev-5' -GGAAGGGGTGTGCGATGAACGGCGGGT- 3' ; T1173R-For-5' -ACGTGCGTGCCTTCAGGCGGGACG-3' , and T1173R-Rev-5' -CGTCCCGCCTGAAGGCACGCACGT- 3' .
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ABCA3 p.Asp253His 22068586:227:45
status: NEWX
ABCA3 p.Asp253His 22068586:227:92
status: NEW230 Cells (1 × 106 ) were transfected with 1 mg of ABCA3-WT, ABCA3-D253H or ABCA3-T1173R plasmid using a nucleofector device (Lonza, Cologne, Germany) as recommended by the manufacturer.
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ABCA3 p.Asp253His 22068586:230:68
status: NEW43 Analysis of genomic DNA from the parents and kindred showed that the compound heterozygous p.R1583W/ p.S128Rfs (Fig. 1A) and p.R208W/p.R1521W (Fig. 1B) mutations were inherited, as well as the homozygous mutations p.T1173R (Fig. 1C) and p.D253H (Fig. 1D).
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ABCA3 p.Asp253His 22068586:43:239
status: NEW56 Genetic analysis results in the 10 children harboring homozygous and compound heterozygous (shaded) or heterozygous ABCA3 mutations Patient NRD Clinical outcome ABCA3 mutation ABCA3 SNPs ABCA3 variants cDNA level Protein level dbSNPs rs# cluster id Missense variants in conserved amino acid 1 Yes ILD c.[3518C.G] + [3518C.G] p.[T1173R] + [T1173R] rs149532, rs13332514 2 Yes ILD c.[757G.C] + [757G.C] p.[D253H] + [D253H] 3 Yes Death c.[1385T.G] + [2890G.A] p.[L462R] + [G964S] rs149532 4 Yes Death c.[4747C.T] + c.[384delC] p.[R1583W] + p.[S128Rfs] rs149532 c.[450G.A] (het) 5 No Death c.[629G.T] + [3079G.C] p.[G210V] + [A1027P] rs149532 6 Yes ILD c.[622C.T] + [4561C.T] p.[R208W] + [R1521W] rs149532, rs323043 7 Yes Death c.[604G.C] + [907C.G] p.[G202R] + [L303V] rs149532, rs323043 (het), rs13332514 8 Yes Death c.[2888A.G] + [?]
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ABCA3 p.Asp253His 22068586:56:403
status: NEWX
ABCA3 p.Asp253His 22068586:56:413
status: NEW70 Pedigree of the families with the ABCA3 mutations p.R1583W/p.S128Rfs (A), p.R1521W/R208W (B), p.T1173R/p.T1173R (C) and p.D253H/ p.T1173R (D).
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ABCA3 p.Asp253His 22068586:70:122
status: NEW81 BALF analysis Western blot analysis of surfactant proteins (Fig. 4) was performed in seven patients, who had the following ABCA3 mutations: p.D253H (patient 2), p.T1173R (patient 1), p.L462R/ p.G964S (patient 3), p.G202R/p.L303V (patient 7), p.Y963C (patient 8), p.R1583W/p.S128Rfs (patient 4) and p.S872G (patient 10), respectively.
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ABCA3 p.Asp253His 22068586:81:142
status: NEW86 Characterization of ABCA3 mutations The two mutations p.T1173R and p.D253H were deliberately chosen for subsequent functional studies because they were homozygous.
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ABCA3 p.Asp253His 22068586:86:69
status: NEW91 (A) HRCT scan, (B) hematoxylin and eosin (HE) staining of lung tissue and (C) electron microscopy of type-II cells from the patient (patient 2) harboring the ABCA3 homozygous mutation p.D253H.
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ABCA3 p.Asp253His 22068586:91:186
status: NEW103 Lamellar bodies in ABCA3 WT, p.D253H and p.T1173R cells.
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ABCA3 p.Asp253His 22068586:103:31
status: NEW108 Cytokine production by ABCA3 WT, p.D253H and p.T1173R cells.
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ABCA3 p.Asp253His 22068586:108:35
status: NEW115 In contrast, IL-8 production by p.D253H cells was similar to that of WT cells (Fig. 8B).
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ABCA3 p.Asp253His 22068586:115:34
status: NEW139 Intracellular localization of wild-type ABCA3 and of the p.D253H and p.T1173R mutants.
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ABCA3 p.Asp253His 22068586:139:59
status: NEW140 A549 cells either non-transfected or transfected with mock vector, wild-type protein ABCA3-WT (A) or mutated proteins p.D253H (B) and p.T1173R (C) were analyzed using confocal microscopy.
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ABCA3 p.Asp253His 22068586:140:120
status: NEW143 Western blot analysis of ABCA3 in cells transiently transfected with ABCA3-WT or the p.D253H or p.T1173R mutation.
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ABCA3 p.Asp253His 22068586:143:87
status: NEW157 To confirm the hypothesis, it would have been interesting to compare the patterns of siblings harboring the p.D253H mutation.
X
ABCA3 p.Asp253His 22068586:157:110
status: NEW164 These abnormalities were also observed in vitro in p.D253H- and p.T1173R-transfected cells, suggesting that ABCA3 abnormalities may consistently induce abnormal lamellar bodies.
X
ABCA3 p.Asp253His 22068586:164:53
status: NEW168 A549 cells transfected with mock vector (pEGFP-N1), ABCA3-WT (A), or mutated ABCA3-D253H (B) or ABCA3-T1173R-GFP were analyzed using electron microscopy.
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ABCA3 p.Asp253His 22068586:168:83
status: NEW169 We performed in vitro experiments to elucidate the pathophysiological effects of two mutations associated with progression towards ILD, p.D253H and T1173R.
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ABCA3 p.Asp253His 22068586:169:138
status: NEW174 The p.D253H and p.T1173R mutations induced abnormal lamellar bodies.
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ABCA3 p.Asp253His 22068586:174:6
status: NEW194 (B) Role for MAPK and NF-kB-dependent signaling in IL-8 secretion by ABCA3-WT, D253H and T1173R cells.
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ABCA3 p.Asp253His 22068586:194:79
status: NEW228 Mutagenesis primers (Sigma) were as follows: D253H-For-5' -ACCCGCCGTTCATCGCACACCCCTTCC-3' , D253H-Rev-5' -GGAAGGGGTGTGCGATGAACGGCGGGT- 3' ; T1173R-For-5' -ACGTGCGTGCCTTCAGGCGGGACG-3' , and T1173R-Rev-5' -CGTCCCGCCTGAAGGCACGCACGT- 3' .
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ABCA3 p.Asp253His 22068586:228:45
status: NEWX
ABCA3 p.Asp253His 22068586:228:92
status: NEW231 Cells (1 &#d7; 106 ) were transfected with 1 mg of ABCA3-WT, ABCA3-D253H or ABCA3-T1173R plasmid using a nucleofector device (Lonza, Cologne, Germany) as recommended by the manufacturer.
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ABCA3 p.Asp253His 22068586:231:67
status: NEW[hide] Genotype-phenotype correlations for infants and ch... Am J Respir Crit Care Med. 2014 Jun 15;189(12):1538-43. doi: 10.1164/rccm.201402-0342OC. Wambach JA, Casey AM, Fishman MP, Wegner DJ, Wert SE, Cole FS, Hamvas A, Nogee LM
Genotype-phenotype correlations for infants and children with ABCA3 deficiency.
Am J Respir Crit Care Med. 2014 Jun 15;189(12):1538-43. doi: 10.1164/rccm.201402-0342OC., [PMID:24871971]
Abstract [show]
RATIONALE: Recessive mutations in the ATP-binding cassette transporter A3 (ABCA3) cause lethal neonatal respiratory failure and childhood interstitial lung disease. Most ABCA3 mutations are private. OBJECTIVES: To determine genotype-phenotype correlations for recessive ABCA3 mutations. METHODS: We reviewed all published and unpublished ABCA3 sequence and phenotype data from our prospective genetic studies of symptomatic infants and children at Washington and Johns Hopkins Universities. Mutations were classified based on their predicted disruption of protein function: frameshift and nonsense mutations were classified as "null," whereas missense, predicted splice site mutations, and insertion/deletions were classified as "other." We compared age of presentation and outcomes for the three genotypes: null/null, null/other, and other/other. MEASUREMENTS AND MAIN RESULTS: We identified 185 infants and children with homozygous or compound heterozygous ABCA3 mutations and lung disease. All of the null/null infants presented with respiratory failure at birth compared with 75% of infants with null/other or other/other genotypes (P = 0.00011). By 1 year of age, all of the null/null infants had died or undergone lung transplantation compared with 62% of the null/other and other/other children (P < 0.0001). CONCLUSIONS: Genotype-phenotype correlations exist for homozygous or compound heterozygous mutations in ABCA3. Frameshift or nonsense ABCA3 mutations are predictive of neonatal presentation and poor outcome, whereas missense, splice site, and insertion/deletions are less reliably associated with age of presentation and prognosis. Counseling and clinical decision making should acknowledge these correlations.
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No. Sentence Comment
134 Alleles with ABCA3 Variants in Cis Allele Number of Subjects with Allele R43C-P1653L 1 D115E-D253H 1 (2 alleles, 1 subject homozygous) V129M-V1495M 1 W179C-P770L 3 (3 subjects heterozygous) E195K-R1271Q 1 R280C-Q1589X 2 (3 alleles, 1 subject homozygous, 1 subject heterozygous) R288K-S693L 2 (2 subjects heterozygous) c.1474_1475insT-D953N 4 (3 siblings homozygous, 1 subject heterozygous) P766S-L960F 4 (4 subjects heterozygous) H778R-L1252P 1 A54T-R1482W-IVS25-98 C .
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ABCA3 p.Asp253His 24871971:134:93
status: NEW[hide] Lost after translation: insights from pulmonary su... Am J Physiol Lung Cell Mol Physiol. 2015 Sep 15;309(6):L507-25. doi: 10.1152/ajplung.00139.2015. Epub 2015 Jul 17. Mulugeta S, Nureki S, Beers MF
Lost after translation: insights from pulmonary surfactant for understanding the role of alveolar epithelial dysfunction and cellular quality control in fibrotic lung disease.
Am J Physiol Lung Cell Mol Physiol. 2015 Sep 15;309(6):L507-25. doi: 10.1152/ajplung.00139.2015. Epub 2015 Jul 17., [PMID:26186947]
Abstract [show]
Dating back nearly 35 years ago to the Witschi hypothesis, epithelial cell dysfunction and abnormal wound healing have reemerged as central concepts in the pathophysiology of idiopathic pulmonary fibrosis (IPF) in adults and in interstitial lung disease in children. Alveolar type 2 (AT2) cells represent a metabolically active compartment in the distal air spaces responsible for pulmonary surfactant biosynthesis and function as a progenitor population required for maintenance of alveolar integrity. Rare mutations in surfactant system components have provided new clues to understanding broader questions regarding the role of AT2 cell dysfunction in the pathophysiology of fibrotic lung diseases. Drawing on data generated from a variety of model systems expressing disease-related surfactant component mutations [surfactant proteins A and C (SP-A and SP-C); the lipid transporter ABCA3], this review will examine the concept of epithelial dysfunction in fibrotic lung disease, provide an update on AT2 cell and surfactant biology, summarize cellular responses to mutant surfactant components [including endoplasmic reticulum (ER) stress, mitochondrial dysfunction, and intrinsic apoptosis], and examine quality control pathways (unfolded protein response, the ubiquitin-proteasome system, macroautophagy) that can be utilized to restore AT2 homeostasis. This integrated response and its derangement will be placed in the context of cell stress and quality control signatures found in patients with familial or sporadic IPF as well as non-surfactant-related AT2 cell dysfunction syndromes associated with a fibrotic lung phenotype. Finally, the need for targeted therapeutic strategies for pulmonary fibrosis that address epithelial ER stress, its downstream signaling, and cell quality control are discussed.
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No. Sentence Comment
267 Summary of reported phenotypic features for surfactant component mutations Mutation (Domain) Clinical Diagnosis Lung Phenotype (in vivo) Subcellular Localization Trafficking Cellular Responses (in vitro) References SFTPA2 F198S (CRD) G231V (CRD) Familial pulmonary fibrosis Total BAL [SP-A] Normal ER retention Intracellular aggregation Not secreted (af9;) ER stress, cleared by ERAD (af9;) TGFbeta1 elaboration 99, 100, 175 SFTPC Group A1 èc;Exon4 (BRICHOS) L188Q (BRICHOS) G100S (BRICHOS) NSIP (Children) IPF/UIP (Adult) Absence of mature SP-C (humans) Arrested lung development (mice) ER stress (humans; mice) 1Sensitivity to bleomycin (mice) Epithelial cytotoxicity ER retention&#a1; aggresomes Intracellular aggregates ERAD requires Erdj 4/5 MG132 blocks degradation 4-PBA improves aggregates (af9;) ER stress (af9;) Apoptosis (af9;) Incomplete or absent proSP-C processing (af9;) IL-8/TGFbeta1 expression (af9;) Polyubiquitinated isoforms 21, 39, 97, 98, 100, 111, 112, 116, 117, 120, 153, 159, 160, 173, 193 Group A2 L110R (BRICHOS) P115L (BRICHOS) A116D (BRICHOS) Unspecified ILD Unspecified ILD Unspecified chILD Phenotype not reported EEA-1 (af9;); Syntaxin2 (afa;) Intracellular aggregation 2 PC secretion (af9;) Aberrant processing, 2 cell viability 1 HSP response (af9;) Congo red aggregates 160, 193 Group B1 E66K (Linker) I73T (Linker) NSIP/PAP (Child) IPF/UIP (Adult) 1 Phospholipid; 1SP-A, PAS positive staining Biopsy: PM and EE localization Misprocessed SP-C (BAL) Misprocessed SP-B (BAL) Plasma membrane&#a1;EE&#a1;LE/MVB (af9;) Aberrantly processed protein (af9;) Late autophagy block 2 Mitophagy 1 Mysfunctional mitochondria 1, 19, 24, 26, 49, 116, 118, 128, 152 Group B2 èc;91-93 (Non-BRICHOS) NSIP/PAP 2 BAL SP-B 1 BAL SP-A 2 Surfactant surface tension (af9;) Intracellular aggregates (af9;) Congo red staining Plasma membraneߥ EEA1 (af9;) compartmentsߥ Not reported 55, 181 Group C P30L (NH2-terminal) Unspecified ILD Phenotype not reported (af9;) ER retention 1 Bip expression (af9;) Polyubiquitinated isoforms 13, 116, 160 ABCA3 Group I (Trafficking Defective) L101P (1st luminal loop) R280C (1st cytosolic loop) L982P (3rd luminal loop) G1221S (11th TM domain) L1553P (COOH-terminal) Q1591P (COOH-terminal) Surfactant deficiency* RDS* chILDߤ Phenotype not reported Phenotype not reported Phenotype not reported (af9;) ER retention Non-LRO cytosolic vesicles (af9;) ER stress 30, 31, 103, 147, 172, 177 Group II (Functionally Defective) R43L (1st luminal loop) D253H (1st luminal loop) E292V (1st cytosolic loop) N568D (ABC1) E690K (ABC1) T1114M (8thTM domain) T1173R (1st luminal loop) L1580P (COOH-terminal) Surfactant deficiency* RDS* chILD (CPI)ߤ Reduced SP-B and SP-C (afa;) ER retention Lysosomes or LROs (normal) Impaired lipid transport Impaired ATP hydrolysis Impaired ATP binding Abnormal LBs 1 IL8 secretion 20, 25, 103, 104, 147, 148, 177 *Seen with homozygous or compound heterozygous ABCA3 expression; ߤfound with heterozugous ABCA3 expression.
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ABCA3 p.Asp253His 26186947:267:2574
status: NEW