ABCA3 p.Leu941Pro
| Predicted by SNAP2: | A: N (53%), C: N (61%), D: D (71%), E: N (53%), F: N (66%), G: D (66%), H: N (57%), I: N (93%), K: D (53%), M: N (93%), N: D (53%), P: D (59%), Q: N (61%), R: D (59%), S: N (53%), T: N (66%), V: N (82%), W: D (66%), Y: N (61%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: N, G: D, H: D, I: N, K: D, M: N, N: D, P: D, Q: D, R: D, S: D, T: D, V: N, W: D, Y: D, |
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[hide] An intronic ABCA3 mutation that is responsible for... Pediatr Res. 2012 Jun;71(6):633-7. doi: 10.1038/pr.2012.21. Epub 2012 Feb 15. Agrawal A, Hamvas A, Cole FS, Wambach JA, Wegner D, Coghill C, Harrison K, Nogee LM
An intronic ABCA3 mutation that is responsible for respiratory disease.
Pediatr Res. 2012 Jun;71(6):633-7. doi: 10.1038/pr.2012.21. Epub 2012 Feb 15., [PMID:22337229]
Abstract [show]
INTRODUCTION: Member A3 of the ATP-binding cassette family of transporters (ABCA3) is essential for surfactant metabolism. Nonsense, missense, frameshift, and splice-site mutations in the ABCA3 gene (ABCA3) have been reported as causes of neonatal respiratory failure (NRF) and interstitial lung disease. We tested the hypothesis that mutations in noncoding regions of ABCA3 may cause lung disease. METHODS: ABCA3-specific cDNA was generated and sequenced from frozen lung tissue from a child with fatal lung disease with only one identified ABCA3 mutation. ABCA3 was sequenced from genomic DNA prepared from blood samples obtained from the proband, parents, and other children with NRF. RESULTS: ABCA3 cDNA from the proband contained sequences derived from intron 25 that would be predicted to alter the structure and function of the ABCA3 protein. Genomic DNA sequencing revealed a heterozygous C>T transition in intron 25 trans to the known mutation, creating a new donor splice site. Seven additional infants with an ABCA3-deficient phenotype and inconclusive genetic findings had this same variant, which was not found in 2,132 control chromosomes. DISCUSSION: These findings support that this variant is a disease-causing mutation that may account for additional cases of ABCA3 deficiency with negative genetic studies.
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80 However, the mechanism to account for this larger aberrant transcript with an additional 249 bases Table 1. Characteristics of subjects with one ABCA3 mutation Patient Ethnicity Presentation Allele 1 mutation Allele 2 mutation Findings consistent with ABCA3 deficiency Outcome A Caucasian Newborn, RDS p.E690K IVS25-98T Case patient; lung histopathology and EM Died B Caucasian RDS p.L941P IVS25-98T Family history of sibling with fatal RDS Died C Caucasian 8 y/old, ILD L212M ?
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ABCA3 p.Leu941Pro 22337229:80:391
status: NEW[hide] Altered surfactant homeostasis and recurrent respi... Respir Res. 2011 Aug 25;12:115. Peca D, Petrini S, Tzialla C, Boldrini R, Morini F, Stronati M, Carnielli VP, Cogo PE, Danhaive O
Altered surfactant homeostasis and recurrent respiratory failure secondary to TTF-1 nuclear targeting defect.
Respir Res. 2011 Aug 25;12:115., [PMID:21867529]
Abstract [show]
BACKGROUND: Mutations of genes affecting surfactant homeostasis, such as SFTPB, SFTPC and ABCA3, lead to diffuse lung disease in neonates and children. Haploinsufficiency of NKX2.1, the gene encoding the thyroid transcription factor-1 (TTF-1)--critical for lung, thyroid and central nervous system morphogenesis and function--causes a rare form of progressive respiratory failure designated brain-lung-thyroid syndrome. Molecular mechanisms involved in this syndrome are heterogeneous and poorly explored. We report a novel TTF-1 molecular defect causing recurrent respiratory failure episodes in an infant. METHODS: The subject was an infant with severe neonatal respiratory distress syndrome followed by recurrent respiratory failure episodes, hypopituitarism and neurological abnormalities. Lung histology and ultrastructure were assessed by surgical biopsy. Surfactant-related genes were studied by direct genomic DNA sequencing and array chromatine genomic hybridization (aCGH). Surfactant protein expression in lung tissue was analyzed by confocal immunofluorescence microscopy. For kinetics studies, surfactant protein B and disaturated phosphatidylcholine (DSPC) were isolated from serial tracheal aspirates after intravenous administration of stable isotope-labeled (2)H(2)O and (13)C-leucine; fractional synthetic rate was derived from gas chromatography/mass spectrometry (2)H and (13)C enrichment curves. Six intubated infants with no primary lung disease were used as controls. RESULTS: Lung biopsy showed desquamative interstitial pneumonitis and lamellar body abnormalities suggestive of genetic surfactant deficiency. Genetic studies identified a heterozygous ABCA3 mutation, L941P, previously unreported. No SFTPB, SFTPC or NKX2.1 mutations or deletions were found. However, immunofluorescence studies showed TTF-1 prevalently expressed in type II cell cytoplasm instead of nucleus, indicating defective nuclear targeting. This pattern has not been reported in human and was not found in two healthy controls and in five ABCA3 mutation carriers. Kinetic studies demonstrated a marked reduction of SP-B synthesis (43.2 vs. 76.5 +/- 24.8%/day); conversely, DSPC synthesis was higher (12.4 vs. 6.3 +/- 0.5%/day) compared to controls, although there was a marked reduction of DSPC content in tracheal aspirates (29.8 vs. 56.1 +/- 12.4% of total phospholipid content). CONCLUSION: Defective TTF-1 signaling may result in profound surfactant homeostasis disruption and neonatal/pediatric diffuse lung disease. Heterozygous ABCA3 missense mutations may act as disease modifiers in other genetic surfactant defects.
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10 Genetic studies identified a heterozygous ABCA3 mutation, L941P, previously unreported.
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ABCA3 p.Leu941Pro 21867529:10:58
status: NEW71 ABCA3 sequencing showed a mono-allelic variation, c3381 T>C, leading to the aminoacidic sequence change L941P, not previously reported, which was carried by the father and was not present in 100 control alleles, hence to be considered a novel heterozygous missense mutation.
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ABCA3 p.Leu941Pro 21867529:71:104
status: NEW70 ABCA3 sequencing showed a mono-allelic variation, c3381 T>C, leading to the aminoacidic sequence change L941P, not previously reported, which was carried by the father and was not present in 100 control alleles, hence to be considered a novel heterozygous missense mutation.
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ABCA3 p.Leu941Pro 21867529:70:104
status: NEW