ABCA3 p.Asp123Asn
| ClinVar: |
c.367G>A
,
p.Asp123Asn
N
, Likely benign
|
| Predicted by SNAP2: | A: D (71%), C: D (75%), E: N (53%), F: D (80%), G: D (66%), H: D (71%), I: D (80%), K: D (66%), L: D (80%), M: D (80%), N: D (66%), P: D (71%), Q: D (66%), R: D (71%), S: D (63%), T: D (59%), V: D (75%), W: D (91%), Y: D (80%), |
| Predicted by PROVEAN: | A: D, C: D, E: N, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: N, P: D, Q: N, R: D, S: N, T: D, V: D, W: D, Y: D, |
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[hide] Identification of early interstitial lung disease ... Chest. 2010 Apr;137(4):969-73. Crossno PF, Polosukhin VV, Blackwell TS, Johnson JE, Markin C, Moore PE, Worrell JA, Stahlman MT, Phillips JA 3rd, Loyd JE, Cogan JD, Lawson WE
Identification of early interstitial lung disease in an individual with genetic variations in ABCA3 and SFTPC.
Chest. 2010 Apr;137(4):969-73., [PMID:20371530]
Abstract [show]
A man with usual interstitial pneumonia (age of onset 58 years) was previously found to have an Ile73Thr (I73T) surfactant protein C (SFTPC) mutation. Genomic DNA from the individual and two daughters (aged 39 and 43 years) was sequenced for the I73T mutation and variations in ATP-binding cassette A3 (ABCA3). All three had the I73T SFTPC mutation. The father and one daughter (aged 39 years) also had a transversion encoding an Asp123Asn (D123N) substitution in ABCA3. The daughters were evaluated by pulmonary function testing and high-resolution CT (HRCT). Neither daughter had evidence of disease, except for focal subpleural septal thickening on HRCT scan in one daughter (aged 39 years). This daughter underwent bronchoscopy with transbronchial biopsies revealing interstitial fibrotic remodeling. These findings demonstrate that subclinical fibrotic changes may be present in family members of patients with SFTPC mutation-associated interstitial lung disease and suggest that ABCA3 variants could affect disease pathogenesis.
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No. Sentence Comment
3 The father and one daughter (aged 39 years) also had a transversion encoding an Asp123Asn (D123N) substitution in ABCA3.
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ABCA3 p.Asp123Asn 20371530:3:80
status: NEWX
ABCA3 p.Asp123Asn 20371530:3:91
status: NEW26 Pedigree demonstrating carrier status of the Ile73Thr SFTPC mutation and Asp123Asn ABCA3 variation.
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ABCA3 p.Asp123Asn 20371530:26:73
status: NEW41 DNA from the father and one daughter (aged 39 years) were also heterozygous for an exon 3 guanine-to-adenosine transition of ABCA3 predicted to convert residue 123 from aspartate to asparagine.
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ABCA3 p.Asp123Asn 20371530:41:160
status: NEW43 Thus, this D123N ABCA3 variation may represent a mutation.
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ABCA3 p.Asp123Asn 20371530:43:11
status: NEW44 One daughter (aged 43 years) did not have the D123N ABCA3 variant.
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ABCA3 p.Asp123Asn 20371530:44:46
status: NEW61 Hematoxylin and eosin-stained lung tissue obtained at transbronchial biopsy from an asymptomatic individual who was heterozygous for both the Ile73Thr SFTPC mutation and Asp123Asn ABCA3 variation.
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ABCA3 p.Asp123Asn 20371530:61:170
status: NEW73 Discussion In this report, we describe the presence of two heterozygous gene variations, I73T SFTPC and D123N ABCA3, within a single family.
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ABCA3 p.Asp123Asn 20371530:73:104
status: NEW76 Immunohistochemistry (IHC) for components of the unfolded protein response (UPR) from lung tissue obtained at transbronchial biopsy from an asymptomatic individual heterozygous for both the Ile73Thr SFTPC mutation and Asp123Asn ABCA3 variation (same individual in Fig 2-4).
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ABCA3 p.Asp123Asn 20371530:76:218
status: NEW89 Although it is not known from our studies how the D123N ABCA3 variation affects ABCA3 function, given prior pediatric reports and the fact that Asp123 is conserved across species, we speculate that this variation could affect surfactant processing and contribute to development of ILD in this family.
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ABCA3 p.Asp123Asn 20371530:89:50
status: NEW93 Electron microscopic images of lung tissue obtained at transbronchial biopsy from an asymptomatic individual heterozygous for both the Ile73Thr SFTPC mutation and Asp123Asn ABCA3 variation.
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ABCA3 p.Asp123Asn 20371530:93:163
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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No. Sentence Comment
231 Specifically, mutation of aspartate to asparagine at residue 123 (D123N) has also been associated with familial ILD with fibrotic lung remodeling.
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ABCA3 p.Asp123Asn 24142515:231:26
status: NEWX
ABCA3 p.Asp123Asn 24142515:231:66
status: NEW[hide] Sequencing of idiopathic pulmonary fibrosis-relate... BMJ Open Respir Res. 2014 Dec 10;1(1):e000057. doi: 10.1136/bmjresp-2014-000057. eCollection 2014. Coghlan MA, Shifren A, Huang HJ, Russell TD, Mitra RD, Zhang Q, Wegner DJ, Cole FS, Hamvas A
Sequencing of idiopathic pulmonary fibrosis-related genes reveals independent single gene associations.
BMJ Open Respir Res. 2014 Dec 10;1(1):e000057. doi: 10.1136/bmjresp-2014-000057. eCollection 2014., [PMID:25553246]
Abstract [show]
BACKGROUND: Previous studies investigating a genetic basis for idiopathic pulmonary fibrosis (IPF) have focused on resequencing single genes in IPF kindreds or cohorts to determine the genetic contributions to IPF. None has investigated interactions among the candidate genes. OBJECTIVE: To compare the frequencies and interactions of mutations in six IPF-associated genes in a cohort of 132 individuals with IPF with those of a disease-control cohort of 192 individuals with chronic obstructive pulmonary disease (COPD) and the population represented in the Exome Variant Server. METHODS: We resequenced the genes encoding surfactant proteins A2 (SFTPA2), and C (SFTPC), the ATP binding cassette member A3 (ABCA3), telomerase (TERT), thyroid transcription factor (NKX2-1) and mucin 5B (MUC5B) and compared the collapsed frequencies of rare (minor allele frequency <1%), computationally predicted deleterious variants in each cohort. We also genotyped a common MUC5B promoter variant that is over-represented in individuals with IPF. RESULTS: We found 15 mutations in 14 individuals (11%) in the IPF cohort: (SFTPA2 (n=1), SFTPC (n=5), ABCA3 (n=4) and TERT (n=5)). No individual with IPF had two different mutations, but one individual with IPF was homozygous for p.E292V, the most common ABCA3 disease-causing variant. We did not detect an interaction between any of the mutations and the MUC5B promoter variant. CONCLUSIONS: Rare mutations in SFTPA2, SFTPC and TERT are collectively over-represented in individuals with IPF. Genetic analysis and counselling should be considered as part of the IPF evaluation.
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No. Sentence Comment
93 Homozygous recessive or compound heterozygous ABCA3 mutations cause neonatal respiratory failure and childhood ILD, and single ABCA3 mutations (p.E292V and p.D123N) interacting with SFTPC p.I73T have been reported in two families, one with childhood ILD and one with IPF.10 34 Our identification of one individual who was homozygous for ABCA3 p.E292V adds to the recent identification of a kindred with pulmonary fibrosis due to a p.G964D thus further supporting the possibility that adult-onset fibrotic lung disease due to homozygous or compound heterozygous mutations in ABCA3 may occur.11 In contrast to our previous study that demonstrated an enrichment of single ABCA3 mutations in newborns with RDS, suggesting a developmental interaction that increased risk or severity of disease, we did not find the frequency of single ABCA3 mutations in the IPF cohort to be greater than the 3-5% in the general population.
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ABCA3 p.Asp123Asn 25553246:93:158
status: NEW