ABCA3 p.Pro147Leu
| Predicted by SNAP2: | A: N (66%), C: N (61%), D: N (78%), E: N (66%), F: D (59%), G: N (61%), H: N (66%), I: D (71%), K: D (75%), L: D (71%), M: N (57%), N: N (72%), Q: N (72%), R: N (61%), S: N (78%), T: N (82%), V: N (61%), W: D (71%), Y: N (53%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Inherited surfactant deficiency caused by uniparen... J Pediatr. 2009 Dec;155(6):854-859.e1. Epub 2009 Aug 3. Hamvas A, Nogee LM, Wegner DJ, Depass K, Christodoulou J, Bennetts B, McQuade LR, Gray PH, Deterding RR, Carroll TR, Kammesheidt A, Kasch LM, Kulkarni S, Cole FS
Inherited surfactant deficiency caused by uniparental disomy of rare mutations in the surfactant protein-B and ATP binding cassette, subfamily a, member 3 genes.
J Pediatr. 2009 Dec;155(6):854-859.e1. Epub 2009 Aug 3., [PMID:19647838]
Abstract [show]
OBJECTIVE: To characterize inheritance of homozygous, rare, recessive loss-of-function mutations in surfactant protein-B (SFTPB) or ATP binding cassette, subfamily A, member 3 (ABCA3) genes in newborns with lethal respiratory failure. STUDY DESIGN: We resequenced genes from parents whose infants were homozygous for mutations in SFTPB or ABCA3. For infants with only 1 heterozygous parent, we performed microsatellite analysis for chromosomes 2 (SFTPB) and 16 (ABCA3). RESULTS: We identified 1 infant homozygous for the g.1549C > GAA mutation (121ins2) in SFTPB for whom only the mother was heterozygous and 3 infants homozygous for mutations in ABCA3 (p.K914R, p.P147L, and c.806_7insGCT) for whom only the fathers were heterozygous. For the SP-B-deficient infant, microsatellite markers confirmed maternal heterodisomy with segmental isodisomy. Microsatellite analysis confirmed paternal isodisomy for the 3 ABCA3-deficient infants. Two ABCA3-deficient infants underwent lung transplantation at 3 and 5 months of age, respectively, and 2 infants died. None exhibited any nonpulmonary phenotype. CONCLUSIONS: Uniparental disomy should be suspected in infants with rare homozygous mutations in SFTPB or ABCA3. Confirmation of parental carrier status is important to provide recurrence risk and to monitor expression of other phenotypes that may emerge through reduction to homozygosity of recessive alleles.
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No. Sentence Comment
3 Results We identified 1 infant homozygous for the g.1549C > GAA mutation (121ins2) in SFTPB for whom only the mother was heterozygous and 3 infants homozygous for mutations in ABCA3 (p.K914R, p.P147L, and c.806_7insGCT) for whom only the fathers were heterozygous.
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ABCA3 p.Pro147Leu 19647838:3:194
status: NEW54 Sequence analysis of ABCA3 revealed a homozygous C>T transition in codon 147 that changes a proline to leucine (c.440C>T; p.P147L) and is predicted to be deleterious by SIFT and Polyphen.
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ABCA3 p.Pro147Leu 19647838:54:124
status: NEW81 Informative variants in ABCA3 Variant ID Child Mother Father ABCA3 infant 1 rs323017 c.2514-93 A > G (Intron 19) G/G A/A A/G rs313908 c.2701-33 C > G (Intron 20) G/G C/C C/G Mutation c.2741A > G (p.K914R) G/G A/A A/G rs313909 c.3004 + 34 C > T (Intron 21) C/C T/T C/T rs1183064 c.3704-116 A > T (Intron 24) T/T A/A A/T ABCA3 infant 2 N/A c.-27 + 126 G > A (Intron 3) A/A G/G A/G Mutation c.440C > T (p.P147L) T/T C/C C/T rs170447 c.1741 + 33 G > A (Intron 14) A/A A/G A/G rs2240523 c.1742-116 C > T (Intron 14) C/C C/T C/T ABCA3 infant 3 Mutation c.806_807insGCT Ins/ins Normal/normal Ins/normal THE JOURNAL OF PEDIATRICS www.jpeds.com Vol. 155, No.
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ABCA3 p.Pro147Leu 19647838:81:402
status: NEW53 Sequence analysis of ABCA3 revealed a homozygous C>T transition in codon 147 that changes a proline to leucine (c.440C>T; p.P147L) and is predicted to be deleterious by SIFT and Polyphen.
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ABCA3 p.Pro147Leu 19647838:53:124
status: NEW[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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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.
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ABCA3 p.Pro147Leu 17517255:51:2052
status: NEW48 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.
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ABCA3 p.Pro147Leu 17517255:48:2057
status: NEW[hide] Disruption of N-linked glycosylation promotes prot... Am J Physiol Lung Cell Mol Physiol. 2013 Dec;305(12):L970-80. doi: 10.1152/ajplung.00184.2013. Epub 2013 Oct 18. Beers MF, Zhao M, Tomer Y, Russo SJ, Zhang P, Gonzales LW, Guttentag SH, Mulugeta S
Disruption of N-linked glycosylation promotes proteasomal degradation of the human ATP-binding cassette transporter ABCA3.
Am J Physiol Lung Cell Mol Physiol. 2013 Dec;305(12):L970-80. doi: 10.1152/ajplung.00184.2013. Epub 2013 Oct 18., [PMID:24142515]
Abstract [show]
The lipid transport protein, ABCA3, expressed in alveolar type 2 (AT2) cells, is critical for surfactant homeostasis. The first luminal loop of ABCA3 contains three putative N-linked glycosylation sites at residues 53, 124, and 140. A common cotranslational modification, N-linked glycosylation, is critical for the proper expression of glycoproteins by enhancing folding, trafficking, and stability through augmentation of the endoplasmic reticulum (ER) folding cycle. To understand its role in ABCA3 biosynthesis, we utilized EGFP-tagged fusion constructs with either wild-type or mutant ABCA3 cDNAs that contained glutamine for asparagine substitutions at the putative glycosylation motifs. In A549 cells, inhibition of glycosylation by tunicamycin increased the electrophoretic mobility (Mr) and reduced the expression level of wild-type ABCA3 in a dose-dependent manner. Fluorescence imaging of transiently transfected A549 or primary human AT2 cells showed that although single motif mutants exhibited a vesicular distribution pattern similar to wild-type ABCA3, mutation of N124 and N140 residues resulted in a shift toward an ER-predominant distribution. By immunoblotting, the N53 mutation exhibited no effect on either the Mr or ABCA3 expression level. In contrast, substitutions at N124 or N140, as well a N124/N140 double mutation, resulted in increased electrophoretic mobility indicative of a glycosylation deficiency accompanied by reduced overall expression levels. Diminished steady-state levels of glycan-deficient ABCA3 isoforms were rescued by treatment with the proteasome inhibitor MG132. These results suggest that cotranslational N-linked glycosylation at N124 and N140 is critical for ABCA3 stability, and its disruption results in protein destabilization and proteasomal degradation.
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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.
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ABCA3 p.Pro147Leu 24142515:229:178
status: NEW