ABCMdb

ABCA3 p.Gln1591Pro

ClinVar:	c.4772A>C , p.Gln1591Pro D , Pathogenic
Predicted by SNAP2:	A: D (53%), C: D (59%), D: D (53%), E: N (61%), F: D (53%), G: D (53%), H: N (66%), I: N (57%), K: N (61%), L: N (53%), M: N (53%), N: N (61%), P: D (53%), R: N (57%), S: N (61%), T: N (61%), V: N (57%), W: D (75%), Y: N (53%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: N, F: D, G: D, H: D, I: D, K: N, L: D, M: D, N: D, P: D, R: N, S: D, T: D, V: D, W: D, Y: D,

[switch to compact view]
Comments [show]

None has been submitted yet.

Publications
[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.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
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
59 Seven missense muta- tionswereidentifiedinconservedaminoacids(Fig. 2), including homozygous substitutions of proline for leucine in codons 101 and 1553 (L101P and L1553P, respectively) and heterozygous substitutions of aspartic acid for asparagine at position 568 (N568D), proline for leucine at position 982 (L982P), serine for glycine at position 1221 (G1221S), proline for leucine at position 1580 (L1580P), and proline for glutamine at position 1591 (Q1591P). 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
106 Nucleotide Affected* Site Affected or Outcome SNP No.† Mutation Exon 5 3, 4 T301C L101P‡ Exon 5 14 C316T R106X‡ Exon 14 20 A1702G N568D Exon 14 13 1644delC Frameshift‡ Exon 21 7, 8 T2945C L982P Exon 23 1, 2 G3426A W1142X‡ Exon 24 7, 8 G3661A G1221S Exon 30 9, 10 T4657C L1553P Exon 30 5, 6 4552insT Frameshift Exon 31 15, 21 4909+1G>A Splice site‡ Exon 31 5, 6 T4739C L1580P Exon 31 19 A4772C Q1591P Polymorphism Exon 5 Multiple Exon 5+50A/G Intron rs46725 Exon 6 20 393C/T A131A Exon 6 18 Exon 6+119G/A Intron rs323059 Exon 7 19 Exon 7-14C/G Intron Exon 8 14 681C/T A227A Exon 10 Multiple Exon 10-105C/A Intron rs323066 Exon 10 Multiple Exon 10-20C/T Intron Exon 10 Multiple 1058C/T F353F Exon 14 Multiple Exon 14+33G/A Intron rs170447 Exon 15 Multiple 1755C/G P585P rs323043 Exon 18 13 Exon 18-17G/A Intron Exon 18 1 2340C/T H780H Exon 21 Multiple Exon 21-20C/G Intron rs313908 Exon 21 Multiple Exon 21+34C/T Intron rs313909 Exon 27 Multiple 4116C/T S1372S rs149532 Exon 32 11 4944C/T V1648V In two patients, a mutation was identified on only one allele. Login to comment
110 One patient, who had a missense mutation (Q1591P) on one allele and an unknown mutation on the other allele, is still alive at six years of age and has chronic lung disease, suggesting that some ABCA3 mutations are not fatal. 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
58 Seven missense muta- tionswereidentifiedinconservedaminoacids(Fig. 2), including homozygous substitutions of proline for leucine in codons 101 and 1553 (L101P and L1553P, respectively) and heterozygous substitutions of aspartic acid for asparagine at position 568 (N568D), proline for leucine at position 982 (L982P), serine for glycine at position 1221 (G1221S), proline for leucine at position 1580 (L1580P), and proline for glutamine at position 1591 (Q1591P). 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
105 Nucleotide Affected* Site Affected or Outcome SNP No.ߤ Mutation Exon 5 3, 4 T301C L101Pߥ Exon 5 14 C316T R106Xߥ Exon 14 20 A1702G N568D Exon 14 13 1644delC Frameshiftߥ Exon 21 7, 8 T2945C L982P Exon 23 1, 2 G3426A W1142Xߥ Exon 24 7, 8 G3661A G1221S Exon 30 9, 10 T4657C L1553P Exon 30 5, 6 4552insT Frameshift Exon 31 15, 21 4909+1G>A Splice siteߥ Exon 31 5, 6 T4739C L1580P Exon 31 19 A4772C Q1591P Polymorphism Exon 5 Multiple Exon 5+50A/G Intron rs46725 Exon 6 20 393C/T A131A Exon 6 18 Exon 6+119G/A Intron rs323059 Exon 7 19 Exon 7-14C/G Intron Exon 8 14 681C/T A227A Exon 10 Multiple Exon 10-105C/A Intron rs323066 Exon 10 Multiple Exon 10-20C/T Intron Exon 10 Multiple 1058C/T F353F Exon 14 Multiple Exon 14+33G/A Intron rs170447 Exon 15 Multiple 1755C/G P585P rs323043 Exon 18 13 Exon 18-17G/A Intron Exon 18 1 2340C/T H780H Exon 21 Multiple Exon 21-20C/G Intron rs313908 Exon 21 Multiple Exon 21+34C/T Intron rs313909 Exon 27 Multiple 4116C/T S1372S rs149532 Exon 32 11 4944C/T V1648V In two patients, a mutation was identified on only one allele. Login to comment
109 One patient, who had a missense mutation (Q1591P) on one allele and an unknown mutation on the other allele, is still alive at six years of age and has chronic lung disease, suggesting that some ABCA3 mutations are not fatal. Login to comment

[hide] Identification and characterization of a novel ABC... Physiol Genomics. 2010 Jan 8;40(2):94-9. Epub 2009 Oct 27. Park SK, Amos L, Rao A, Quasney MW, Matsumura Y, Inagaki N, Dahmer MK
Identification and characterization of a novel ABCA3 mutation.
Physiol Genomics. 2010 Jan 8;40(2):94-9. Epub 2009 Oct 27., [PMID:19861431]

Abstract [show]
Mutations in the gene coding for ATP-binding cassette protein A3 (ABCA3) are recognized as a genetic cause of lung disease of varying severity. Characterization of a number of mutant ABCA3 proteins has demonstrated that the mutations generally affect intracellular localization or the ability of the protein to hydrolyze ATP. A novel heterozygous mutation that results in the substitution of cysteine for arginine at amino acid 295 in ABCA3 was identified in a premature infant with chronic respiratory insufficiency and abnormal lamellar bodies. Sequencing of DNA performed in study participants demonstrated that this was a mutation and not a common variant. Plasmid vectors containing ABCA3 with the identified novel mutation tagged with green fluorescent protein on the carboxy terminus were generated. The effect of the mutation on protein function was characterized by examining the glycosylation state of the mutant protein in transiently transfected HEK293 cells and by examining ATP hydrolysis activity of the mutant protein with a vanadate-induced nucleotide trapping assay in stably transfected HEK293 cells. The ABCA3 protein containing the R295C mutation undergoes normal glycosylation and intracellular localization but has dramatically reduced ATP hydrolysis activity (12% of wild type). The identification of one copy of this novel mutation in a premature infant with chronic respiratory insufficiency suggests that ABCA3 haploinsufficiency together with lung prematurity may result in more severe, or more prolonged, respiratory failure.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
99 Type I mutations include L101P, L982P, L1553P, and Q1591P; type II mutations include E292V, N568D, E690K, T1114, G1221S, and L1580P (13, 14). Login to comment
94 Type I mutations include L101P, L982P, L1553P, and Q1591P; type II mutations include E292V, N568D, E690K, T1114, G1221S, and L1580P (13, 14). Login to comment

[hide] Clinical, radiological and pathological features o... Thorax. 2008 Apr;63(4):366-73. Epub 2007 Nov 16. Doan ML, Guillerman RP, Dishop MK, Nogee LM, Langston C, Mallory GB, Sockrider MM, Fan LL
Clinical, radiological and pathological features of ABCA3 mutations in children.
Thorax. 2008 Apr;63(4):366-73. Epub 2007 Nov 16., [PMID:18024538]

Abstract [show]
BACKGROUND: Mutations in the ABCA3 gene can result in fatal surfactant deficiency in term newborn infants and chronic interstitial lung disease in older children. Previous studies on ABCA3 mutations have focused primarily on the genetic abnormalities and reported limited clinical information about the resultant disease. A study was undertaken to analyse systematically the clinical presentation, pulmonary function, diagnostic imaging, pathological features and outcomes of children with ABCA3 mutations. METHODS: The records of nine children with ABCA3 mutations evaluated at Texas Children's Hospital between 1992 and 2005 were reviewed and their current clinical status updated. Previous diagnostic imaging studies and lung biopsy specimens were re-examined. The results of DNA analyses were confirmed. RESULTS: Age at symptom onset ranged from birth to 4 years. Cough, crackles, failure to thrive and clubbing were frequent findings. Mean lung function was low but tended to remain static. CT scans commonly revealed ground-glass opacification, septal thickening, parenchymal cysts and pectus excavatum. Histopathological patterns included pulmonary alveolar proteinosis, desquamative interstitial pneumonitis and non-specific interstitial pneumonitis, and varied with age. Dense abnormalities of lamellar bodies, characteristic of ABCA3 mutations, were seen by electron microscopy in all adequate specimens. Outcomes varied with the age at which the severity of lung disease warranted open lung biopsy, and some patients have had prolonged survival without lung transplantation. CONCLUSIONS: The presentation and course of interstitial lung disease due to ABCA3 mutations are variable, and open lung biopsy and genetic testing are warranted early in the evaluation of children with a consistent clinical picture.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
45 Five patients eventually Table 1 Characteristics of nine children with ABCA3 mutations Patient no Age of onset, manifestation Clinical features (age at evaluation) CT imaging (age at examination) Mutational analysis Outcomes (current age) 1 Newborn, respiratory failure Ta, Cr, Wh, Cl, Hy (4 years) GGO, ST, PE (2 weeks) Nt622C.T (R208W) Nt2279T.G (M760R) Transplanted (died) (5 years)* 2 Newborn, respiratory failure Ta, Hy (1 month) None Nt289insA Nt4648C.T (R1550W) Transplanted (died) (3 months)* 3 3 months, acute respiratory distress Ta, FTT, Hy (3 months) GGO, ST (3 months) Nt2646insC Nt3757C.T (P1253S) Died (4 months)* 4 2 years, acute respiratory distress Ta, Cr, Cl, FTT, Hy (2 years) GGO, ST, PE (2 years) Nt4732G.A (E1578K) Nt4772A.C (Q1591P) Alive, ILD score 4 (15 years) 5 1 year, recurrent hypoxaemia Ta, Cl, FTT, Hy (3 years) GGO, ST, PE, cysts (2 years) Nt59G.T (R20L) Nt2879T.C (L960S) Alive, ILD score 4 (8 years) 6 Newborn, pneumonia Ta, Cr, Cl, FTT, Hy (10 years) GGO, ST, PE (4 years) Nt875A.T (E292V) Nt3341C.T (T1114M) Transplanted (alive) (12 years)* 7 Newborn, respiratory failure Ta, Cl, FTT (6 years) GGO, ST, PE, cysts (6 years) Nt875A.T (E292V) Nt4706delTCA (deltaI1569) Alive, ILD score 1 (18 years) 8 Newborn, pneumonia Ta, Cr, Cl, Hy (6 years) GGO, PE (6 years) Nt629G.T (G210V) Nt3609delCTT (deltaF1203) Alive, ILD score 3 (11 years) 9 4 years, recurrent hypoxaemia Ta, Cr, Hy (exertional) (8 years) GGO, ST (7 years) Nt128G.A (R43H) Nt1609 in/del (end exon 13) Alive, ILD score 2 (13 years) Ta, tachypnoea; Cr, crackles; Wh, wheezing; Cl, clubbing; Hy, hypoxaemia; FTT, failure to thrive; GGO, ground-glass opacification; ST, septal thickening; PE, pectus excavatum. Login to comment
83 Five of these mutations (R20L, DF1203, E292V, T114M, Q1591P) have been previously identified in subjects with chILD, whereas the remainder are novel. Login to comment

[hide] Haplotype analysis of ABCA3: association with resp... Ann Med. 2008;40(1):56-65. Karjalainen MK, Haataja R, Hallman M
Haplotype analysis of ABCA3: association with respiratory distress in very premature infants.
Ann Med. 2008;40(1):56-65., [PMID:18246475]

Abstract [show]
BACKGROUND: Adenosine triphosphate (ATP)-binding cassette transporter A3 (ABCA3) gene mutations cause fatal respiratory failure in term infants, but common ABCA3 polymorphisms have remained uncharacterized at the population level. AIM: To define a subset of tagging single-nucleotide polymorphisms (tSNPs) which capture most of the variation within the ABCA3 gene, and to assess ABCA3 as a novel candidate gene for susceptibility to respiratory distress syndrome (RDS) in preterm infants. METHODS: Based on an initial screen, nine tSNPs were selected. These 9 tSNPs and a length variation, representing > 90% of haplotypic variation of the gene, and 5 nonsynonymous coding SNPs were genotyped in 267 preterm infants. SNP rs13332514 was genotyped in an additional 48 infants. RESULTS: The fourth common haplotype was overrepresented in very premature infants with RDS, being accounted for by SNP rs13332514 (F353F), with an increased minor allele frequency in RDS. Furthermore, rs13332514 associated significantly with chronic lung disease defined as a requirement for supplemental O2 at 28 postnatal days in very premature infants. CONCLUSIONS: The results are suggestive of an association of a synonymous SNP in the ABCA3 gene with a prolonged course of respiratory distress syndrome in very premature infants and serve as a reference for further population-based studies of ABCA3.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
90 SNP rs149532 (corresponding to residue S1372S) was rare (MAF50.02) in our population, and it was thus excluded from further analysis, together with the nonpolymorphic cSNPs (rs28936412, 875AwT, rs13332760, rs28936690, and rs28936691, corresponding to residues L101P, E292V, V839F, L1552P, and Q1591P, respectively). Login to comment
94 SNP No. or position a Alleles (major/minor) Position b Location Affected residue Minor allele frequency tSNPs c Best pairwise r2 value and the corresponding tSNP d rs28936412 T/C 2316029 Exon 5 L101P 0 - 320-17GwA G/A 2314550 Intron 5 0.055 tSNP1 875AwT A/T 2307765 Exon 9 E292V 0 - rs13332547 C/T 2307425 Intron 9 0.093 tSNP2, r2 51 rs13332514 C/T 2307337 Exon 10 F353F 0.093 tSNP2 rs323069 G/C 2304052 Intron 10 0.271 tSNP3 rs323073 C/T 2298761 Intron 10 0.283 tSNP3, r2 50.831 rs323074 G/A 2298314 Intron 11 0.201 tSNP5, r2 50.848 rs323033 A/G 2296546 Intron 11 0.259 tSNP4 rs323040 G/A 2290527 Intron 12 0.168 tSNP5 rs170447 A/G 2289372 Intron 14 0.396 tSNP6, r2 50.832 rs2240523 T/C 2288658 Intron 14 0.381 tSNP6, r2 50.849 rs17183533 A/G 2285389 Intron 18 0.420 tSNP7, r2 50.986 rs13332760 G/T 2279621 Exon 20 V839F 0 - rs313909 C/T 2277994 Intron 21 0.373 tSNP6 rs2014467 A/G 2276395 Intron 22 0.424 tSNP7 rs2238464 G/A 2272578 Intron 26 0.420 tSNP8 rs149532 T/C 2271431 Exon 27 S1372S 0.020 - rs150926 G/C 2270170 Intron 28 0.372 tSNP6, r2 50.975 rs150928 C/T 2268651 Intron 29 0.226 tSNP9 rs28936690 T/C 2268353 Exon 30 L1552P 0 - rs28936691 A/C 2268018 Exon 31 Q1591P 0 - a rs numbers are shown for SNPs with entries in dbSNP. SNPs without entries in dbSNP are numbered from start codon as advised in (34). Login to comment
129 None of the five nonsynonymous cSNPs (rs28936412, 875AwT, rs13332760, rs28936690, and rs28936691, corresponding to residues L101P, E292V, V839F, L1552P, and Q1591P, respectively) were detected in any individuals. Login to comment
212 Of these, two (corresponding to L101P and Q1591P) have been previously identified in term infants with fatal surfactant deficiency or chronic lung disease (13). 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.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
3 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. Login to comment
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
98 To examine the effect of the mutations found in fatal surfactant deficiency patients on subcellular localization of ABCA3, wild-type and mutant ABCA3-GFP (seven missense mutations L101P, N568D, L982P, G1221S, L1553P, L1580P, and Q1591P, and one nonsense mutation, Ins1518fs) were transiently expressed in HEK293 cells (Fig. 1A). Login to comment
100 In contrast, the L101P, L982P, L1553P, Q1591P, and Ins1518fs mutant proteins were barely detectable at the LAMP3-positive intracellular vesicle membrane (Fig. 2B panels j-l for L101P and data not shown for others). Login to comment
102 In another cell line, mouse lung epithelial MLE12 cells, transiently expressed GFP-tagged wild-type and N568D, G1221S, and L1580P mutant proteins were mainly localized at the intracellular vesicle membrane, whereas the L101P, L982P, L1553P, Q1591P, and Ins1518fs mutant proteins were mainly localized to the ER (data not shown), confirming defective intracellular sorting of L101P, L982P, L1553P, Q1591P, and Ins1518fs ABCA3 mutant proteins. Login to comment
106 In contrast, in the L101P, L982P, L1553P, and Q1591P mutant proteins, which were mainly localized at the ER, the amount of the 180-kDa cleaved form was considerably decreased, compared with that of wild-type protein, to an undetectable level (Fig. 3A). Login to comment
107 In the L982P, L1553P, and Q1591P mutant proteins, although the amount of 220-kDa noncleaved-form protein appears increased compared with that of wild-type protein in Fig. 3A, the total amount of ABCA3-GFP (220-kDa noncleaved form plus 180-kDa cleaved form) did not differ significantly among seven missense mutant proteins and the wild-type protein (n ϭ 3, data not shown). Login to comment
122 Merged images are shown in panels c, f, i, and l. C, HEK293 cells transiently co-expressing mutant ABCA3-GFP proteins (panels a, d, g, j, and m) and DsRed2-ER (panels b, e, h, k, and n) are shown: L101P (panels a-c), L982P (panels d-f), L1553P (panels g-i), Q1591P (panels j-l), and Ins1518fs (panels m-o). Login to comment
124 The scale bar represents 5 ␮m. kDa wild-type ABCA3-GFP and the seven missense mutant (L101P, N568D, L982P, G1221S, L1553P, L1580P, and Q1591P) proteins to produce a 210-kDa deglycosylated protein (Fig. 3B). Login to comment
129 However, in the L101P, L982P, L1553P, Q1591P, and Ins1518fs mutant proteins, the levels of complex-type protein (band I) were dramatically decreased compared with that of wild-type protein (Fig. 3, C and D). Login to comment
131 These results indicate that the N568D, G1221S, and L1580P mutant proteins are mainly localized at the intracellular vesicle membrane accompanied by processing of oligosaccharide from high mannose type to complex type, whereas the four missense mutant (L101P, L982D, L1553P, and Q1591P) and one nonsense mutant (Ins1518fs) proteins remain localized at the ER, with impaired processing of oligosaccharide. 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
221 Interestingly, a single amino acid is substituted with a proline residue in the four mutant ABCA3 proteins (L101P, L982P, L1553P, and Q1591P) that are retained at the ER. Login to comment
215 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
220 Interestingly, a single amino acid is substituted with a proline residue in the four mutant ABCA3 proteins (L101P, L982P, L1553P, and Q1591P) that are retained at the ER. 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.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
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] 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.

Comments [show]

None has been submitted yet.

Sentences [show]
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
304 Although not restricted to any particular domain, functional characterization of a subgroup of ABCA3 mutations (including L101P, L982P, L1553P, Q1591P, G1221S) by transient or stable expression results in their total or partial retention in the ER (30, 103). Login to comment