ABCMdb

ABCA3 p.Arg208Trp

Predicted by SNAP2:	A: D (71%), C: D (71%), D: D (71%), E: D (66%), F: D (71%), G: D (66%), H: N (53%), I: D (71%), K: N (61%), L: D (71%), M: D (71%), N: N (53%), P: D (71%), Q: D (53%), S: D (53%), T: N (53%), V: D (71%), W: D (80%), Y: D (66%),
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: N, P: D, Q: N, 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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39 The two mutations p.G210V and p.R208W have been already identified (13,14). Login to comment
41 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). Login to comment
54 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] + [?] Login to comment
68 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). Login to comment
43 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). Login to comment
56 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] + [?] Login to comment
70 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). 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.

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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

[hide] Unexplained neonatal respiratory distress due to c... J Pediatr. 2007 Jun;150(6):649-53, 653.e1. Somaschini M, Nogee LM, Sassi I, Danhaive O, Presi S, Boldrini R, Montrasio C, Ferrari M, Wert SE, Carrera P
Unexplained neonatal respiratory distress due to congenital surfactant deficiency.
J Pediatr. 2007 Jun;150(6):649-53, 653.e1., [PMID:17517255]

Abstract [show]
Genetic abnormalities of pulmonary surfactant were identified by DNA sequence analysis in 14 (12 full-term, 2 preterm) of 17 newborn infants with fatal respiratory distress of unknown etiology. Deficiency of adenosine triphosphate-binding cassette protein, member A3 (n = 12) was a more frequent cause of this phenotype than deficiency of surfactant protein B (n = 2).

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42 Conservation of codons between orthologs (canis, mus, rattus, fugu, drosophila) was evaluated on amino acid sequences aligned using computer software (data not shown).10 Two of the missense mutations (R155Q and R208W) were found on more than 1 affected chromosome in unrelated patients. Login to 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
39 Conservation of codons between orthologs (canis, mus, rattus, fugu, drosophila) was evaluated on amino acid sequences aligned using computer software (data not shown).10 Two of the missense mutations (R155Q and R208W) were found on more than 1 affected chromosome in unrelated patients. 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

[hide] Persistent tachypnea and hypoxia in a 3-month-old ... J Pediatr. 2006 Nov;149(5):702-706. Prestridge A, Wooldridge J, Deutsch G, Young LR, Wert SE, Whitsett JA, Nogee L
Persistent tachypnea and hypoxia in a 3-month-old term infant.
J Pediatr. 2006 Nov;149(5):702-706., [PMID:17095348]

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82 Subsequent analysis of archived lung tissue indicated that the child was a compound heterozygote for 2 ABCA3 missense mutations (R208W and M760R), finally establishing a specific etiologic cause for the child`s lung disease. Login to comment
81 Subsequent analysis of archived lung tissue indicated that the child was a compound heterozygote for 2 ABCA3 missense mutations (R208W and M760R), finally establishing a specific etiologic cause for the child`s lung disease. Login to comment

[hide] Single ABCA3 mutations increase risk for neonatal ... Pediatrics. 2012 Dec;130(6):e1575-82. doi: 10.1542/peds.2012-0918. Epub 2012 Nov 19. Wambach JA, Wegner DJ, Depass K, Heins H, Druley TE, Mitra RD, An P, Zhang Q, Nogee LM, Cole FS, Hamvas A
Single ABCA3 mutations increase risk for neonatal respiratory distress syndrome.
Pediatrics. 2012 Dec;130(6):e1575-82. doi: 10.1542/peds.2012-0918. Epub 2012 Nov 19., [PMID:23166334]

Abstract [show]
BACKGROUND AND OBJECTIVE: Neonatal respiratory distress syndrome (RDS) due to pulmonary surfactant deficiency is heritable, but common variants do not fully explain disease heritability. METHODS: Using next-generation, pooled sequencing of race-stratified DNA samples from infants >/=34 weeks' gestation with and without RDS (n = 513) and from a Missouri population-based cohort (n = 1066), we scanned all exons of 5 surfactant-associated genes and used in silico algorithms to identify functional mutations. We validated each mutation with an independent genotyping platform and compared race-stratified, collapsed frequencies of rare mutations by gene to investigate disease associations and estimate attributable risk. RESULTS: Single ABCA3 mutations were overrepresented among European-descent RDS infants (14.3% of RDS vs 3.7% of non-RDS; P = .002) but were not statistically overrepresented among African-descent RDS infants (4.5% of RDS vs 1.5% of non-RDS; P = .23). In the Missouri population-based cohort, 3.6% of European-descent and 1.5% of African-descent infants carried a single ABCA3 mutation. We found no mutations among the RDS infants and no evidence of contribution to population-based disease burden for SFTPC, CHPT1, LPCAT1, or PCYT1B. CONCLUSIONS: In contrast to lethal neonatal RDS resulting from homozygous or compound heterozygous ABCA3 mutations, single ABCA3 mutations are overrepresented among European-descent infants >/=34 weeks' gestation with RDS and account for ~10.9% of the attributable risk among term and late preterm infants. Although ABCA3 mutations are individually rare, they are collectively common among European- and African-descent individuals in the general population.

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57 Although the European-descent RDS infants had a lower mean gestational age than non-RDS infants (Table 1), there was no statistical difference in mean gestational age or birth weight for European-descent infants with or without ABCA3 mutations, thereby suggesting that ABCA3 mutations are associated with RDS rather than TABLE 3 Rare Mutations Identified Among Infants of European Descent Gene Mutation RDS (n = 112) Non-RDS (n = 161) Missouri Population (n = 871) ESP (n = 3510) ABCA3 R20W 2 R43C 1 V129M 1 A132T 1 V133M 1 R208W 1 L212M 3 14 P246L 1 R280C 1 R280H 12 R288K 6 (5.3%)a 2 (1.2%)a 14 (1.6%)a 54 (1.5%)a E292V 7 (6.2%)a 1 (0.6%)a 1 (0.1%)a 32 (0.9%)a V480M 1 E522K 1 I561F 1 G594R 1 L654V 2 G668D 1 R671C 1 S693L 1 7 E725K 1 T761K 1 R1081W 1 I1117M 1 A1119E 1 A1297T 1 I1382M 1 T1424M 1 M1428L 2 R1457Q 1 A1466T 1 R1474W 1 3 8 29 V1495M 1 S1516N 1 R1561Q 1 V1588M 1 c.3863-98 C.T 1 ABCA3 allele (carrier) frequency 16 (14.3%)a 6 (3.7%)a 31 (3.6%)a 176 (5.0%)a SFTPC D15N 1 I26V 1 A53T 1 1 L110R 1 SFTPC allele (carrier) frequency 1 (0.1%)a 4 (0.1%)a CHPT1 S40W 4 W60C 1 D132E 2 CHPT1 allele (carrier) frequency 7 (0.2%)a LPCAT1 G110S 1 P230S 1 R237Q 1 M298V 1 E312K 1 F460V 1 R526W 1 LPCAT1 allele (carrier) frequency 1 (0.1%)a 6 (0.2%)a PCYT1B V192F 1(0.03%)a Identified mutations are predicted to be damaging according to both SIFT and PolyPhen (accessed March 2012) or previous association with pediatric respiratory disease. Blank boxes indicate the mutations were not observed in that specific cohort. Login to comment