ABCMdb

ABCA3 p.Arg43Leu

None has been submitted yet.

Publications

PMID: 21567408 [PubMed] Nakagawa H et al: "Ubiquitin-mediated proteasomal degradation of ABC transporters: a new aspect of genetic polymorphisms and clinical impacts."

No. Sentence Comment

155 Effect of Mutations and Nonsynonymous SNPs on Protein Trafficking, Maturation, or ERAD of ABC Transporters Protein AA Mutation/SNP Effect on Protein Reference ABCA1 W590S Mutation Functional defect 115 R587W Mutation Impaired glycol processing 115 Q597R Mutation Impaired glycol processing, ERAD 115,116 Y1532C Mutation Altered protein trafficking 117 R1925Q Mutation Altered protein trafficking 118 ABCA3 R43L Mutation Altered protein trafficking 119 L101P Mutation Altered protein trafficking 119 R280C Mutation Altered protein trafficking 119 ABCA4 L541P Mutation Mislocalization 120 R602W Mutation Mislocalization 120 A1038V Mutation Mislocalization 120 C1490Y Mutation Mislocalization 120 ABCB1a G268V Mutation ERAD 121 G341C Mutation ERAD 121 I1196S Mutation Reduced glycosylation 122 ABCB4 I541F Mutation Accumulation in ER 123 ABCB11a E135K Mutation Reduced level of mature protein 124 L198P Mutation Reduced level of mature protein 124 E297G Mutation Reduced level of mature protein 124 L413W Mutation Reduced level of mature protein 124 R432T Mutation Reduced level of mature protein 124 D482G Mutation Immature protein in ER 124,125 N490D Mutation Reduced level of mature protein 124 A570T Mutation Reduced level of mature protein 124 T655I Mutation Reduced level of mature protein 124 Y818F SNP Moderate reduction of protein 124 G982R Mutation Retention in ER 125 R1153C Mutation ERAD 125 R1286Q Mutation Retention in ER 125 ABCC2a R768W Mutation Impaired protein trafficking 126 I1173F Mutation Impaired protein maturation 127 R1392 Mutation Impaired protein maturation 128 M1393 Mutation Impaired protein maturation 129 ABCC4a E757K SNP Altered protein trafficking 23 ABCC7 F508 Mutation Misfolding, ERAD 36-39,130 G85E Mutation Impaired protein maturation 130-132 G91R Mutation Impaired protein maturation 130-132 N1303K Mutation Impaired protein maturation 130-132 ABCC8 WT Wild type Ubiquitin-proteasome degradation 133 A116P Mutation Ubiquitin-proteasome degradation 133 V187D Mutation Ubiquitin-proteasome degradation 133 F1388 Mutation Impaired protein trafficking 134 L1544P Mutation Impaired protein trafficking 135,136 ABCC11a G180R SNP Ubiquitin-proteasome degradation 50 27 Mutation Ubiquitin-proteasome degradation 50 ABCG2a V12M SNP Altered protein localization 96 Q141K SNP Ubiquitin-proteasome degradation 102 F208S SNP Ubiquitin-proteasome degradation 78,99 S441N SNP Ubiquitin-proteasome degradation 78,99 Mutations of ABCA1, ABCA3, ABCA4, ABCB4, ABCB11, ABCC2, ABCC7 (CFTR), and ABCC8 are associated with Tangier disease, fatal surfactant deficiency, Stargardt disease, progressive familial intrahepatic cholestasis type 3 (PFIC-3), progressive familial intrahepatic cholestasis type 2 (PFIC-2), Dubin-Johnson syndrome, cystic fibrosis, and familial hyperinsulinism, respectively. Login to comment

PMID: 21214890 [PubMed] Weichert N et al: "Some ABCA3 mutations elevate ER stress and initiate apoptosis of lung epithelial cells."

No. Sentence Comment

4 Methods: Human alveolar epithelial A549 cells were transfected with vectors expressing wild-type ABCA3 or one of the three ABCA3 mutant forms, R43L, R280C and L101P, C-terminally tagged with YFP or hemagglutinin-tag. Login to comment
9 R43L mutation, resulting in a functional defect of the properly localized ABCA3, had no effect on intracellular stress and apoptotic signaling. Login to comment
35 Fibrosis is one of the hallmarks documented in ABCA3-associated ILD [12,16,17] and knowing that ABCA3 mutations can cause ER retention of the mutated transporter [6,20], we investigated the influence of three ABCA3 mutations, R43L, R280C and L101P, found in children with surfactant deficiency and chronic ILD [10,14,19], on ER stress and apoptosis induction in lung epithelial A549 cells. Login to comment
39 Three hABCA3 point mutations R43L, R280C and L101P were introduced in the WT ABCA3 in both vector types by PCR-based site-directed mutagenesis (QuickChange Site-Directed Mutagenesis, Stratagene, La Jolla, CA). Login to comment
40 Mutagenesis primers were as follows: R43L-For 5`-CAT CTG GCT CCTCTT GAA GAT TC-3`, R43L-Rev 5`-GAA TCT TCA AGAGGA GCC AGA TG-3`, L101P-For 5`-CAG TGC GCA GGG CAC CTG TGA TCA AC-3`, L101P-Rev 5`- GTT GAT CAC AGG TGC CCT GCG CAC TG-3`, R280C-For 5`-CAT TGC CTG TGC TGT CGT G-3`, R280C-Rev 5`-CAC GAC AGC ACAGGC AAT G-3`. Login to comment
82 Results General characterization of R43L, R280C and L101P ABCA3 mutations A) Localization and trafficking Three clinically relevant ABCA3 mutations identified in patients with neonatal surfactant deficiency (R43L and L101P) and chronic ILD (R280C) were chosen for the study. Login to comment
83 While cell biology of R43L and R280C mutations has not been studied yet, L101P mutation was previously described as a trafficking/folding defect resulting in the ER accumulation of L101P protein [6,20] and was deliberately chosen for this study as a cause for the ABCA3 ER retention. Login to comment
84 Initially we investigated intracellular localization of the WT and R43L, R280C and L101P transporters. Login to comment
88 Similar was observed for the R43L mutant, which showed a vesicular signal that overlapped with LAMP3 fluorescence (Figure 1A). Login to comment
89 For both WT and R43L mutant, very little to no colocalization was detected with calnexin (Figure 1B). Login to comment
90 WT and R43L might colocalize with the ER-resident protein calnexin during their folding in the ER as expected during the protein maturation process. Login to comment
93 This suggests correct localization of the WT and R43L transporters in the LAMP3-positive (LAMP3+ ) vesicles and almost full retention of the L101P mutant in the ER, possibly as a result of protein misfolding. Login to comment
95 B) Processing and maturation In immunoblots with anti-GFP antibody on cell lysates from transfected A549 cells expressing YFP labeled WT, R43L and R280C proteins, two protein bands of 180 kDa (150 kDa ABCA3 plus 30 kDa YFP) and 220 kDa (190 kDa ABCA3 plus 30 kDa YFP) were detected (Figure 2A). Login to comment
99 Processing of oligosaccharides and protein progress down the ER-Golgi maturation pathway Figure 1 Intracellular localization of the WT and mutant R43L, R280C and L101P ABCA3 proteins. Login to comment
101 YFP fluorescence of ABCA3-YFP fusions (green) was used to detect ABCA3 WT and R43L, R280C and L101P proteins. Login to comment
103 WT and R43L localized in LAMP3+ vesicles, R280C partially in LAMP3+ vesicles and partially in the ER and L101P completely in the ER. Login to comment
107 Both sugar types were present in WT, R43L and R280C proteins, as visible by the resistance of a portion of the 220 kDa band to the EndoH treatment. Login to comment
109 This confirms the localization studies showing retention of the L101P mutant in the ER and ability of WT, R43L and R280C to progress further from the ER to the Golgi. Login to comment
111 However, R43L and R280C mutation are mostly (R280C) or completely (R43L) correctly localized and potentially functional (Figure 1A, B). Login to comment
113 Liposomes containing NBD-labeled major surfactant phospholipid phosphatidyl-choline (C12-NBD-PC) and NBD-labeled minor surfactant phospholipid phosphatidylethanol-amine (C12-NBD-PE) were incubated with A549 cells expressing WT, R43L, R280C and L101P HA-tagged proteins. Login to comment
116 Interestingly, uptake of fluorescent liposomes into A549 cells was prominent in all cells, including those expressing L101P mutants (Figure 3) and therefore Figure 2 Processing of the WT and mutant R43L, R280C and L101P ABCA3. Login to comment
117 (A) Immunodetection with anti-GFP antibody showed two ABCA3 protein bands (180 kDa and 220 kDa) in whole cell lysates of A549 cells expressing WT and R43L and R280C mutations, and only one protein band in the cells expressing L101P mutation. Login to comment
118 (B) Deglycosylation assay with PNGaseF and EndoH on the membrane fractions from A549 cells transfected with pEYFP-N1/ ABCA3 plasmids and subsequent ABCA3-YFP immunodetection with anti-GFP antibody showed presence of high-mannose and complex oligosaccharides in WT, R43L and R280C proteins, as well as only high-mannose and no complex oligosaccharides in the L101P mutant resulting from the L101P ER retention. Login to comment
119 Figure 3 Function of the R43L and R280C transporters. Login to comment
122 HA-tag was used to detect ABCA3 WT and R43L, R280C and L101P by immunofluorescence (red). Login to comment
123 Both C12-NBD-PC and C12-NBD-PE fluorescence (green) frequently colocalized with the ring-like ABCA3 WT signal as well as within the ABCA3-WT vesicles and almost never with the R43L and R280C vesicles. Login to comment
127 WT ABCA3 (green) induced biogenesis of LAMP3+ vesicles (red) increasing their number and size in A549 cells, while R43L, R280C and L101P proteins showed no such effect (the same was observed in A549 pEYFP-N1/ABCA3 transfected cells - not shown). Login to comment
133 Similar colocalization of NBD fluorescence with ABCA3-HA vesicles was extremely rarely observed in cells expressing R43L and R280C mutations (Figure 3A, B). Login to comment
134 This probably indicates the ability of WT-ABCA3-HA vesicles to take up and accumulate both fluorescent lipids, while R280C-ABCA3-HA and R43L-ABCA3-HA vesicles did not show such ability. Login to comment
137 Expression of R43L, R280C and L101P mutations had a negative effect on vesicle formation and induced a lower number of smaller compact LAMP3+ vesicles, with the most drastic effect in L101P mutant (Figure 3D). Login to comment
139 Decreased uptake of NBD fluorescence in lamellar bodies and impact on lamellar body biogenesis together suggest functional impairment of the R43L and R280C proteins. Login to comment
143 No significant BiP increase was detectable between WT and correctly localized R43L mutation. Login to comment
156 Probably because of the robustness of the method, finer differences between WT and R43L and R280C were not observable, and the effect was measurable only in the case of the L101P mutant with the strongest protein defect (Figure 5A, D). Login to comment
161 (A) XBP1 splicing in untransfected A549 cells with and without tunicamycin (TM) treatment (10 μg/ml, 14 h) and in A549 cells with R43L, R280C and L101P mutations. Login to comment
168 Lower effect of L101P mutation on XBP1 splicing in A549 cells and no effect in A549 with WT and R43L and R280C mutations were observed. Login to comment
172 However, after exposure to tunicamycin XBP1 splicing was considerably more pronounced in R280C and L101P mutations if compared to A549 cells with WT and R43L mutations (Figure 5B, E). Login to comment
178 Flow cytometry assay of Cy5-coupled Annexin V surface binding showed an increase in the number of annexin V+ /PI- cells in transfected YFP+ cells in the case of R280C and L101P mutations when compared to WT and R43L indicating an early apoptotic state of those cells (Figure 6A). Login to comment
181 Intracellular GSH level, measured by flow cytometry of monochlorobimane binding to GSH and generation of a fluorescent adduct, was decreased in the YFP+ cells with L101P protein compared to YFP+ WT, R43L and also compared to R280C (Figure 6B). Login to comment
185 Via flow cytometry assay of intracellular active caspase 3 we found an increase in caspase 3 activation in cells expressing ER retained L101P mutant in comparison to the WT and R43L cells (Figure 6C). Login to comment
190 In summary, while R43L mutation did not raise apoptotic signaling above the A549 or WT level, R280C mutation increased one early apoptotic marker and ER-localized L101P mutations significantly elevated early and late apoptotic markers, indicating injury of the cells with L101P protein. Login to comment
195 Immunoblotting of whole cell lysates from the cells expressing WT or R43L, R280C or L101P mutations showed insignificant changes in pro-caspase 4 level between WT and mutations, but the level of pro-caspase 4 was somewhat higher in transfected cells then in A549 (Figure 7B). Login to comment
197 Changes measured between R43L and WT were not significant (Figure 7C). Login to comment
201 In this study we investigated the influence of three ABCA3 mutations, R43L, R280C and L101P, on intracellular stress and induction of apoptosis in cultured lung epithelial A549 cells. Login to comment
202 All three mutations were found in children with ABCA3-associated lung disease being either fatal neonatal respiratory distress syndrome (L101P and R43L [10,14]) or chronic ILD (R280C; own unpublished data, [19]). Login to comment
203 While cell biology of R43L and R280C mutations was studied here for the first time, L101P mutation was used as a known example of the trafficking/folding defect leading to the ER retention of ABCA3 with no information on ER stress [6,20]. Login to comment
205 We showed correct localization of WT and R43L proteins in LAMP3+ vesicles and dual localization of R280C protein in LAMP3+ vesicles Figure 7 Apoptotic signaling in cells with L101P and R280C mutations is activated by ER stress. Login to comment
207 No significant changes in the pro-caspase 4 level in transfected cells with WT, R43L, R280C and L101P mutations were detected but pro-caspase 4 was slightly increased in transfected cells compared to A549 (B). Login to comment
212 R43L and R280C proteins showed WT-processing with two protein bands (Figure 2A) and presence of complex oligosaccharides (Figure 2B) confirming their ability to proceed from the ER to the Golgi. Login to comment
214 While ER retention of L101P excludes ABCA3 function, the function of R43L and R280C transporters was studied additionally. Login to comment
220 In the case of R43L and R280C mutations such colocalization was rarely observed suggesting functional impairment of R43L and R280C proteins. Login to comment
234 Correctly localized R43L mutation, despite its influence on the ABCA3 function and lamellar body biogenesis, had almost no impact on stress and apoptosis under any conditions above the range of the WT values (Figure 4, 5, 6 and 7). Login to comment

PMID: 17517255 [PubMed] Somaschini M et al: "Unexplained neonatal respiratory distress due to congenital surfactant deficiency."

No. Sentence Comment

51 Characteristics of patients n GA (W) BW (G) Sex Familial Therapies Age at death Gene/mutation Histology Immunostaining Electron microscopy 1 40 3400 M No MV, surfactant, HFOV 4 hours No mutations NA NA NA 2 40 3700 F No MV 2 hours No mutations NA NA NA 3 37 3110 M No Corticosteroids, MV, surfactant, prostacyclin, HFOV 3 days No mutations HMD ϩ SP-B - proSP-C, alveolar epithelium NA 4 40 3050 F Yes Corticosteroids, MV, surfactant, prostacyclin, iNO, HFOV 28 days SFTPB mutations 121ins2/ 122delC PAP Absent SP-B and proSP-B PAP material pro-SP-C ϩ NA 5 39 3200 F Yes MV, surfactant 38 days SFTPB mutations 121ins2/ 122delC PAP Absent SP-B and proSP-B PAP material pro-SP-C ϩ NA 6 38 3650 F Yes MV, surfactant 27 days ABCA3 mutations 4240delC/ W165X DIP ϩ SP-B ϩ proSP-C, alveolar epithelium NA 7 39 2850 M No MV 2 days ABCA3 mutation R280C/wt NA NA NA 8 35 3000 M No MV, surfactant 2 days ABCA3 mutation E292V/wt NA NA NA 9 40 3700 F No MV, surfactant 37 days ABCA3 mutations R208W/ T1423I DIP ϩ SP-B ϩ proSP-C, alveolar epithelium Numerous small LBs with dense cores 10 40 3220 M Yes MV, surfactant 30 days ABCA3 mutations 3997delAG/3997delAG DIP ϩ SP-B ϩ proSP-C, alveolar epithelium Few small LBs with dense cores 11 38 2700 F Yes MV, surfactant, corticosteroids 13 days ABCA3 mutations R155Q/ R155Q DIP ϩ SP-B ϩ proSP-C, alveolar epithelium 12 40 3050 M No MV, surfactant, iNO, prostacyclin 30 days ABCA3 mutations R43L/ R1482W DIP ϩ SP-B ϩ proSP-C, alveolar epithelium Numerous small LBs with dense cores 13 41 3420 F No MV, surfactant 180 days ABCA3 mutation S341N/wt NA NA NA 14 39 3150 M Yes MV, surfactant 64 days ABCA3 mutations P248L/ P248L DIP ϩ SP-B ϩ proSP-C, alveolar epithelium NA 15 38 3280 M Yes MV, surfactant, HFOV, corticosteroids 66 days ABCA3 mutations 4240delC/ W165X NA NA NA 16 41 3000 F No MV, surfactant, HFOV 50 days ABCA3 mutations R208W/ 4296_4301delATCACG NA NA NA 17 33 1750 M No MV, surfactant, HFOV 206 days ABCA3 mutations P147L/ R155Q DIP ϩ SP-B ϩ proSP-C, alveolar epithelium Numerous small LBs with dense cores GA, gestational age; BW, birth weight; MV, mechanical ventilation; HFOV, high-frequency oscillatory ventilation; iNO, inhaled nitric oxide; wt, wild type; LB, lamellar body; HMD, hyaline membrane disease; PAP, pulmonary alveolar proteinosis; DIP, desquamative intersititial pneumonia; HMD, hyaline membrane disease; NA, not available. Login to comment
48 Characteristics of patients n GA (W) BW (G) Sex Familial Therapies Age at death Gene/mutation Histology Immunostaining Electron microscopy 40 3400 M No MV, surfactant, HFOV 4 hours No mutations NA NA NA 2 40 3700 F No MV 2 hours No mutations NA NA NA 3 37 3110 M No Corticosteroids, MV, surfactant, prostacyclin, HFOV 3 days No mutations HMD af9; SP-B afa; proSP-C, alveolar epithelium NA 4 40 3050 F Yes Corticosteroids, MV, surfactant, prostacyclin, iNO, HFOV 28 days SFTPB mutations 121ins2/ 122delC PAP Absent SP-B and proSP-B PAP material pro-SP-C af9; NA 5 39 3200 F Yes MV, surfactant 38 days SFTPB mutations 121ins2/ 122delC PAP Absent SP-B and proSP-B PAP material pro-SP-C af9; NA 6 38 3650 F Yes MV, surfactant 27 days ABCA3 mutations 4240delC/ W165X DIP af9; SP-B af9; proSP-C, alveolar epithelium NA 7 39 2850 M No MV 2 days ABCA3 mutation R280C/wt NA NA NA 8 35 3000 M No MV, surfactant 2 days ABCA3 mutation E292V/wt NA NA NA 9 40 3700 F No MV, surfactant 37 days ABCA3 mutations R208W/ T1423I DIP af9; SP-B af9; proSP-C, alveolar epithelium Numerous small LBs with dense cores 10 40 3220 M Yes MV, surfactant 30 days ABCA3 mutations 3997delAG/3997delAG DIP af9; SP-B af9; proSP-C, alveolar epithelium Few small LBs with dense cores 11 38 2700 F Yes MV, surfactant, corticosteroids 13 days ABCA3 mutations R155Q/ R155Q DIP af9; SP-B af9; proSP-C, alveolar epithelium 12 40 3050 M No MV, surfactant, iNO, prostacyclin 30 days ABCA3 mutations R43L/ R1482W DIP af9; SP-B af9; proSP-C, alveolar epithelium Numerous small LBs with dense cores 13 41 3420 F No MV, surfactant 180 days ABCA3 mutation S341N/wt NA NA NA 14 39 3150 M Yes MV, surfactant 64 days ABCA3 mutations P248L/ P248L DIP af9; SP-B af9; proSP-C, alveolar epithelium NA 15 38 3280 M Yes MV, surfactant, HFOV, corticosteroids 66 days ABCA3 mutations 4240delC/ W165X NA NA NA 16 41 3000 F No MV, surfactant, HFOV 50 days ABCA3 mutations R208W/ 4296_4301delATCACG NA NA NA 17 33 1750 M No MV, surfactant, HFOV 206 days ABCA3 mutations P147L/ R155Q DIP af9; SP-B af9; proSP-C, alveolar epithelium Numerous small LBs with dense cores GA, gestational age; BW, birth weight; MV, mechanical ventilation; HFOV, high-frequency oscillatory ventilation; iNO, inhaled nitric oxide; wt, wild type; LB, lamellar body; HMD, hyaline membrane disease; PAP, pulmonary alveolar proteinosis; DIP, desquamative intersititial pneumonia; HMD, hyaline membrane disease; NA, not available. Login to comment

PMID: 16728712 [PubMed] Brasch F et al: "Alteration of the pulmonary surfactant system in full-term infants with hereditary ABCA3 deficiency."

No. Sentence Comment

123 MUTATIONS OF THE ABCA3 GENE IN THE STUDY GROUP AND ABCA3 PROTEIN EXPRESSION IN TYPE II PNEUMOCYTES IN INDEX PATIENTS ABCA3 Protein Expression in Type II Pneumocytes in Index Patients Family Localization* Nucleotide Deviation Structural Relevance Affected Domain (immunohistochemical score)† 1 Exon 15 c1755C Ͼ G Silent polymorphism - Weak (1) Exon 15 c1814G Ͼ A R605Q (Arg Ͼ Gln) NBD 1 Exon 31 c4877-8delAG Frameshift/Stop C-terminus 2 Exon 10 c1058C Ͼ T Silent polymorphism - Weak (1) Intron 15 c1897-1G Ͼ C Acceptor splice-site mutation NBD 1 3 Exon 8 c643C Ͼ A Q215K (Gln Ͼ Lys) First extracellular loop Absent (0) Exon 8 c863G Ͼ A R288K (Arg Ͼ Lys) First extracellular loop 4 Intron 21 c3005-1G Ͼ A Acceptor splice-site mutation Second half-size transporter Weak (1) 5 Exon 5 c128G Ͼ T (het) R43L (Arg Ͼ Leu) First extracellular loop Absent (0) Exon 8 c863G Ͼ A (het) R288K (Arg Ͼ Lys) First extracellular loop Exon 15 c1755C Ͼ G (het) Silent polymorphism - Exon 31 c4751delT (het) Frameshift/Stop C-terminus 6 Exon 14 c1736T Ͼ C (het) L579P (Leu Ͼ Pro) NBD 1 Weak (1) Exon 25 c3812delG (het) Frameshift/Stop Last extracellular loop, C-terminus 7 Exon 30 c4681 C Ͼ T R1561X (Arg Ͼ Stop) C-terminus Weak (1) 8 Exon 19 c2429-30delTT Frameshift/Stop Second half-size transporter Weak (1) Definition of abbreviation: NBD ϭ nucleotide-binding domain. Login to comment

PMID: 16641205 [PubMed] Garmany TH et al: "Surfactant composition and function in patients with ABCA3 mutations."

No. Sentence Comment

66 ABCA3 patient data Patient Sex Age at sample acquisition (mo) Allele 1 Allele 2 Histopathologic diagnosis PC/lipid (%) Surface tension (mN/m) Lipid/ protein SP-A (␮g)* SP-B (ng)* 1 M 5 R194G delF1203 Chronic pneumonitis of infancy 59.6 28 0.76 533 448 2 F 3 L1595P D253Y Interstitial pneumonitis/alveolar hypoplasia NA NA NA 21.3 212 3 F 5 1112-20 GϾA 3163del10 Pulmonary alveolar proteinosis/interstitial pneumonitis 25.4 37.8 0.33 60.8 66.5 4 F 2 M1I delE203 Interstitial pneumonitis 31.2 34.6 0.39 68 24 5 M 15 1126ins15 1866del25 Interstitial fibrosis/interstitial pneumonitis 23.8 28.5 0.43 NA 18 6 F 3 P766S-L960F 1729delTC Pulmonary alveolar proteinosis NA NA NA 135 193 7 F 4 W179C 1382delTG Interstitial pneumonitis/dysmature alveolar segments 78.1 11.1 0.48 51.9 59.1 8 F 4 R43L P264R Chronic interstitial pneumonitis 39.8 34.3 0.25 22.7 40 NA, not available. Login to comment

PMID: 24142515 [PubMed] Beers MF et al: "Disruption of N-linked glycosylation promotes proteasomal degradation of the human ATP-binding cassette transporter ABCA3."

No. Sentence Comment

229 In contrast, a second group of lung disease-associated mutations that are proximal to N-glycan sites and/or that could profoundly alter the structural makeup of the loop such as P147L (23) and R43L (6, 20) may adversely influence glycosylation and subsequent ABCA3 biosynthesis. Login to comment

PMID: 24871971 [PubMed] Wambach JA et al: "Genotype-phenotype correlations for infants and children with ABCA3 deficiency."

No. Sentence Comment

109 Seven unrelated individuals from diverse ethnic and geographic origins had a mutation in codon 43 (p.R43C, p.R43H, and p.R43L, Subjects 92 and 93 [siblings], 101, 104, 105, 118, 173, 174) and these mutations have been reported in other ABCA3-deficient patients from diverse geographic locations (12, 28, 29), suggesting that this codon may be particularly susceptible to mutation. Login to comment

PMID: 26186947 [PubMed] Mulugeta S et al: "Lost after translation: insights from pulmonary surfactant for understanding the role of alveolar epithelial dysfunction and cellular quality control in fibrotic lung disease."

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. Login to comment