ABCC6 p.Thr944Ile
| LOVD-ABCC6: |
p.Thr944Ile
D
|
| Predicted by SNAP2: | A: D (71%), C: D (75%), D: D (91%), E: D (91%), F: D (85%), G: D (80%), H: D (85%), I: D (85%), K: D (91%), L: D (80%), M: D (85%), N: D (80%), P: D (85%), Q: D (91%), R: D (91%), S: D (71%), V: D (80%), W: D (95%), Y: D (80%), |
| Predicted by PROVEAN: | A: N, C: N, D: D, E: N, F: N, G: D, H: D, I: N, K: N, L: N, M: N, N: N, P: N, Q: N, R: N, S: N, V: N, W: N, Y: N, |
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[hide] Mutation detection in the ABCC6 gene and genotype-... J Med Genet. 2007 Oct;44(10):621-8. Epub 2007 Jul 6. Pfendner EG, Vanakker OM, Terry SF, Vourthis S, McAndrew PE, McClain MR, Fratta S, Marais AS, Hariri S, Coucke PJ, Ramsay M, Viljoen D, Terry PF, De Paepe A, Uitto J, Bercovitch LG
Mutation detection in the ABCC6 gene and genotype-phenotype analysis in a large international case series affected by pseudoxanthoma elasticum.
J Med Genet. 2007 Oct;44(10):621-8. Epub 2007 Jul 6., [PMID:17617515]
Abstract [show]
BACKGROUND: Pseudoxanthoma elasticum (PXE), an autosomal recessive disorder with considerable phenotypic variability, mainly affects the eyes, skin and cardiovascular system, characterised by dystrophic mineralization of connective tissues. It is caused by mutations in the ABCC6 (ATP binding cassette family C member 6) gene, which encodes MRP6 (multidrug resistance-associated protein 6). OBJECTIVE: To investigate the mutation spectrum of ABCC6 and possible genotype-phenotype correlations. METHODS: Mutation data were collected on an international case series of 270 patients with PXE (239 probands, 31 affected family members). A denaturing high-performance liquid chromatography-based assay was developed to screen for mutations in all 31 exons, eliminating pseudogene coamplification. In 134 patients with a known phenotype and both mutations identified, genotype-phenotype correlations were assessed. RESULTS: In total, 316 mutant alleles in ABCC6, including 39 novel mutations, were identified in 239 probands. Mutations were found to cluster in exons 24 and 28, corresponding to the second nucleotide-binding fold and the last intracellular domain of the protein. Together with the recurrent R1141X and del23-29 mutations, these mutations accounted for 71.5% of the total individual mutations identified. Genotype-phenotype analysis failed to reveal a significant correlation between the types of mutations identified or their predicted effect on the expression of the protein and the age of onset and severity of the disease. CONCLUSIONS: This study emphasises the principal role of ABCC6 mutations in the pathogenesis of PXE, but the reasons for phenotypic variability remain to be explored.
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262 Genotype-phenotype correlations The comparison of subjects whose mutations would probably have resulted in no functional protein with those whose mutations would probably have resulted in some functional Table 2 Distinct mutations identified in the international case series of 271 patients with PXE Nucleotide change*À Predicted consequenceÀ Frequency (alleles) Exon-intron location Domain affected` Mutant alleles (%) References1 c.105delA p.S37fsX80 2 2 0.6 28 c.177-185del9 p.R60_Y62del 1 2 0.3 9, 28 c.179del12ins3 p. R60_W64del L60_R61ins 1 2 0.3 c.220-1gRc SJ 1 IVS 2 0.3 c.724gRt p.E242X 1 7 0.3 c.938insT FS 1 8 0.3 25 c.998+2delT SJ 1 IVS 8 0.3 2, 21 c.998+2del2 SJ 1 IVS 8 0.3 18 c.951cRg p.S317R 2 9 TM6 0.6 28 c.1087cRt p.Q363X 1 9 0.3 c.1091gRa p.T364R 1 9 TM7 0.3 9, 19, 21, 28 c.1132cRt p.Q378X 4 9 1.2 9, 17-19, 28, 37 c.1144cRt p.R382W 2 9 IC4 0.6 c.1171aRg p.R391G 3 9 IC4 0.9 9, 18, 28, 37 c.1176gRc p.K392N 1 9 IC4 0.3 c.1388tRa p.L463H 1 11 TM9 0.3 c.1484tRa p.L495H 1 12 IC5 0.3 28 c.1552cRt p.R518X 2 12 0.6 18, 19, 27, 28, 37 c.1553gRa p.R518Q 4 12 IC5 1.2 18, 19, 24, 28, 31 c.1603tRc p.S535P 1 12 TM10 0.3 c.1703tRc p.F568S 1 13 TM11 0.3 24 c.1798cRt p.R600C 1 14 TM11 0.3 c.1857insC FS 1 14 0.3 c.1987gRt p.G663C 1 16 NBF1 0.3 c.1999delG FS 1 16 0.3 c.2070+5GRA SJ 2 IVS 16 0.6 c.2093aRc p.Q698P 2 17 NBF1 0.6 c.2097gRt p.E699D 1 17 NBF1 0.3 c.2177tRc p.L726P 1 17 NBF1 0.3 c.2237ins10 FS 2 17 0.6 c.2252tRa p.M751K 1 18 NBF1 0.3 20, 37 c.2263gRa p.G755R 2 18 NBF1 0.6 c.2278cRt p.R760W 3 18 NBF1 0.9 20, 28, 32, 37 c.2294gRa p.R765Q 2 18 NBF1 0.6 20-22, 25, 28, 32, 37 c.2329gRa p.D777N 1 18 NBF1 0.3 c.2359gRt p.V787I 1 18 NBF1 0.3 c.2432cRt p.T811M 1 19 IC6 0.3 6 c.2643gRt p.R881S 1 20 IC6 0.3 c.2787+1GRT SJ 9 IVS 21 2.8 17, 20, 24, 28, 31, 37 c.2814cRg p.Y938X 1 22 0.3 c.2820insC FS 1 22 0.3 c.2831cRt p.T944I 1 22 TM12 0.3 c.2848gRa p.A950T 1 22 TM12 0.3 c.2974gRc p.G992R 1 22 TM13 0.3 2, 42 c.3340cRt p.R1114C 2 24 IC8 0.6 19, 28, 32, 37, 41 c.3389cRt p.T1130M 3 24 IC8 0.9 18, 19, 21, 22, 28, 30, 32, 37, 41 c.3398gRc p.G1133A 1 24 IC8 0.3 c.3412gRa p.R1138W 7 24 IC8 2.2 28, 30, 37 c.3413cRt p.R1138Q 7 24 IC8 2.2 18, 19, 24, 25, 28, 30, 32, 37, 41 c.3415gRa p.A1139T 2 24 IC8 0.6 c.3415gRa & c.2070+5GRA* p.A1139T & SJ 1 24, IVS 16 IC8 0.3 c.3415gRa & c.4335delG* p.A1139T & FS 1 24, 30 IC8 0.3 c.3421cRt p.R1141X 92 24 29.3 5, 9, 15,18, 19, 21, 22, 24, 28, 30-32, 33, 37, 41 c.3427cRt p.Q1143X 1 24 0.3 c.3490cRt p.R1164X 15 24 4.7 18, 27, 28, 31, 33 c.3491gRa p.R1164Q 1 24 IC8 0.3 28 c.3661cRt p.R1221C 1 26 IC9 0.3 21, 22, 28, 29 c.3662gRa p.R1221H 2 26 IC9 0.6 40 c.3676cRa p.L1226I 1 26 IC9 0.3 c.3722gRa p.W1241X 2 26 0.6 c.3774insC FS 2 27 0.6 c.3775delT p.G1259fsX1272 3 27 0.9 15, 25, 28, 41 c.3880-3882del p.K1294del 1 27 0.3 c.3883-5GRA SJ 1 IVS 27 0.3 c.3892gRt p.V1298F 1 28 NBF2 0.3 25 c.3904gRa p.G1302R 7 28 NBF2 2.2 21, 22, 25, 28 c.3907gRc p.A1303P 1 28 NBF2 0.3 21, 22, 25, 28 c.3912delG FS 1 28 0.3 28 c.3940cRt p.R1314W 4 28 NBF2 1.2 24, 25, 32, 36 c.3941gRa p.R1314Q 1 28 NBF2 0.3 25, 28, 32, 36, 41 c.4004tRa p.L1335Q 1 28 NBF2 0.3 c.4015cRt p.R1339C 16 28 NBF2 5.0 19, 25, 28, 33 c.4016gRa p.R1339H 2 28 NBF2 0.6 c.4025tRc p.I1342T 1 28 NBF2 0.3 protein did not yield significant differences.
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ABCC6 p.Thr944Ile 17617515:262:1850
status: NEW[hide] Added value of infrared, red-free and autofluoresc... Br J Ophthalmol. 2010 Apr;94(4):479-86. Epub 2009 Sep 1. De Zaeytijd J, Vanakker OM, Coucke PJ, De Paepe A, De Laey JJ, Leroy BP
Added value of infrared, red-free and autofluorescence fundus imaging in pseudoxanthoma elasticum.
Br J Ophthalmol. 2010 Apr;94(4):479-86. Epub 2009 Sep 1., [PMID:19726431]
Abstract [show]
PURPOSE: Pseudoxanthoma elasticum (PXE) is an autosomal recessive disorder caused by mutations in the ABCC6 gene and primarily affects the oculocutaneous and cardiovascular systems. However, the phenotype, including the ophthalmological manifestations, varies in severity. The present study aims to evaluate the added value of novel funduscopic imaging techniques, such as near-infrared reflectance, red-free and autofluorescence imaging in PXE. METHODS: In 22 molecularly proven PXE patients and 25 obligate carriers, PXE retinopathy was evaluated using funduscopy, white light, red-free, infrared and autofluorescence imaging. RESULTS: At least one characteristic of PXE retinopathy was evident on funduscopy of all eyes. Angioid streaks could be subdivided in those with (brick red) or without (feathered) adjacent RPE alterations. Infrared imaging showed the brick-red-coloured streaks as well-demarcated dark fissures, even when these passed unnoticed on funduscopy. Feathered types were detected as triangular areas of hypoautofluorescence. The peau d'orange was much more visible and much more widespread on infrared imaging, with extension from the posterior pole towards the whole midperiphery. Comets and comet tails were best seen with red-free imaging. CONCLUSIONS: Infrared, red-free and autofluorescence imaging are more sensitive than white light funduscopy and imaging in visualising early retinal signs of PXE. In addition, this specialised imaging allows a better appreciation of the extent of lesions. Hence, such imaging increases the chances of making a correct diagnosis early, and aids in the accurate evaluation of evolution of disease in the ophthalmic follow-up of PXE patients.
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No. Sentence Comment
78 In 55% of fundi (24/44), the Table 1 Ophthalmological characteristics of patients Case Age, sex Eye BCVA AS Pd`O C(T) ODD NV PDT Anti-VEGF ABCC6 mutations 1 61, F OD 2/10 + + + À + + À p.R1459C/e OS 9/10 + + + À + + À 2 43, F OD 12/10 + + + À À À À p.R1141X/p.R1141X OS 12/10 + + + À À À À 3 35, M OD 11/10 + + + À À À À p.E125K/p.L1025P OS 1/300 + + + À + + + 4 21, M OD 10/10 + + + À À À À p.R1141X/p.R1141X OS 10/10 + + + + À À À 5 11, M OD 10/10 À + + À À À À c.3506+2T/C/e 3506+2T/COS 10/10 À + + À À À À 6 55, F OD 1/20 + + + À + À À p.R1141X/p.R1141X OS 1.5/10 + + + À + À À 7 40, M OD 4/10 + + + À + + À p.R265G/p.R1141X OS 1/10 + + + À + + À 8 22, F OD 10/10 + + + À À À À p.R1141X/p.R1141X OS 10/10 + + + À À À À 9 29, F OD 10/10 + + + À À À À p.G1263R/c.4182delGG OS 10/10 + + + À À À À 10 20, M OD 10/10 + + + + À À À c.3507-3C/A/p.T944I OS 10/10 + + + + À À À 11 37, F OD 10/10 + + + + À À À p.Q154R/e OS 9/10 + + + + À À À 12 66, F OD 1/20 + À À À + À À p.R1141X/p.R1141X OS 1/10 + À À À + À À 13 68, F OD 10/10 + À À À À À À p.R760Q/p.R1141X OS 10/10 + À À À À À À 14 68, M OD 2/10 + À + À + À À p.A1303P/p.L946I OS CF + À + À + À À 15 58, F OD 7/10 + + + À + À + p.R1141X/c.4103delC OS CF + + + À + + À 16 62,M OD 1/20 + + + À + À + p.R1141X/p.Q1237X OS CF + + + À + À À 17 47, F OD 10/10 + À À À À À À c.3506+2T/C/e OS 10/10 + À À À À À À 18 54, F OD 10/10 + + + À + À + p.R1141X/p.A1303P OS 10/10 + + + À À À À 19 30, F OD 10/10 + + + À À À À p.S398R/c.3364delT OS 10/10 + + + À À À À 20 39, F OD 12/10 + + + À À À À p.R1141X/e OS 10/10 + + + À À À À 21 30, F OD 10/10 + + + À À À À p.G666R/c.1868-5T/G OS 10/10 + + + + À À À 22 34, M OD 12/10 + + + À À À À c.3364delT/p.R518X OS 12/10 + + + À À À À anti-VEGF, anti-vascular endothelial growth factor antibodies; AS, angioid streaks; BCVA, best-corrected visual acuity (Snellen); CF, counting fingers; C(T), Comet (tails); F, female; M, male; MD, macular degeneration; NV, neovascularisation; ODD, optic disc drusen; Pd`O, Peau d`Orange; PDT, photodynamic therapy.
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ABCC6 p.Thr944Ile 19726431:78:1159
status: NEW