ABCMdb

ABCA3 p.Arg1583Trp

Predicted by SNAP2:	A: D (80%), C: D (80%), D: D (75%), E: D (75%), F: D (80%), G: D (75%), H: D (71%), I: D (80%), K: N (57%), L: D (80%), M: D (80%), N: D (59%), P: D (75%), Q: D (71%), S: D (66%), T: D (63%), V: D (80%), W: D (91%), Y: D (80%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: N, L: D, M: D, N: D, P: D, Q: D, S: D, T: D, V: D, W: D, Y: D,

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[hide] Molecular and cellular characteristics of ABCA3 mu... Hum Mol Genet. 2012 Feb 15;21(4):765-75. Epub 2011 Nov 7. Flamein F, Riffault L, Muselet-Charlier C, Pernelle J, Feldmann D, Jonard L, Durand-Schneider AM, Coulomb A, Maurice M, Nogee LM, Inagaki N, Amselem S, Dubus JC, Rigourd V, Bremont F, Marguet C, Brouard J, de Blic J, Clement A, Epaud R, Guillot L
Molecular and cellular characteristics of ABCA3 mutations associated with diffuse parenchymal lung diseases in children.
Hum Mol Genet. 2012 Feb 15;21(4):765-75. Epub 2011 Nov 7., [PMID:22068586]

Abstract [show]
ABCA3 (ATP-binding cassette subfamily A, member 3) is expressed in the lamellar bodies of alveolar type II cells and is crucial to pulmonary surfactant storage and homeostasis. ABCA3 gene mutations have been associated with neonatal respiratory distress (NRD) and pediatric interstitial lung disease (ILD). The objective of this study was to look for ABCA3 gene mutations in patients with severe NRD and/or ILD. The 30 ABCA3 coding exons were screened in 47 patients with severe NRD and/or ILD. ABCA3 mutations were identified in 10 out of 47 patients, including 2 homozygous, 5 compound heterozygous and 3 heterozygous patients. SP-B and SP-C expression patterns varied across patients. Among patients with ABCA3 mutations, five died shortly after birth and five developed ILD (including one without NRD). Functional studies of p.D253H and p.T1173R mutations revealed that p.D253H and p.T1173R induced abnormal lamellar bodies. Additionally, p.T1173R increased IL-8 secretion in vitro. In conclusion, we identified new ABCA3 mutations in patients with life-threatening NRD and/or ILD. Two mutations associated with ILD acted via different pathophysiological mechanisms despite similar clinical phenotypes.

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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
79 BALF analysis Western blot analysis of surfactant proteins (Fig. 4) was performed in seven patients, who had the following ABCA3 mutations: p.D253H (patient 2), p.T1173R (patient 1), p.L462R/ p.G964S (patient 3), p.G202R/p.L303V (patient 7), p.Y963C (patient 8), p.R1583W/p.S128Rfs (patient 4) and p.S872G (patient 10), respectively. Login to comment
132 Finally, parents heterozygous for the p.R1583W, p.S128Rfs, p.R1521W or p.R208V mutations were not affected. 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
81 BALF analysis Western blot analysis of surfactant proteins (Fig. 4) was performed in seven patients, who had the following ABCA3 mutations: p.D253H (patient 2), p.T1173R (patient 1), p.L462R/ p.G964S (patient 3), p.G202R/p.L303V (patient 7), p.Y963C (patient 8), p.R1583W/p.S128Rfs (patient 4) and p.S872G (patient 10), respectively. Login to comment
134 Finally, parents heterozygous for the p.R1583W, p.S128Rfs, p.R1521W or p.R208V mutations were not affected. Login to comment

[hide] Hereditary interstitial lung diseases manifesting ... Pediatr Res. 2014 Nov;76(5):453-8. doi: 10.1038/pr.2014.114. Epub 2014 Aug 8. Akimoto T, Cho K, Hayasaka I, Morioka K, Kaneshi Y, Furuta I, Yamada M, Ariga T, Minakami H
Hereditary interstitial lung diseases manifesting in early childhood in Japan.
Pediatr Res. 2014 Nov;76(5):453-8. doi: 10.1038/pr.2014.114. Epub 2014 Aug 8., [PMID:25105258]

Abstract [show]
BACKGROUND: Genetic variations associated with interstitial lung diseases (ILD) have not been extensively studied in Japanese infants. METHODS: Forty-three infants with unexplained lung dysfunction were studied. All 43, 22, and 17 infants underwent analyses of surfactant protein (SP)-C gene (SFTPC) and ATP-binding cassette A3 gene (ABCA3), SP-B gene (SFTPB), and SP-B western blotting, respectively. Two and four underwent assessment of granulocyte macrophage colony-stimulating factor-stimulating phosphorylation of signal transducer and activator of transcription-5 (pSTAT-5) and analyses of FOXF1 gene (FOXF1), respectively. RESULTS: ILD were diagnosed clinically in nine infants: four, three, and two had interstitial pneumonitis, hereditary pulmonary alveolar proteinosis (hPAP), and alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV), respectively. Genetic variations considered responsible were detected in six (67%) of the nine infants with ILD: three with hPAP (SFTPC p.Leu45Arg and p.Gln145fs, and ABCA3 p.Arg1583Trp/p.Val1495CysfsX21), two with interstitial pneumonitis (SFTPC p.Lys63Glu and p.Ser72Asn/p.Gly100Ala), and one with ACD/MPV (FOXF1 p.Leu300ArgfsX79). None showed SFTPB mutations or defects in pSTAT-5. The 17 bronchoalveolar lavage or tracheal aspirates contained enough SP-B protein. CONCLUSION: The SP-C abnormality was most prevalent, and SP-B deficiency was rare in Japanese infants with hereditary ILD.

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5 Genetic variations considered responsible were detected in six (67%) of the nine infants with ILD: three with hPAP (SFTPC p.Leu45Arg and p.Gln145fs, and ABCA3 p.Arg1583Trp/p.Val1495CysfsX21), two with interstitial pneumonitis (SFTPC p.Lys63Glu and p.Ser72Asn/p.Gly100Ala), and one with ACD/MPV (FOXF1 p.Leu300ArgfsX79). Login to comment
64 To our knowledge, 10 other mutations in six cases (cases 2-5, 7, and 8) have not been reported to date, i.e., four SFTPC mutations of heterozygous p.Gln145fs, heterozygous p.Lys63Glu, p.Ser72Asn, and p.Gly100Ala, and six ABCA3 mutations of p.Arg1583Trp, p.Val1495CysfsX21, p.Pro73Leu, p.Gly1205Arg, p.Thr761Met, and p.Ala1362Val. Login to comment
67 Frameshift mutations were detected in case 2 Table 3.ߒ Eight patients in whom genetic variations were found Case BW/GW Onset Diagnosis AV iNO Genotype SIFT/ polyphen-2 Origin of variations Treatment Outcome 1 3,204/40 0 d hPAP Yes No SFTPC c.134T>C: p.Leu45Arg (het) Damaging/ damaging Denovo Surfactant, steroids, and Hch Undergoing treatment, 43 mo 2 2,600/40 6 d hPAP Yes No SFTPC c.433delC: p.Gln145fs (het) Not done Unknownc Surfactant, steroids, and Hch Died, 77 d 3 3,230/40 0 d hPAP Yes Yes ABCA3 c.4747C>T: p.Arg1583Trp, Damaging/ damaging Mother (asymptomatic) Surfactant, steroids, and Hch Died, 7 mo ABCA3 c.4483_4507del25: p.Val1495CysfsX21 Not done Father (asymptomatic) 4 3,060/41 5 mo IPa No No SFTPC c.187A>G: p.Lys63Glu (het) Damaging/ damaging Mother (asymptomatic) and mother`s father (pulmonary fibrosis) Steroids and Hch Undergoing treatment, 54 mo 5 3,520/38 2 wk IP Yes No SFTPC c.215G>A: p.Ser72Asn Damaging/ damaging Unknownc Steroids, CsA, CPM, and AZP Undergoing treatment, 13 y SFTPC c.299G>C: p.Gly100Ala Damaging/ benign 6 3,344/41 3 mo ACD/MPV Yes Yes FOXF1 c.899delT: p.Leu300ArgfsX79 (het) Not done Denovo Steroids, vasodilator Undergoing treatment, 24 mo 7 3,194/40 0 d URD Yes No ABCA3 c.218C>T: p.Pro73Leu Tolerated/ benignb Unknownc None Recovered ABCA3 c.3613G>A: p.Gly1205Arg Tolerated/ benignb 8 778/27 8 mo CLD, PH Yes No ABCA3 c.2282C>T: p.Thr761Met, Damaging/ damaging Mother (asymptomatic) Vasodilator Undergoing treatment, 17 mo ABCA3 c.4085C>T: p.Ala1362Val Tolerated/ benignb Father (asymptomatic) ACD/MPV, alveolar capillary dysplasia with misalignment of pulmonary veins; AV, assisted ventilation; AZP, azathioprine; BW/GW, birth weight/gestational week at delivery; CLD, chronic lung disease; CPM, cyclophosphamide; CsA, cyclosporine A; Hch, hydroxychloroquine; hPAP, hereditary pulmonary alveolar proteinosis; iNO, inhaled nitric oxide; IP, interstitial pneumonitis; PH, pumonary hypertension; URD, unexplained respiratory distress. Login to comment
74 The p.Arg1583Trp in case 3 was judged as "damaging" with both SIFT and polyphen-2. Login to comment