ABCMdb

ABCA3 p.Trp1142*

ClinVar:

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[hide] ABCA3 gene mutations in newborns with fatal surfac... N Engl J Med. 2004 Mar 25;350(13):1296-303. Shulenin S, Nogee LM, Annilo T, Wert SE, Whitsett JA, Dean M
ABCA3 gene mutations in newborns with fatal surfactant deficiency.
N Engl J Med. 2004 Mar 25;350(13):1296-303., [PMID:15044640]

Abstract [show]
BACKGROUND: Pulmonary surfactant forms a lipid-rich monolayer that coats the airways of the lung and is essential for proper inflation and function of the lung. Surfactant is produced by alveolar type II cells, stored intracellularly in organelles known as lamellar bodies, and secreted by exocytosis. The gene for ATP-binding cassette transporter A3 (ABCA3) is expressed in alveolar type II cells, and the protein is localized to lamellar bodies, suggesting that it has an important role in surfactant metabolism. METHODS: We sequenced each of the coding exons of the ABCA3 gene in blood DNA from 21 racially and ethnically diverse infants with severe neonatal surfactant deficiency for which the etiologic process was unknown. Lung tissue from four patients was examined by high-resolution light and electron microscopy. RESULTS: Nonsense and frameshift mutations, as well as mutations in highly conserved residues and in splice sites of the ABCA3 gene were identified in 16 of the 21 patients (76 percent). In five consanguineous families with mutations, each pair of siblings was homozygous for the same mutation and each mutation was found in only one family. Markedly abnormal lamellar bodies were observed by ultrastructural examination of lung tissue from four patients with different ABCA3 mutations, including nonsense, splice-site, and missense mutations. CONCLUSIONS: Mutation of the ABCA3 gene causes fatal surfactant deficiency in newborns. ABCA3 is critical for the proper formation of lamellar bodies and surfactant function and may also be important for lung function in other pulmonary diseases. Since it is closely related to ABCA1 and ABCA4, proteins that transport phospholipids in macrophages and photoreceptor cells, it may have a role in surfactant phospholipid metabolism.

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44 Family History/ Consanguinity Outcome Histologic Findings ABCA3 Mutation 1 White F 1 Yes/Yes Death within 3 mo after birth DIP, PAP W1142X/W1142X 2 White F 1 Yes/Yes Death during neonatal period DIP, PAP W1142X/W1142X 3 Black M 2 Yes/Yes Death during neonatal period NA L101P/L101P 4 Black M 2 Yes/Yes Death during neonatal period NA L101P/L101P 5 White F 3 Yes/No Death during neonatal period NA 4552insT/L1580P 6 White F 3 Yes/No Death during neonatal period NA 4552insT/L1580P 7 White M 4 Yes/No Death within 3 mo after birth PAP G1221S/L982P 8 White M 4 Yes/No Death during neonatal period PAP G1221S/L982P 9 Middle Eastern M 5 Yes/Yes Death during neonatal period DIP, PAP L1553P/L1553P 10 Middle Eastern M 5 Yes/Yes Death during neonatal period NA L1553P/L1553P 11 White M 6 Yes/No Recovery from RDS NA None found 12 White M 6 Yes/No Recovery from RDS NA None found 13 Middle Eastern M 7 No/Yes Unknown NA 1644delC/1644delC 14 Middle Eastern M 8 Yes/No Death during neonatal period DIP, PAP R106X/R106X 15 Asian F 9† Yes/Yes Death during neonatal period NA 4909+1G>A/4909+1G>A 16 White M 10 Yes/Yes Death during neonatal period NA None found 17 White M 11 No/No Recovery from RDS NA None found 18 White F 12 No/No Death during neonatal period NA None found 19 White M 13 Yes/No Chronic lung disease CPI, DIP Q1591P/-‡ 20 Hispanic M 14 No/No Death after lung transplantation PAP N568D/-‡ 21 Asian F 9† Yes/Yes Death during neonatal period PAP 4909+1G>A/4909+1G>A entorganisms,weusedthededucedaminoacidse- quence of ABCA3 (GenBank accession number NP_001080) to search the sequence data base using the BLAST program (http://www.ncbi.nlm.nih. Login to comment
77 Electron micrographs of lung tissue from Patient 21 (who was homozygous for the 4909+1G>A mutation) revealed lamellarbodies(Fig.3)thatweresmallerthanthose from control lung tissue, with more densely packed membranes and eccentrically placed, dense inclusion bodies, similar to those previously described in Patients 1 and 2, who were homozygous for the W1142X mutation.17 Similarly abnormal lamellar bodies were observed in lung tissue from Patient 8 (who was heterozygous for the G1221S and L982P mutations) and Patient 9 (who was homozygous for the L1553P mutation). Login to comment
87 Human Mouse Rat Puffer fish ETVRRALVIN ETVKREFMIK EAVRREFMIK EDVRGKLELS QDVQQNLVRG L101P NGAGKTT NGAGKTT NGAGKTT NGAGKTT NGAGKTT N568D VARRLL VARRLL VARRLL VARRLL L1553P Q1591P T301C(L101P) C316T(R106X) A1702G(N568D) 1644delC G3426A(W1142X) G3661A(G1221S) T4657C(L1553P) 4552insT A4771C(Q1591P) 4909+1G>A G1221S LSGIAT LSGIAT LSGIAT ATP-binding domains L982P QQLSEHL QQLSENL QQLSEHL T2945C(L982P) ECEALC LAIMVQGQFKC ECEALC ECEALC L1580P T4739C(L1580P) Nonsense MissenseSpliceFrameshift LAIMVQGQFKC LAIMVQGQFKC LAVMVNGQFKC Zebra fish LAVMVNGQFKC tified occur in residues that are highly conserved (Fig.2).Theaminoacidalignmentwasusedtopro- duce a phylogenetic tree of the ABCA3-related proteins showing the relation of the proteins from different organisms (see Supplementary Appendix 2, available with the full text of this article at www. nejm.org).ThefishABCA3proteinsclusterwiththe mammalian ABCA3 proteins and are distinct from other, more distant ABCA-family proteins, such as the mouse Abca14, Abca15, and Abca16 proteins and the sea-urchin ABCA proteins (see Supplementary Appendix 2. Login to comment
43 Family History/ Consanguinity Outcome Histologic Findings ABCA3 Mutation 1 White F 1 Yes/Yes Death within 3 mo after birth DIP, PAP W1142X/W1142X 2 White F 1 Yes/Yes Death during neonatal period DIP, PAP W1142X/W1142X 3 Black M 2 Yes/Yes Death during neonatal period NA L101P/L101P 4 Black M 2 Yes/Yes Death during neonatal period NA L101P/L101P 5 White F 3 Yes/No Death during neonatal period NA 4552insT/L1580P 6 White F 3 Yes/No Death during neonatal period NA 4552insT/L1580P 7 White M 4 Yes/No Death within 3 mo after birth PAP G1221S/L982P 8 White M 4 Yes/No Death during neonatal period PAP G1221S/L982P 9 Middle Eastern M 5 Yes/Yes Death during neonatal period DIP, PAP L1553P/L1553P 10 Middle Eastern M 5 Yes/Yes Death during neonatal period NA L1553P/L1553P 11 White M 6 Yes/No Recovery from RDS NA None found 12 White M 6 Yes/No Recovery from RDS NA None found 13 Middle Eastern M 7 No/Yes Unknown NA 1644delC/1644delC 14 Middle Eastern M 8 Yes/No Death during neonatal period DIP, PAP R106X/R106X 15 Asian F 9ߤ Yes/Yes Death during neonatal period NA 4909+1G>A/4909+1G>A 16 White M 10 Yes/Yes Death during neonatal period NA None found 17 White M 11 No/No Recovery from RDS NA None found 18 White F 12 No/No Death during neonatal period NA None found 19 White M 13 Yes/No Chronic lung disease CPI, DIP Q1591P/-ߥ 20 Hispanic M 14 No/No Death after lung transplantation PAP N568D/-ߥ 21 Asian F 9ߤ Yes/Yes Death during neonatal period PAP 4909+1G>A/4909+1G>A entorganisms,weusedthededucedaminoacidse- quence of ABCA3 (GenBank accession number NP_001080) to search the sequence data base using the BLAST program (http://www.ncbi.nlm.nih. Login to comment
76 Electron micrographs of lung tissue from Patient 21 (who was homozygous for the 4909+1G>A mutation) revealed lamellarbodies(Fig.3)thatweresmallerthanthose from control lung tissue, with more densely packed membranes and eccentrically placed, dense inclusion bodies, similar to those previously described in Patients 1 and 2, who were homozygous for the W1142X mutation.17 Similarly abnormal lamellar bodies were observed in lung tissue from Patient 8 (who was heterozygous for the G1221S and L982P mutations) and Patient 9 (who was homozygous for the L1553P mutation). Login to comment
86 Human Mouse Rat Puffer fish ETVRRALVIN ETVKREFMIK EAVRREFMIK EDVRGKLELS QDVQQNLVRG L101P NGAGKTT NGAGKTT NGAGKTT NGAGKTT NGAGKTT N568D VARRLL VARRLL VARRLL VARRLL L1553P Q1591P T301C(L101P) C316T(R106X) A1702G(N568D) 1644delC G3426A(W1142X) G3661A(G1221S) T4657C(L1553P) 4552insT A4771C(Q1591P) 4909+1G>A G1221S LSGIAT LSGIAT LSGIAT ATP-binding domains L982P QQLSEHL QQLSENL QQLSEHL T2945C(L982P) ECEALC LAIMVQGQFKC ECEALC ECEALC L1580P T4739C(L1580P) Nonsense Missense Splice Frameshift LAIMVQGQFKC LAIMVQGQFKC LAVMVNGQFKC Zebra fish LAVMVNGQFKC tified occur in residues that are highly conserved (Fig.2).Theaminoacidalignmentwasusedtopro- duce a phylogenetic tree of the ABCA3-related proteins showing the relation of the proteins from different organisms (see Supplementary Appendix 2, available with the full text of this article at www. nejm.org).ThefishABCA3proteinsclusterwiththe mammalian ABCA3 proteins and are distinct from other, more distant ABCA-family proteins, such as the mouse Abca14, Abca15, and Abca16 proteins and the sea-urchin ABCA proteins (see Supplementary Appendix 2. Login to comment

[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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23 For example, patients with type I homozygous ABCA3 mutations such as W1142X/W1142X or type I/type II compound heterozygous ABCA3 mutations such as L982P/G1221S die of surfactant deficiency within the neonatal period (27). Login to comment
230 Although E292V, E690K, and T1114M mutant proteins were found to traffic to intracellular vesicles, the lipid transport function of E292V mutant protein was partially impaired, and those of E690K and T1114M mutant protein were severely impaired, accompanied by an aberrant catalytic cycle. Login to comment
233 Patients with fatal surfactant deficiency carrying a type I homozygous ABCA3 mutation (W1142X/W1142X, L101P/ L101P, or L1553P/L1553P) or a type I/type II compound heterozygous mutation (L982P/G1221S or Ins1518/L1580P) die within the neonatal period (Table 1) (27). Login to comment
252 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. Login to comment
18 For example, patients with type I homozygous ABCA3 mutations such as W1142X/W1142X or type I/type II compound heterozygous ABCA3 mutations such as L982P/G1221S die of surfactant deficiency within the neonatal period (27). Login to comment
249 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. Login to comment

[hide] Characterization and classification of ATP-binding... J Biol Chem. 2006 Nov 10;281(45):34503-14. Epub 2006 Sep 7. Matsumura Y, Ban N, Ueda K, Inagaki N
Characterization and classification of ATP-binding cassette transporter ABCA3 mutants in fatal surfactant deficiency.
J Biol Chem. 2006 Nov 10;281(45):34503-14. Epub 2006 Sep 7., [PMID:16959783]

Abstract [show]
The ATP-binding cassette transporter ABCA3 is expressed predominantly at the limiting membrane of the lamellar bodies in lung alveolar type II cells. Recent study has shown that mutation of the ABCA3 gene causes fatal surfactant deficiency in newborns. In this study, we investigated in HEK293 cells the intracellular localization and N-glycosylation of the ABCA3 mutants so far identified in fatal surfactant deficiency patients. Green fluorescent protein-tagged L101P, L982P, L1553P, Q1591P, and Ins1518fs/ter1519 mutant proteins remained localized in the endoplasmic reticulum, and processing of oligosaccharide was impaired, whereas wild-type and N568D, G1221S, and L1580P mutant ABCA3 proteins trafficked to the LAMP3-positive intracellular vesicle, accompanied by processing of oligosaccharide from high mannose type to complex type. Vanadate-induced nucleotide trapping and ATP-binding analyses showed that ATP hydrolysis activity was dramatically decreased in the N568D, G1221S, and L1580P mutants, accompanied by a moderate decrease in ATP binding in N568D and L1580P mutants but not in the G1221S mutant, compared with the wild-type ABCA3 protein. In addition, mutational analyses of the Gly-1221 residue in the 11th transmembrane segment and the Leu-1580 residue in the cytoplasmic tail, and homology modeling of nucleotide binding domain 2 demonstrate the significance of these residues for ATP hydrolysis and suggest a mechanism for impaired ATP hydrolysis in G1221S and L1580P mutants. Thus, surfactant deficiency because of ABCA3 gene mutation may be classified into two categories as follows: abnormal intracellular localization (type I) and normal intracellular localization with decreased ATP binding and/or ATP hydrolysis of the ABCA3 protein (type II). These distinct pathophysiologies may reflect both the severity and effective therapy for surfactant deficiency.

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35 Partial cDNA fragments containing various fatal surfactant deficiency mutations (L101P, N568D, L982P, G1221S, L1553P, L1580P, Q1591P, W1142X, and Ins1518fs (abbreviation of Ins1518fs/ter1519 in this study), see Fig. 1A), were generated with PCR methods and replaced with the corresponding fragment of pEGFPN1-ABCA3. Login to comment
216 Investigating the intracellular localization and N-glycosylation of these ABCA3 mutant proteins in HEK293 cells, we found the missense L101P, L982P, L1553P, Q1591P, and nonsense Ins1518fs mutant proteins to be predominantly localized at the ER, with impaired processing of oligosaccharide. Login to comment
217 W1142X mutant ABCA3 protein, another nonsense mutant reported in fatal surfactant deficiency (12), also was predominantly localized at the ER with impaired processing of oligosaccharide (data not shown). Login to comment
222 As three of these mutations (L101P, L982P, and L1553P) are located in the predicted ␣-helical structure of the ABCA3 protein (32) and the proline residue is known to be helix breaker (39), its introduction into the ABCA3 protein might well disrupt the ␣-helical structure and hamper proper folding and intracellular translocation. Login to comment
223 The large C-terminal deletion of the ABCA3 protein (Ins1518fs and W1142X) also might hamper this process. Login to comment
224 Indeed, patients with homozygous mutations of L101P, L1553P, and W1142X have been reported to die of surfactant deficiency during the neonatal period, and electron microscopic study of lung tissue from patients with homozygous L1553P and W1142X mutations revealed smaller lamellar bodies than those in normal lung tissue (12). Login to comment

[hide] Mutations in the ABCA3 gene are associated with ca... Invest Ophthalmol Vis Sci. 2014 Nov 18;55(12):8031-43. doi: 10.1167/iovs.14-14098. Chen P, Dai Y, Wu X, Wang Y, Sun S, Xiao J, Zhang Q, Guan L, Zhao X, Hao X, Wu R, Xie L
Mutations in the ABCA3 gene are associated with cataract-microcornea syndrome.
Invest Ophthalmol Vis Sci. 2014 Nov 18;55(12):8031-43. doi: 10.1167/iovs.14-14098., [PMID:25406294]

Abstract [show]
PURPOSE: Cataract-microcornea syndrome (CCMC) is an autosomal dominant inherited disease characterized by the association of congenital cataract and microcornea without any other systemic anomaly or dysmorphism. Although mutations of several genes have been shown to cause dominant CCMC, in many patients the causative gene has not yet been identified. Our aim was to identify the disease-associated gene in Chinese patients with CCMC. METHODS: The CCMC patients from two unrelated Chinese families and 26 sporadic patients were enrolled. All the patients were screened by Sanger sequencing with no identified mutations. Genetic variations were screened by whole-exome sequencing and then validated using Sanger sequencing. RESULTS: By sequencing the whole exome of three patients in a Chinese four-generation dominant CCMC family (Family A), three heterozygous missense mutation (c.115C>G, c.277G>A, and c.4393G>A) were identified in ATP-binding cassette protein A3 (ABCA3). At highly conserved positions, changes (c.115C>G and c.4393G>A) were predicted to have functional impacts and completely cosegregated with the phenotype. We further confirmed our finding by identifying another heterozygous missense mutation, c.2408C>T, in ABCA3 in an additional dominant CCMC family (Family B), which also cosegregated with the phenotype. Moreover, four heterozygous mutations, two missense mutations (c.4253A>T, c.2069A>T) and two splice site mutations (c.4053+2T>C, c.2765-1G>T) were identified from the sporadic patients. The ABCA3 protein was expressed in human lens capsule, choroid-retinal pigment epithelium and retinal pigment epithelial cells. CONCLUSIONS: Mutations in the human ABCA3 gene were associated with lethal respiratory distress. Our study showed, for the first time to our knowledge, that mutations in ABCA3 were associated with CCMC, warranting further investigations on the pathogenesis of this disorder.

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293 Genetic Variants Identified in ABCA3 in Patients With Surfactant Metabolism Dysfunction-3 (SMDP3) dbSNP rs# Cluster ID Codons Substitution Mutation Type Mutation Mode rs121909181 c.3426G>A W1142X Missense Homozygosity rs121909182 c.301T>C L101P Missense Homozygosity rs121909183 c.4657T>C L1553P Missense Homozygosity rs28936691 c.4772A>C Q1591P Missense Heterozygosity rs121909184 c.1702G>A N568D Missense Heterozygosity - c.4909&#fe;1G>A - Splice site Homozygosity rs121909185 c.977T>C L326P Missense Homozygosity 19. Login to comment

[hide] Structural Features of the ATP-Binding Cassette (A... Int J Mol Sci. 2015 Aug 19;16(8):19631-44. doi: 10.3390/ijms160819631. Paolini A, Baldassarre A, Del Gaudio I, Masotti A
Structural Features of the ATP-Binding Cassette (ABC) Transporter ABCA3.
Int J Mol Sci. 2015 Aug 19;16(8):19631-44. doi: 10.3390/ijms160819631., [PMID:26295388]

Abstract [show]
In this review we reported and discussed the structural features of the ATP-Binding Cassette (ABC) transporter ABCA3 and how the use of bioinformatics tools could help researchers to obtain a reliable structural model of this important transporter. In fact, a model of ABCA3 is still lacking and no crystallographic structures (of the transporter or of its orthologues) are available. With the advent of next generation sequencing, many disease-causing mutations have been discovered and many more will be found in the future. In the last few years, ABCA3 mutations have been reported to have important pediatric implications. Thus, clinicians need a reliable structure to locate relevant mutations of this transporter and make genotype/phenotype correlations of patients affected by ABCA3-related diseases. In conclusion, we strongly believe that the model preliminarily generated by these novel bioinformatics tools could be the starting point to obtain more refined models of the ABCA3 transporter.

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111 In particular, we focused on the following mutations: p.E292V, p.E690K, p.R1333G, p.W1142X, p.Y1515X, and p.L1553P. Login to comment
116 More difficult is to hypothesize a role for p.W1142X and p.R1333G both residing in b1;-helices of the transmembrane domain 2 (TMD2). Login to comment