ABCMdb

ABCA3 p.Arg288Lys

Predicted by SNAP2:	A: N (53%), C: N (53%), D: D (59%), E: D (53%), F: N (53%), G: D (53%), H: N (72%), I: N (61%), K: N (97%), L: N (57%), M: N (61%), N: N (66%), P: N (53%), Q: N (66%), S: N (66%), T: N (72%), V: D (53%), W: D (66%), Y: N (57%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: N, F: D, G: D, H: N, I: D, K: N, L: D, M: D, N: N, P: D, Q: N, S: N, T: N, V: D, W: D, Y: D,

[switch to compact view]
Comments [show]

None has been submitted yet.

Publications
[hide] Respiratory syncytial virus potentiates ABCA3 muta... Hum Mol Genet. 2012 Jun 15;21(12):2793-806. Epub 2012 Mar 20. Kaltenborn E, Kern S, Frixel S, Fragnet L, Conzelmann KK, Zarbock R, Griese M
Respiratory syncytial virus potentiates ABCA3 mutation-induced loss of lung epithelial cell differentiation.
Hum Mol Genet. 2012 Jun 15;21(12):2793-806. Epub 2012 Mar 20., [PMID:22434821]

Abstract [show]
ATP-binding cassette transporter A3 (ABCA3) is a lipid transporter active in lung alveolar epithelial type II cells (ATII) and is essential for their function as surfactant-producing cells. ABCA3 mutational defects cause respiratory distress in newborns and interstitial lung disease (ILD) in children. The molecular pathomechanisms are largely unknown; however, viral infections may initiate or aggravate ILDs. Here, we investigated the impact of the clinically relevant ABCA3 mutations, p.Q215K and p.E292V, by stable transfection of A549 lung epithelial cells. ABCA3 mutations strongly impaired expression of the ATII differentiation marker SP-C and the key epithelial cell adhesion proteins E-cadherin and zonula occludens-1. Concurrently, cells expressing ABCA3 mutation acquired mesenchymal features as observed by increased expression of SNAI1, MMP-2 and TGF-beta1, and elevated phosphorylation of Src. Infection with respiratory syncytial virus (RSV), the most common viral respiratory pathogen in small children, potentiated the observed mutational effects on loss of epithelial and acquisition of mesenchymal characteristics. In addition, RSV infection of cells harboring ABCA3 mutations resulted in a morphologic shift to a mesenchymal phenotype. We conclude that ABCA3 mutations, potentiated by RSV infection, induce loss of epithelial cell differentiation in ATII. Loss of key epithelial features may disturb the integrity of the alveolar epithelium, thereby comprising its functionality. We suggest the impairment of epithelial function as a mechanism by which ABCA3 mutations cause ILD.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
42 Immunohistochemical analysis of the lung tissue of this patient who was the compound heterozygote for ABCA3 p.Q215K and p.R288K showed no ABCA3 staining in ATII cells, and electron microscopy revealed the presence of many electron-dense bodies in the absence of LBs (9). Login to comment
44 Immunohistochemical analysis of the lung tissue of this patient who was the compound heterozygote for ABCA3 p.Q215K and p.R288K showed no ABCA3 staining in ATII cells, and electron microscopy revealed the presence of many electron-dense bodies in the absence of LBs (9). Login to comment

[hide] Surfactant protein C mutations are the basis of a ... Am J Respir Crit Care Med. 2010 Dec 1;182(11):1419-25. Epub 2010 Jul 23. van Moorsel CH, van Oosterhout MF, Barlo NP, de Jong PA, van der Vis JJ, Ruven HJ, van Es HW, van den Bosch JM, Grutters JC
Surfactant protein C mutations are the basis of a significant portion of adult familial pulmonary fibrosis in a dutch cohort.
Am J Respir Crit Care Med. 2010 Dec 1;182(11):1419-25. Epub 2010 Jul 23., [PMID:20656946]

Abstract [show]
RATIONALE: Familial clustering of adult idiopathic interstitial pneumonias (IIP) suggests that genetic factors might play an important role in disease development. Mutations in the gene encoding surfactant protein C (SFTPC) have been found in children and families with idiopathic pneumonias, whereas cocarriage of a mutation in ATP-binding cassette subfamily A member 3 (ABCA3) was postulated to have a disease-modifying effect. OBJECTIVES: To investigate the contribution of SFTPC mutations to adult familial pulmonary fibrosis (FPF) and the disease-modifying effect of mutations in ABCA3 within their families. METHODS: Twenty-two unrelated patients with FPF (10%) were identified within our single-center cohort of 229 patients with IIP. SFTPC was sequenced in 20 patients with FPF and 20 patients with sporadic IIP. In patients with an SFTPC mutation, sequencing of ABCA3 was performed. Discovered variants were typed in more than 100 control subjects and 121 additional patients with sporadic IIP. MEASUREMENTS AND MAIN RESULTS: In 5/20 unrelated patients with FPF (25%; confidence interval, 10-49) a mutation in SFTPC was detected: M71V, IVS4+2, and three times I73T. No mutations were detected in the sporadic or control cohort. Patients with SFTPC mutations presented with a histopathological pattern of usual interstitial pneumonia and nodular septa thickening and multiple lung cysts in combination with ground glass or diffuse lung involvement on chest high-resolution computed tomography. Two variants in ABCA3 were found in adult patients with FPF but not in affected children. CONCLUSIONS: Mutations in SFTPC are a frequent cause of FPF in adult patients in our cohort. Nonclassifiable radiological patterns with cystic changes and histopathological patterns of usual interstitial pneumonia are characteristics of adult SFTPC mutation carriers.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
57 Variations SFTPC M71V, SFTPC IVS412, and ABCA3 R288K were analyzed with high-resolution melting analysis (ABI Fast 7500RT; Applied Biosystems, Foster City, CA). Login to comment
79 ABCA3 Mutation Analysis Sequencing of exonic ABCA3 gene regions in patients with FPF with SFTPC mutations revealed two amino acid substitutions: S1262G and R288K (Table 3, Figure 2). Login to comment
80 In the kindred of FPF9, S1262G did not segregate with disease but was inherited from her healthy father. Login to comment
81 ABCA3-R288K was found in FPF20, whereas a third ABCA3 variant, R280H, was found in one patient with sporadic disease. Login to comment
154 NEWLY IDENTIFIED VARIANTS IN SURFACTANT PROTEIN C AND ATP-BINDING CASSETTE SUBFAMILY A MEMBER 3 Allele Frequency Gene cDNA Position Variant Name Consequence FPF sp.IIP Control Subjects SFTPC c.211 A.G M71V Nonsynonymous FPF7 0 0 c.218 T.C I73T Nonsynonymous FPF9, FPF18, FPF20 0 0 c.43512 T.C IVS412 Splice site FPF10 0 0 ABCA3 c.839G.A R280H Nonsynonymous - 0.004 0.015 c.863G.A R288K Nonsynonymous FPF20 0 0.015 c.3784 A.G S1262G Nonsynonymous FPF9 0 0.005 Definition of abbreviations: ABCA3 5 gene encoding ATP-binding cassette subfamily A member 3; SFTPC 5 gene encoding surfactant protein C; sp.IIP 5 sporadic idiopathic interstitial pneumonia. Login to comment
58 Variations SFTPC M71V, SFTPC IVS412, and ABCA3 R288K were analyzed with high-resolution melting analysis (ABI Fast 7500RT; Applied Biosystems, Foster City, CA). Login to comment
82 ABCA3-R288K was found in FPF20, whereas a third ABCA3 variant, R280H, was found in one patient with sporadic disease. Login to comment
155 NEWLY IDENTIFIED VARIANTS IN SURFACTANT PROTEIN C AND ATP-BINDING CASSETTE SUBFAMILY A MEMBER 3 Allele Frequency Gene cDNA Position Variant Name Consequence FPF sp.IIP Control Subjects SFTPC c.211 A.G M71V Nonsynonymous FPF7 0 0 c.218 T.C I73T Nonsynonymous FPF9, FPF18, FPF20 0 0 c.43512 T.C IVS412 Splice site FPF10 0 0 ABCA3 c.839G.A R280H Nonsynonymous - 0.004 0.015 c.863G.A R288K Nonsynonymous FPF20 0 0.015 c.3784 A.G S1262G Nonsynonymous FPF9 0 0.005 Definition of abbreviations: ABCA3 5 gene encoding ATP-binding cassette subfamily A member 3; SFTPC 5 gene encoding surfactant protein C; sp.IIP 5 sporadic idiopathic interstitial pneumonia. Login to comment

[hide] Alteration of the pulmonary surfactant system in f... Am J Respir Crit Care Med. 2006 Sep 1;174(5):571-80. Epub 2006 May 25. Brasch F, Schimanski S, Muhlfeld C, Barlage S, Langmann T, Aslanidis C, Boettcher A, Dada A, Schroten H, Mildenberger E, Prueter E, Ballmann M, Ochs M, Johnen G, Griese M, Schmitz G
Alteration of the pulmonary surfactant system in full-term infants with hereditary ABCA3 deficiency.
Am J Respir Crit Care Med. 2006 Sep 1;174(5):571-80. Epub 2006 May 25., [PMID:16728712]

Abstract [show]
RATIONALE: ABCA3 mutations are known to cause fatal surfactant deficiency. OBJECTIVE: We studied ABCA3 protein expression in full-term newborns with unexplained respiratory distress syndrome (URDS) as well as the relevance of ABCA3 mutations for surfactant homeostasis. METHODS: Lung tissue of infants with URDS was analyzed for the expression of ABCA3 in type II pneumocytes. Coding exons of the ABCA3 gene were sequenced. Surfactant protein expression was studied by immunohistochemistry, immunoelectron microscopy, and Western blotting. RESULTS: ABCA3 protein expression was found to be greatly reduced or absent in 10 of 14 infants with URDS. Direct sequencing revealed distinct ABCA3 mutations clustering within vulnerable domains of the ABCA3 protein. A strong expression of precursors of surfactant protein B (pro-SP-B) but only low levels and aggregates of mature surfactant protein B (SP-B) within electron-dense bodies in type II pneumocytes were found. Within the matrix of electron-dense bodies, we detected precursors of SP-C (pro-SP-C) and cathepsin D. SP-A was localized in small intracellular vesicles, but not in electron-dense bodies. SP-A and pro-SP-B were shown to accumulate in the intraalveolar space, whereas mature SP-B and SP-C were reduced or absent, respectively. CONCLUSION: Our data provide evidence that ABCA3 mutations are associated not only with a deficiency of ABCA3 but also with an abnormal processing and routing of SP-B and SP-C, leading to severe alterations of surfactant homeostasis and respiratory distress syndrome. To identify infants with hereditary ABCA3 deficiency, we suggest a combined diagnostic approach including immunohistochemical, ultrastructural, and mutation analysis.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
123 MUTATIONS OF THE ABCA3 GENE IN THE STUDY GROUP AND ABCA3 PROTEIN EXPRESSION IN TYPE II PNEUMOCYTES IN INDEX PATIENTS ABCA3 Protein Expression in Type II Pneumocytes in Index Patients Family Localization* Nucleotide Deviation Structural Relevance Affected Domain (immunohistochemical score)† 1 Exon 15 c1755C Ͼ G Silent polymorphism - Weak (1) Exon 15 c1814G Ͼ A R605Q (Arg Ͼ Gln) NBD 1 Exon 31 c4877-8delAG Frameshift/Stop C-terminus 2 Exon 10 c1058C Ͼ T Silent polymorphism - Weak (1) Intron 15 c1897-1G Ͼ C Acceptor splice-site mutation NBD 1 3 Exon 8 c643C Ͼ A Q215K (Gln Ͼ Lys) First extracellular loop Absent (0) Exon 8 c863G Ͼ A R288K (Arg Ͼ Lys) First extracellular loop 4 Intron 21 c3005-1G Ͼ A Acceptor splice-site mutation Second half-size transporter Weak (1) 5 Exon 5 c128G Ͼ T (het) R43L (Arg Ͼ Leu) First extracellular loop Absent (0) Exon 8 c863G Ͼ A (het) R288K (Arg Ͼ Lys) First extracellular loop Exon 15 c1755C Ͼ G (het) Silent polymorphism - Exon 31 c4751delT (het) Frameshift/Stop C-terminus 6 Exon 14 c1736T Ͼ C (het) L579P (Leu Ͼ Pro) NBD 1 Weak (1) Exon 25 c3812delG (het) Frameshift/Stop Last extracellular loop, C-terminus 7 Exon 30 c4681 C Ͼ T R1561X (Arg Ͼ Stop) C-terminus Weak (1) 8 Exon 19 c2429-30delTT Frameshift/Stop Second half-size transporter Weak (1) Definition of abbreviation: NBD ϭ nucleotide-binding domain. 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.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
52 Two mutations previously associated with respiratory disease in newborns and children, p.R288K (c.863G.A) and p.E292V (c.875A.T),22-24 accounted for 13 of the 16 mutated alleles among RDS infants. Login to comment
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
74 TABLE 4 Rare Mutations Identified Among Infants of African Descent Gene Mutations RDS (n = 44) Non-RDS (n = 196) Missouri Population (n = 195) ESP (n = 1869) ABCA3 R20W 2 V129M 12 F245L 1 R280C 1 R280H 2 R288K 7 (0.4%)a E292V 4 (0.2%)a F353L 3 N555S 5 G571R 1 T574I 1 2 P585S 1 L707F 14 G739A 2 15 V968M 1 1 F1164V 1 N1418S 1 R1474W 1 1 A1660V 1 Infants with variant 2 (4.5%)a 3 (1.5%)a 3 (1.5%)a 72 (3.9%)a SFTPC R35C 1 V39M 1 G57S 1 R81C 1 SFTPC allele (carrier) frequency 4 (0.2%)a CHPT1 G70R 2 T87M 1 G115A 1 Y365H 3 CHPT1 allele (carrier) frequency 7 (0.4%)a LPCAT1 A194V 6 L255Q 2 D392H 1 R526W 1 LPCAT1 allele (carrier) frequency 10 (0.5%)a PCYT1B G199D 1 (0.05%)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
91 For example, p.R288K is predicted to be benign (tolerated) by both prediction algorithms and would not have been included in our analysis had it not been previously associated with pediatric respiratory disease.22 Its threefold to fourfold enrichment among the European-descent RDS infants suggests an important role in the genetic pathogenesis of RDS. Login to comment

[hide] Genotype-phenotype correlations for infants and ch... Am J Respir Crit Care Med. 2014 Jun 15;189(12):1538-43. doi: 10.1164/rccm.201402-0342OC. Wambach JA, Casey AM, Fishman MP, Wegner DJ, Wert SE, Cole FS, Hamvas A, Nogee LM
Genotype-phenotype correlations for infants and children with ABCA3 deficiency.
Am J Respir Crit Care Med. 2014 Jun 15;189(12):1538-43. doi: 10.1164/rccm.201402-0342OC., [PMID:24871971]

Abstract [show]
RATIONALE: Recessive mutations in the ATP-binding cassette transporter A3 (ABCA3) cause lethal neonatal respiratory failure and childhood interstitial lung disease. Most ABCA3 mutations are private. OBJECTIVES: To determine genotype-phenotype correlations for recessive ABCA3 mutations. METHODS: We reviewed all published and unpublished ABCA3 sequence and phenotype data from our prospective genetic studies of symptomatic infants and children at Washington and Johns Hopkins Universities. Mutations were classified based on their predicted disruption of protein function: frameshift and nonsense mutations were classified as "null," whereas missense, predicted splice site mutations, and insertion/deletions were classified as "other." We compared age of presentation and outcomes for the three genotypes: null/null, null/other, and other/other. MEASUREMENTS AND MAIN RESULTS: We identified 185 infants and children with homozygous or compound heterozygous ABCA3 mutations and lung disease. All of the null/null infants presented with respiratory failure at birth compared with 75% of infants with null/other or other/other genotypes (P = 0.00011). By 1 year of age, all of the null/null infants had died or undergone lung transplantation compared with 62% of the null/other and other/other children (P < 0.0001). CONCLUSIONS: Genotype-phenotype correlations exist for homozygous or compound heterozygous mutations in ABCA3. Frameshift or nonsense ABCA3 mutations are predictive of neonatal presentation and poor outcome, whereas missense, splice site, and insertion/deletions are less reliably associated with age of presentation and prognosis. Counseling and clinical decision making should acknowledge these correlations.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
134 Alleles with ABCA3 Variants in Cis Allele Number of Subjects with Allele R43C-P1653L 1 D115E-D253H 1 (2 alleles, 1 subject homozygous) V129M-V1495M 1 W179C-P770L 3 (3 subjects heterozygous) E195K-R1271Q 1 R280C-Q1589X 2 (3 alleles, 1 subject homozygous, 1 subject heterozygous) R288K-S693L 2 (2 subjects heterozygous) c.1474_1475insT-D953N 4 (3 siblings homozygous, 1 subject heterozygous) P766S-L960F 4 (4 subjects heterozygous) H778R-L1252P 1 A54T-R1482W-IVS25-98 C . Login to comment