ABCA3 p.Thr803Met
| Predicted by SNAP2: | A: N (61%), C: N (57%), D: N (53%), E: N (66%), F: D (59%), G: N (61%), H: N (78%), I: N (57%), K: N (72%), L: N (57%), M: N (61%), N: N (78%), P: N (57%), Q: N (66%), R: N (61%), S: N (82%), V: N (61%), W: D (71%), Y: N (53%), |
| Predicted by PROVEAN: | A: N, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: N, V: N, W: D, Y: D, |
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[hide] Mutations in the ABCA3 gene are associated with ca... Invest Ophthalmol Vis Sci. 2014 Nov 18;55(12):8031-43. doi: 10.1167/iovs.14-14098. Chen P, Dai Y, Wu X, Wang Y, Sun S, Xiao J, Zhang Q, Guan L, Zhao X, Hao X, Wu R, Xie L
Mutations in the ABCA3 gene are associated with cataract-microcornea syndrome.
Invest Ophthalmol Vis Sci. 2014 Nov 18;55(12):8031-43. doi: 10.1167/iovs.14-14098., [PMID:25406294]
Abstract [show]
PURPOSE: Cataract-microcornea syndrome (CCMC) is an autosomal dominant inherited disease characterized by the association of congenital cataract and microcornea without any other systemic anomaly or dysmorphism. Although mutations of several genes have been shown to cause dominant CCMC, in many patients the causative gene has not yet been identified. Our aim was to identify the disease-associated gene in Chinese patients with CCMC. METHODS: The CCMC patients from two unrelated Chinese families and 26 sporadic patients were enrolled. All the patients were screened by Sanger sequencing with no identified mutations. Genetic variations were screened by whole-exome sequencing and then validated using Sanger sequencing. RESULTS: By sequencing the whole exome of three patients in a Chinese four-generation dominant CCMC family (Family A), three heterozygous missense mutation (c.115C>G, c.277G>A, and c.4393G>A) were identified in ATP-binding cassette protein A3 (ABCA3). At highly conserved positions, changes (c.115C>G and c.4393G>A) were predicted to have functional impacts and completely cosegregated with the phenotype. We further confirmed our finding by identifying another heterozygous missense mutation, c.2408C>T, in ABCA3 in an additional dominant CCMC family (Family B), which also cosegregated with the phenotype. Moreover, four heterozygous mutations, two missense mutations (c.4253A>T, c.2069A>T) and two splice site mutations (c.4053+2T>C, c.2765-1G>T) were identified from the sporadic patients. The ABCA3 protein was expressed in human lens capsule, choroid-retinal pigment epithelium and retinal pigment epithelial cells. CONCLUSIONS: Mutations in the human ABCA3 gene were associated with lethal respiratory distress. Our study showed, for the first time to our knowledge, that mutations in ABCA3 were associated with CCMC, warranting further investigations on the pathogenesis of this disorder.
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No. Sentence Comment
57 The c.2408C>T generated a heterozygous missense mutation (p.Thr803Met).
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ABCA3 p.Thr803Met 25406294:57:60
status: NEW62 The p.Thr803Met mutation was located in the loop between the first nucleotide binding domain and the seventh membrane-spanning domain (Fig. 6A).
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ABCA3 p.Thr803Met 25406294:62:6
status: NEW117 Genetic Variants Identified in ABCA3 in the Two Chinese Families and the 5 Sporadic Patients With Cataract-Microcornea Syndrome Patient Chromosome/ Position/Gene Name dbSNP rs# Cluster ID Mutation Type Codons Substitution Prediction From SIFT Prediction From PolyPhen-2 Score of Prediction From PolyPhen-2 II2, III1, III4 (family A) chr16/2329098/ABCA3 rs201955122 Missense GAT4393AAT D1465N DAMAGING PROBABLY DAMAGING 0.994 II2, III1, III4 (family A) chr16/2376215/ABCA3 rs200090198 Missense CTC115GTC L39V TOLERATED POSSIBLY DAMAGING 0.857 II2, III1, III4 (family A) chr16/2376053/ABCA3 rs199840288 Missense GTC277ATC V93I TOLERATED BENIGN 0.006 III2, III3, III7, IV2, IV5 (family B) chr16/2345597/ABCA3 Novel Missense ACG2408ATG T803M DAMAGING POSSIBLY DAMAGING 0.801 Sporadic 4 chr16/2331134/ABCA3 Novel Missense AAT4253ATT N1418I DAMAGING PROBABLY DAMAGING 0.996 Sporadic 13 chr16/2347524/ABCA3 Novel Missense GAG2069GTG E690V DAMAGING PROBABLY DAMAGING 1.0 Sporadic13 chr16/2347541/ABCA3 Novel Splice site - - - - - Sporadic12, 15, 17 chr16/2333185/ABCA3 Novel Splice site - - - - - database.
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ABCA3 p.Thr803Met 25406294:117:732
status: NEW123 All five clinically affected subjects, but none of those who were unaffected in Family B, carried the heterozygous c.2408C>T mutation resulting in a T803M amino acid change (Table 3; Fig. 4).
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ABCA3 p.Thr803Met 25406294:123:149
status: NEW124 Thus, the heterozygous missense mutation T803M in ABCA3 completely cosegregated with the dominant CCMC phenotype within Family B.
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ABCA3 p.Thr803Met 25406294:124:41
status: NEW140 The c.2408C>T generated a heterozygous missense mutation (p.Thr803Met).
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ABCA3 p.Thr803Met 25406294:140:60
status: NEW145 The p.Thr803Met mutation was located in the loop between the first nucleotide binding domain and the seventh membrane-spanning domain (Fig. 6A).
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ABCA3 p.Thr803Met 25406294:145:6
status: NEW191 (B) Alignment of sequences surrounding the L39V, V93I, E690V, T803M, N1418I, and D1465N mutation in human, chimpanzee, monkey, pig, rat, and mouse.
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ABCA3 p.Thr803Met 25406294:191:62
status: NEW192 The five mutations (L39V, E690V, T803M, N1418I, and D1465N) in ABCA3 are highly conserved among different species.
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ABCA3 p.Thr803Met 25406294:192:33
status: NEW216 The p.Thr803Met mutation was located in the loop between the first nucleotide binding domain and the seventh membrane-spanning domain.
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ABCA3 p.Thr803Met 25406294:216:6
status: NEW