ABCC6 p.Arg1114Cys
| ClinVar: |
c.3341G>C
,
p.Arg1114Pro
D
, Pathogenic
|
| LOVD-ABCC6: |
p.Arg1114Pro
D
p.Arg1114His D p.Arg1114Cys D |
| Predicted by SNAP2: | A: D (91%), C: D (91%), D: D (95%), E: D (95%), F: D (95%), G: D (95%), H: D (85%), I: D (95%), K: D (91%), L: D (95%), M: D (91%), N: D (95%), P: D (63%), Q: D (91%), S: D (95%), T: D (91%), V: D (91%), W: D (95%), Y: D (95%), |
| Predicted by PROVEAN: | A: D, 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, S: D, T: D, V: D, W: D, Y: D, |
[switch to compact view]
Comments [show]
None has been submitted yet.
[hide] ABCC6 mutations in Italian families affected by ps... Hum Mutat. 2004 Nov;24(5):438-9. Gheduzzi D, Guidetti R, Anzivino C, Tarugi P, Di Leo E, Quaglino D, Ronchetti IP
ABCC6 mutations in Italian families affected by pseudoxanthoma elasticum (PXE).
Hum Mutat. 2004 Nov;24(5):438-9., [PMID:15459974]
Abstract [show]
Pseudoxanthoma elasticum (PXE) is a genetic disorder, characterized by cutaneous, ocular and cardiovascular clinical symptoms, caused by mutations in a gene (ABCC6) that encodes for MRP6 (Multidrug Resistance associated Protein 6), an ATP-binding cassette membrane transporter. The ABCC6 gene was sequenced in 38 unrelated PXE Italian families. The mutation detection rate was 82.9%. Mutant alleles occurred in homozygous, compound heterozygous and heterozygous forms, however the great majority of patients were compound heterozygotes. Twenty-three different mutations were identified, among which 11 were new. Fourteen were missense (61%); five were nonsense (22%); two were frameshift (8.5%) and two were putative splice site mutations (8.5%). The great majority of mutations were located from exon 24 to 30, exon 24 being the most affected. Among the others, exons 9 and 12 were particularly involved. Almost all mutations were located in the intracellular site of MRP6. A positive correlation was observed between patient's age and severity of the disorder, especially for eye alterations. The relevant heterogeneity in clinical manifestations between patients with identical ABCC6 mutations, even within the same family, seems to indicate that, apart from PXE causative mutations, other genes and/or metabolic pathways might influence the clinical expression of the disorder.
Comments [show]
None has been submitted yet.
No. Sentence Comment
77 Exon 24 was affected by other types of mutations [c.3340C>T (p.R1114C), c.3380C>T (p.M1127T), c.3389C>T (p.T1130M), c.3413G>A (R1138Q)] in four families, for a total of 17 out of 38 families (44.7%) and for a total of 24 alleles over the 76 examined (31.6%).
X
ABCC6 p.Arg1114Cys 15459974:77:63
status: NEW64 PXE-causative Mutations Recognized (on one and both alleles) in Italian Patients Family/ Proband Affected subjects Age / gender Clinical score Tot Mutations* Allele 1 Allele 2 Mutation type 001 32 F S2,E2 4 p.R518Q p.T1130MI-3097 002 36 M S3,E2,V2,C2 9 p.R518Q p.T1130M I-3013 001 46 F S1,E3 4 p.R1339C None found I-3094 001 57 F S2,E2 4 p.C440G p.P1346S I-3103 001 57 M E2 2 p.V810M p.R1114C I-3076 001 57 F S2,E4,V3 9 p.R1339C p.R1339C I-3016 001 69 F S3,E2,V2 7 p.N411K p.R1138Q missense I-3082 001 23 M S1,E2 3 p.R518Q p.R1141X I-3074 001 27 F S2,E2 4 p.T364R p.R518X I-3015 001 27 F S2,E3 5 p.Q378X p.R600G I-3062 001 45 M S2,E4,V2 8 p.R1141X p.E1400K 001 50 F S1 1 p.R1275X p.E1400K 002 60 F S3,E3 6 p.R1275X p.E1400K I-3067 003 66 F S2,E2 4 p.R1275X p.E1400K 001 61 F S3,E2 4 p.R518Q p.R1141XI-3027 002 63 F S3,E4,V3 10 p.R518Q p.R1141X missense + nonsense 001 23 F S3,E2 5 p.R1141X p.R1141XI-3056** 002 32 M S2,E2 4 p.R1141X p.R1141X 001 27 F S1,E2 3 p.R1141X p.R1141XI-3057** 002 31 M S3,E2 5 p.R1141X p.R1141X 001 28 M S1,E2 3 p.R1141X None foundI-3045 002 32 F S3,E2,V1 6 p.R1141X None found I-3107 001 29 M S2,E1 3 p.R1030X p.R1141X I-3073 001 31 F S3,E2 5 p.R1141X p.R1141X I-3111 001 32 F S1,E2 3 p.R1141X p.R1141X I-3090 001 34 F S2,E1 3 p.R1141X p.R1141X I-3001 001 37 F S3,E2,V2 7 p.R1030X None found 001 40 F S2,E2 4 p.R1141X p.R1141XI-3007** 002 48 F S1,E2 3 p.R1141X p.R1141X I-3114 001 40 M S2,E2,V3,C1,G2 10 p.R518X p.R518X I-3054 001 44 F S2,E3 5 p.R518X p.R518X 001 47 F S3,E4,C2,G1 10 p.R1141X p.R1141XI-3055** 002 50 F S3,E3 6 p.R1141X p.R1141X 001 50 F S3,E4,V3,C2 12 p.R518X p.R1030X 002 52 F S3,E4,V3 10 p.R518X p.R1030X I-3017 003 55 F S3,E2 5 p.R518X p.R1030X I-3100 001 52 M S3,E3 6 p.Q378X p.Q378X I-3051 001 53 F S3,E4,V2 9 p.R1141X p.R1141X I-3034 001 53 M S3,E4,V3 10 p.R1141X p.R1141X I-3093 001 57 F S3,E3,V2,C3 11 p.R518X None found I-3087 001 57 F S3,E4,V2,C2 11 p.Q378X p.Q378X I-3040 001 60 F S3,E4,V2 9 p.R1141X None found I-3033 001 62 F S3,E4 7 p.R1141X p.R1141X nonsense I-3026 001 36 F S3,E2,G1 6 p.R518X c.2248-2_2248- 1del I-3024 001 40 F S1,E2,V3 6 p.R518X p.L1182PfsX96 I-3072 001 41 F S2,E2,C2 6 p.M1127T c.3736-1G>A I-3002 001 50 F S3,E2 5 p.A820P c.3736-1G>A others Family/ Proband Affected subjects Age / gender Clinical score Tot Mutations* Allele 1 Allele 2 Mutation type 002 57 F S2,E4 6 p.A820P c.3736-1G>A I-3008 001 53 F S2,E2,C1 5 p.M1440CfsX24 p.M1440CfsX24 Patients are identified by an international code: I = Italian, 3001 = family number (European patients are numerated from 3000), 001 = subject number.
X
ABCC6 p.Arg1114Cys 15459974:64:386
status: NEW72 ABCC6/MRP6 Mutations Found in Italian PXE Patients Number of families INTRON EXON cDNA* PROTEIN* References 1 9 c.1091C>G p.T364R Pulkkinen et al., 2001 3 9 c.1132C>T p.Q378X Pulkkinen et al., 2001; Cai et al., 2001 1 10 c.1318T>G p.C440G Present study 1 10 c.1233T>G p.N411K Le Saux et al., 2001 7 12 c.1552C>T p.R518X Meloni et al., 2001; Chassaing et al., 2004 3 12 c.1553G>A p.R518Q Le Saux et al., 2001; Chassaing et al., 2004 1 14 c.1798C>T p.R600G Present study 1 17 c.2248-2_2248- 1del - Present study 1 19 c.2428G>A p.V810M Present study 1 19 c.2458G>C p.A820P Present study 3 23 c.3088C>T p.R1030X Le Saux et al., 2001 1 24 c.3340C>T p.R1114C Present study 1 24 c.3380C>T p.M1127T Present study 1 24 c.3389C>T p.T1130M Chassaing et al., 2004; Gotting et al., 2004 1 24 c.3413G>A p.R1138Q Le Saux et al., 2000; Ringpfeil et al., 2000; Le Saux et al., 2001 13 24 c.3421C>T p.R1141X Bergen et al., 2000; Germain et al., 2000; Ringpfeil et al., 2000; Le Saux et al., 2001; Pulkkinen et al., 2001; Uitto et al., 2001; Hu et al., 2003 ; Gotting et al., 2004 1 25 c.3544_3544dupC p.L1182PfsX96 Present study 2 26 c.3736-1G>A - Ringpfeil et al., 2000; Le Saux et al., 2001 1 27 c.3823C>T p.R1275X Present study 2 28 c.4015C>T p.R1339C Le Saux et al., 2001 1 28 c.4036C>T p.P1346S Present study 2 29 c.4198G>A p.E1400K Chassaing et al., 2004 1 30 c.4318_4318delA p.M1440CfsX24 Present study The number of families in which a specific mutation was found (in heterozygous and in homozygous state) is reported.
X
ABCC6 p.Arg1114Cys 15459974:72:646
status: NEW97 The majority of missense mutations would probably result in alterations of the MRP6 conformation [c.1318T>G (p.C440G), c.1798C>T (p.R600G), c.2428G>A (p.V810M), c.2458G>C (p.A820P), c.3340C>T (p.R1114C), c.3380C>T (p.M1127T)], whereas c.4036C>T (p.P1346S) mutation would probably cause a loss of function of MRP6, since previous studies have shown that missense mutations located in the second NBF (Nucleotyde Binding Fold) of MRP6 are able to completely abolish the transport activity of the protein (Ilias et al., 2002).
X
ABCC6 p.Arg1114Cys 15459974:97:195
status: NEW[hide] Pseudoxanthoma elasticum: a clinical, pathophysiol... J Med Genet. 2005 Dec;42(12):881-92. Epub 2005 May 13. Chassaing N, Martin L, Calvas P, Le Bert M, Hovnanian A
Pseudoxanthoma elasticum: a clinical, pathophysiological and genetic update including 11 novel ABCC6 mutations.
J Med Genet. 2005 Dec;42(12):881-92. Epub 2005 May 13., [PMID:15894595]
Abstract [show]
Pseudoxanthoma elasticum (PXE) is an inherited systemic disease of connective tissue primarily affecting the skin, retina, and cardiovascular system. It is characterised pathologically by elastic fibre mineralisation and fragmentation (so called "elastorrhexia"), and clinically by high heterogeneity in age of onset and the extent and severity of organ system involvement. PXE was recently associated with mutations in the ABCC6 (ATP binding cassette subtype C number 6) gene. At least one ABCC6 mutation is found in about 80% of patients. These mutations are identifiable in most of the 31 ABCC6 exons and consist of missense, nonsense, frameshift mutations, or large deletions. No correlation between the nature or location of the mutations and phenotype severity has yet been established. Recent findings support exclusive recessive inheritance. The proposed prevalence of PXE is 1/25,000, but this is probably an underestimate. ABCC6 encodes the protein ABCC6 (also known as MRP6), a member of the large ATP dependent transmembrane transporter family that is expressed predominantly in the liver and kidneys, and only to a lesser extent in tissues affected by PXE. The physiological substrates of ABCC6 remain to be determined, but the current hypothesis is that PXE should be considered to be a metabolic disease with undetermined circulating molecules interacting with the synthesis, turnover, or maintenance of elastic fibres.
Comments [show]
None has been submitted yet.
No. Sentence Comment
378 Interestingly, among the 49 different missense mutations in ABCC6 (42 previously published and seven new ones in the present study), the majority (43) replace critical amino acids in intracellular domains (seven and 19 mutations are located in I1424T R1459C 4220insAGAA 4318delA G1354R D1361N K1394N E1400K R1298X 410delC 418delG 3775delT R1275X R1221C D1238H W1223X Q1237X IVS26-1G→A R1114C R1114H R1114P S1121W M1127T T1130M R1138P R1138Q R1138W R1141X R1164X R765Q A766D Y768X A781V 2322delC IVS19-2delAG T364R R391G Q378X Q363_R373del 938_939insT 960delC IVS8+2delTG G199X Y227X 179_195del 179_187del G226R V74del Q749X IVS17-12delTT IVS14-5T→G IVS13-29T→A R600G V1298F G1299S T1301I G1302R A1303P S1307P R1314Q R1314W G1321S L1335P R1339C P1346S Q1347H R1030X F1048del R807Q V810M A820P 254delG L673P 1944_1966del 1995delG R518Q R518X K502M A455P G992R IVS21+1G→T G1203DF568SN411K C440G IVS25-3C→A 3544dupC Ex23_29del 30 Ex15del ABCC6del 252015105 Figure 10 Position of the mutations in the ABCC6 gene.
X
ABCC6 p.Arg1114Cys 15894595:378:392
status: NEW379 Table 2 ABCC6 mutations Nucleotide variation Protein alteration Location (gene ) Location (protein) Reference Missense 676 GRA G226R Exon 7 CL 3 This study 1091 CRG T364R Exon 9 TS 7 63, 78 1171 ARG R391G Exon 9 CL 4 88 1233 TRG N411K Exon 10 CL 4 63, 90 1318 TRG C440G Exon 10 TS 8 63 1363 GRC A455P Exon 11 TS 9 86 1505 ART K502M Exon 12 CL 5 This study 1553 GRA R518Q Exon 12 CL 5 63, 86, 88, 90 1703 TRC F568S Exon 13 ECL 5 90 1798 CRT R600G Exon 14 CL 6 63 2018 TRC L673P Exon 16 NBF 1 90 2294 GRA R765Q Exon 18 NBF 1 87, 90 2297 CRA A766D Exon 18 NBF 1 88 2342 CRT A781V Exon 18 NBF 1 This study 2420 GRA R807Q Exon 19 NBF 1 This study 2428 GRA V810M Exon 19 NBF1 63 2458 GRC A820P Exon 19 NBF1 63 2965 GRC G992R Exon 22 ECL 6 This study 3340 CRT R1114C Exon 24 CL 8 63 3341 GRA R1114H Exon 24 CL 8 87 3341 GRC R1114P Exon 24 CL 8 90 3362 CRG S1121W Exon 24 CL 8 90 3380 CRT M1127T Exon 24 CL 8 63 3389 CRT T1130M Exon 24 CL 8 63, 87, 88 3412 CRT R1138W Exon 24 CL 8 17 3413 GRC R1138P Exon 24 CL 8 90 3413 GRA R1138Q Exon 24 CL 8 17, 63, 88, 90 3608 GRA G1203D Exon 25 TS17 90 3663 CRT R1221C Exon 26 COOH 87 3712 GRC D1238H Exon 26 COOH 88 3892 GRT V1298F Exon 28 NBF 2 90 3895 GRA G1299S Exon 28 NBF 2 This study 3902 CRT T1301I Exon 28 NBF 2 90 3904 GRA G1302R Exon 28 NBF 2 87, 90 3907 GRC A1303P Exon 28 NBF 2 87, 90 3919 TRC S1307P Exon 28 NBF 2 This study 3940 CRT R1314W Exon 28 NBF 2 90 3941 GRA R1314Q Exon 28 NBF 2 90 3961 GRA G1321S Exon 28 NBF 2 90 4004 TRC L1335P Exon 28 NBF 2 88 4015 CRT R1339C Exon 28 NBF 2 18, 63, 90 4036 CRT P1346S Exon 28 NBF 2 63 4041 GRC Q1347H Exon 28 NBF 2 90 4060 GRC G1354R Exon 29 NBF 2 78, 86 4081 GRA D1361N Exon 29 NBF 2 90 4182 GRT K1394N Exon 29 NBF 2 87 4198 GRA E1400K Exon 29 NBF 2 63, 88 4271 TRC I1424T Exon 30 NBF 2 90 4377 CRT R1459C Exon 30 NBF 2 87 Nonsense 595 CRT G199X Exon 5 89 681 CRG Y227X Exon 7 84 1132 CRT Q378X Exon 9 63, 78, 83 1552 CRT R518X Exon 12 63, 84, 88 2245 CRT Q749X Exon 17 87 2304 CRA Y768X Exon 18 90 3088 CRT R1030X Exon 23 63, 90 3421 CRT R1141X Exon 24 15, 17, 18, 63, 78, 85, 87, 88, 90 3490 CRT R1164X Exon 24 84, 85, 88 3668 GRA W1223X Exon 26 88 3709 CRT Q1237X Exon 26 90 3823 CRT R1275X Exon 27 63 4192 CRT R1398X Exon 29 90 Splicing alteration IVS8+2delTG Intron 8 This study IVS13-29 TRA Intron 13 This study IVS14-5 TRG Intron 14 This study IVS17-12delTT Intron 17 87 IVS18-2delAG Intron 17 63 IVS21+1 GRT Intron 21 86, 90 IVS25-3 CRA Intron 25 88 IVS26-1 GRA Intron 26 17, 63, 90 Insertion 938_939insT Frameshift Exon 8 90 3544dupC Frameshift Exon 25 63 4220insAGAA Frameshift Exon 30 15, 87 Small deletion 179_187del Frameshift Exon 2 78 179_195del Frameshift Exon 2 90 Pseudoxanthoma elasticum www.jmedgenet.com NBF1 and NBF2, respectively), four are located in transmembrane domains, and only two mutations have been identified in extracellular domains.
X
ABCC6 p.Arg1114Cys 15894595:379:753
status: NEW[hide] Analysis of sequence variations in the ABCC6 gene ... J Vasc Res. 2005 Sep-Oct;42(5):424-32. Epub 2005 Aug 26. Schulz V, Hendig D, Schillinger M, Exner M, Domanovits H, Raith M, Szliska C, Kleesiek K, Gotting C
Analysis of sequence variations in the ABCC6 gene among patients with abdominal aortic aneurysm and pseudoxanthoma elasticum.
J Vasc Res. 2005 Sep-Oct;42(5):424-32. Epub 2005 Aug 26., [PMID:16127278]
Abstract [show]
Abdominal aortic aneurysm (AAA) is characterized by dilatation of arterial walls, which is accompanied by degradation of elastin and collagen molecules. Biochemical and environmental factors are known to be relevant for AAA development, and familial predisposition is well recognized. A connective tissue disorder that is also associated with fragmentation of elastic fibers is Pseudoxanthoma elasticum (PXE). PXE is caused by mutations in the ABCC6 gene and mainly affects dermal, ocular and all vascular tissues. To investigate whether variations in ABCC6 are found in AAA patients and to determine mutations in PXE patients, we analyzed seven selected ABCC6 exons of 133 AAA and 54 PXE patients subjected to mutational analysis. In our cohort of AAA patients, we found five ABCC6 alterations, which result in missense or silent amino acid variants. The allelic frequencies of these sequence variations were not significantly different between AAA patients and healthy controls. Therefore, we suggest that alterations in ABCC6 are not a genetic risk factor for AAA. Mutational screening of the PXE patients revealed 19 different ABCC6 variations, including two novel PXE-causing mutations. These results expand the ABCC6 mutation database in PXE.
Comments [show]
This is erroneously identified as a reported sequence variant. In the cited article E18L is the name of a PCR primer.
aranyi on 2012-05-05 13:15:49
aranyi on 2012-05-05 13:15:49
No. Sentence Comment
109 In addition, we detected a silent variation (p.V725V) and 14 missense mutations (p.R724K, p.I742V, p.M751K, p.R760W, p.R765Q, p.R1114C, p.R1114H, p.T1130M, p.R1138Q, p.T1301I, p.G1311E, p.R1314Q, p.R1314W and p.S1403R) in their heterozygous, compound heterozygous and homozygous forms in 17 PXE patients.
X
ABCC6 p.Arg1114Cys 16127278:109:128
status: NEW113 Novel ABCC6 Sequence Alterations Among the 22 ABCC6 sequence variations found in this study, 17 had been previously described as PXE-causing mutations and ABCC6 polymorphisms [16, 19, 22-24, 30, 35, 36], and 5 were novel DNA alterations resulting in the missense and silent variants p.Q655R, p.P664S, p.R1114C, p.G1311E and p.R1418R.
X
ABCC6 p.Arg1114Cys 16127278:113:303
status: NEW116 The variations p.R1114C and p.G1311E occurred in a heterozygous form in 2 PXE patients, and RFLP or DHPLC analysis revealed that they were not present in our groups of healthy controls Exona Sequence variation Allele frequency AAA patients PXE patients PXE relatives blood donors 16 c.1964A>G (p.Q655R) 1 0 0 0/286 16 c.1990C>T (p.P664S) 0 0 0 1/286 16 c.1995delG (frameshift) 0 3 0 0/286 17 c.2171G>A (p.R724K) 3 1 1 2/254 17 c.2175A>T (p.V725V) 3 1 1 2/254 17 c.2224A>G (p.I742V) 3 1 1 2/254 i-17 IVS17+22T>G 1 0 0 0/254 18 c.2252T>A (p.M751K) 0 2 0 0/204 18 c.2278C>T (p.R760W) 0 1 0 0/204 18 c.2294G>A (p.R765Q) 0 3 0 0/204 24 c.3340C>T (p.R1114C) 0 1 0 0/400 24 c.3341G>A (p.R1114H) 0 1 0 0/400 24 c.3389C>T (p.T1130M) 0 2 0 0/400 24 c.3413G>A (p.R1138Q) 0 2 0 ND 24 c.3421C>T (p.R1141X) 0 28 9 1/1,820b i-24 IVS24+15G>A 1 0 0 ND 28 c.3902C>T (p.T1301I) 0 1 0 ND 28 c.3932G>A (p.G1311E) 0 1 0 0/400 28 c.3940C>T (p.R1314W) 0 1 0 ND 28 c.3941G>A (p.R1314Q) 0 1 1 ND i-28 IVS28+49C>T 59 ND ND ND i-28 IVS28-30C>T 48 ND ND ND 29 c.4182delG (frameshift) 0 3 0 0/400 i-29 IVS29+9G>A 5 ND ND ND 30 c.4209C>A (p.S1403R) 0 1 0 0/244 30 c.4254G>A (p.R1418R) 6 0 0 2/244 i-30 IVS30+11C>G 0 2 0 0/244 23-29 Ex23_Ex29del 0 5 3 ND i = intron; ND = not determined.
X
ABCC6 p.Arg1114Cys 16127278:116:17
status: NEWX
ABCC6 p.Arg1114Cys 16127278:116:644
status: NEW123 DNA sequencing of all 31 ABCC6 exons showed that the first PXE patient was compound heterozygous for p.R1114C and the known PXE mutation c.1995delG in exon 16, whereas the second carried the new variant p.G1311E and the PXE-causing exon 24 mutation p.R1141X in a compound heterozygous state.
X
ABCC6 p.Arg1114Cys 16127278:123:103
status: NEW141 Two ABCC6 sequence alterations were novel, namely the alterations p.R1114C and p.G1311E.
X
ABCC6 p.Arg1114Cys 16127278:141:68
status: NEW143 In addition, both mutations alter amino acid residues, which are conserved in the human, mouse and rat MRP6 proteins and, in the case of p.R1114C, also in the human MRP protein family.
X
ABCC6 p.Arg1114Cys 16127278:143:139
status: NEW145 However, the assumption that the novel mutations are disease-causing is confirmed by the fact that those PXE patients who were identified to be heterozygous carriers of the p.R1114C and p.G1311E mutations were found to be compound heterozygous for only one other PXE-causing ABCC6 mutation.
X
ABCC6 p.Arg1114Cys 16127278:145:175
status: NEW[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.
Comments [show]
None has been submitted yet.
No. Sentence Comment
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.
X
ABCC6 p.Arg1114Cys 17617515:262:1952
status: NEW[hide] [Pseudoxanthoma elasticum]. Ophthalmologe. 2006 Jun;103(6):537-51; quiz 552-3. Ladewig MS, Gotting C, Szliska C, Issa PC, Helb HM, Bedenicki I, Scholl HP, Holz FG
[Pseudoxanthoma elasticum].
Ophthalmologe. 2006 Jun;103(6):537-51; quiz 552-3., [PMID:16763870]
Abstract [show]
Pseudoxanthoma elasticum (PXE) is an inherited disorder that is associated with accumulation of mineralized and fragmented elastic fibers in the skin, vessel walls, and Bruch's membrane. Clinically, patients exhibit characteristic lesions of the skin (soft, ivory-colored papules in a reticular pattern that predominantly affect the neck), the posterior segment of the eye (peau d'orange, angioid streaks, choroidal neovascularizations), and the cardiovascular system (peripheral arterial occlusive disease, coronary occlusion, gastrointestinal bleeding). There is no causal therapy. Recent studies suggest that PXE is inherited almost exclusively as an autosomal recessive trait. Its prevalence has been estimated to be 1:25,000-100,000. The ABCC6 gene on chromosome 16p13.1 is associated with the disease. Mutations within the ABCC6 gene cause reduced or absent transmembraneous transport that leads to accumulation of substrate and calcification of elastic fibers. Although based on clinical features the diagnosis appears readily possible, variability in phenotypic expressions and the low prevalence may be responsible that the disease is underdiagnosed. This review covers current knowledge of PXE and presents therapeutic approaches.
Comments [show]
None has been submitted yet.
No. Sentence Comment
272 Internetadressen PXE-Selbsthilfegruppe Deutschland : http://www.pxe-groenblad.de PXE International: http://www.pxe.org Tabelle 5 PXE verursachende Mutationen imabcc6-Gen Klassifikation Lokalisation Gen Protein Missense Exon 9 Exon 9 Exon 10 Exon 10 Exon 11 Exon 12 Exon 13 Exon 14 Exon 16 Exon 18 Exon 18 Exon 18 Exon 18 Exon 19 Exon 19 Exon 19 Exon 22 Exon 24 Exon 24 Exon 24 Exon 24 Exon 24 Exon 24 Exon 24 Exon 24 Exon 24 Exon 25 Exon 26 Exon 26 Exon 26 Exon 28 Exon 28 Exon 28 Exon 28 Exon 28 Exon 28 Exon 28 Exon 28 Exon 28 Exon 28 Exon 28 Exon 28 Exon 28 Exon 29 Exon 29 Exon 29 Exon 29 Exon 29 Exon 30 Exon 30 Exon 30 c.1091CaG c.1171AaG c.1233TaG c.1318TaG c.1363GaC c.1553GaA c.1703TaC c.1798CaT c.2018TaC c.2252TaA c.2278CaT c.2294GaA c.2297CaA c.2428GaA c.2458GaC c.2552TaC c.2855TaG c.3340CaT c.3341GaA c.3341GaC c.3362CaG c.3380CaT c.3389CaT c.3412CaT c.3413GaA c.3413GaC c.3608GaA c.3661CaT c.3712GaC c.3715TaC c.3892GaT c.3902CaT c.3904GaA c.3907GaC c.3932GaA c.3940CaT c.3941GaA c.3961GaA c.3976GaA c.4004TaC c.4015CaT c.4036CaT c.4041GaC c.4060GaC c.4069CaT c.4081GaA c.4182GaT c.4198GaA c.4209CaA c.4271TaC c.4377CaT p.T364R p.R391G p.N411K p.C440G p.A455P p.R518Q p.F568S p.R600G p.L673P p.M751K p.R760W p.R765Q p.A766D p.V810M p.A820P p.L851P p.F952C p.R1114C p.R1114H p.R1114P p.S1121W p.M1127T p.T1130M p.R1138W p.R1138Q p.R1138P p.G1203D p.R1221C p.D1238H p.Y1239H p.V1298F p.T1301I p.G1302R p.A1303P p.G1311E p.R1314W p.R1314Q p.G1321S p.D1326N p.L1335P p.R1339C p.P1346S p.Q1347H p.G1354R p.R1357W p.D1361N p.K1394N p.E1400K p.S1403R p.I1424T p.R1459C Klassifikation Lokalisation Gen Protein Nonsense Exon 9 Exon 12 Exon 17 Exon 18 Exon 23 Exon 24 Exon 24 Exon 26 Exon 26 Exon 27 Exon 29 c.1132CaT c.1552CaT c.2247CaT c.2304CaA c.3088CaT c.3421CaT c.3490CaT c.3668GaA c.3709CaT c.3823CaT c.4192CaT p.Q378X p.R518X p.Q749X p.Y768X p.R1030X p.R1141X p.R1164X p.W1223X p.Q1237X p.R1275X p.R1398X Spleißstellen Intron 21 Intron 25 Intron 26 c.2787+1GaT c.3634-3CaA c.3736-1GaA Insertion Exon 8 Exon 25 Exon 30 c.938-939insT c.3544dupC c.4220insAGAA Deletion Exon 2 Exon 2 Exon 3 Exon 8 Exon 9 Exon 16 Exon 16 Exon 18 Exon 19 Exon 22 Exon 27 Exon 29 Exon 29 Exon 30 Exon 31 c.179del9 c.179-195del c.220-222del c.960delC c.1088-1120del c.1944del22 c.1995delG c.2322delC c.2542delG c.2835-2850del16 c.3775delT c.4101delC c.4182delG c.4318delA c.4434delA Intragenische Deletion Exon 15 Exon 18 Exon 23-29 delEx15 delEx18 delEx23-29 Intergenische Deletion ABCC6 delABCC6 Fazit für die Praxis Eine spezifische Behandlung der Grunderkrankung ist nicht bekannt.
X
ABCC6 p.Arg1114Cys 16763870:272:1274
status: NEW[hide] Mutational analysis of the ABCC6 gene and the prox... Hum Mutat. 2006 Aug;27(8):831. Schulz V, Hendig D, Henjakovic M, Szliska C, Kleesiek K, Gotting C
Mutational analysis of the ABCC6 gene and the proximal ABCC6 gene promoter in German patients with pseudoxanthoma elasticum (PXE).
Hum Mutat. 2006 Aug;27(8):831., [PMID:16835894]
Abstract [show]
Pseudoxanthoma elasticum (PXE) is a genetic disorder characterized by calcification of elastic fibers in dermal, ocular, and cardiovascular tissues. Recently, ABCC6 mutations were identified as causing PXE. In this follow-up study we report the investigation of 61 German PXE patients from 53 families, hitherto the largest cohort of German PXE patients screened for the complete ABCC6 gene. In addition, we characterized the proximal ABCC6 promoter of PXE patients according to mutation. In this study we identified 32 disease-causing ABCC6 variants, which had been described previously by us and others, and 10 novel mutations (eight missense mutations and two splice site alterations). The mutation detection rate among index patients was 87.7%. Frequent alterations were the PXE-mutations p.R1141X, Ex23,_Ex29del, and c.2787+1G > T. In the ABCC6 promoter we found the polymorphisms c.-127C > T, c.-132C > T, and c.-219A > C. The difference in the c.-219A > C frequencies between PXE patients and controls were determined as statistically significant. Interestingly, c.-219A > C is located in a transcriptional activator sequence of the ABCC6 promoter and occurred in a binding site for a transcriptional repressor, predominantly found in genes that participate in lipid metabolism. Obtaining these genetic data signifies our contribution to elucidating the pathogenetics of PXE.
Comments [show]
None has been submitted yet.
No. Sentence Comment
82 Summary of ABCC6/MRP6 mutations identified in German PXE patients Change in Number of Allelic frequency Exona nucleotideb Amino acid Statusc families in blood donorsd Referenceg i-1e c.37-1G>Af altered splicing hm 1 0 / 200 This study 2 c.113G>C p.W38S ht 1 0 / 200 This study i-3 c.346-6G>A altered splicing ht 2 Nd A, B 7 c.754C>T p.L252F ht 1 0 / 200 This study 9 c.1132C>T p.Q378X ht 4 Nd B, C 9 c.1171A>G p.R391G ht 1 Nd B, D 10 c.1244T>C p.V415A ht 1 0 / 200 This study 12 c.1460G>A p.R487Q ht 1 0 / 200 This study 12 c.1491C>A p.N497K ht 1 0 / 200 This study 12 c.1552C>T p.R518X ht 1 Nd B, E i-12 c.1574_1575insG p.L525fsX73 ht 1 0 / 200 This study 16 c.1995delG p.A667fsX20 ht 3 Nd A, F, G 18 c.2252T>A p.M751K ht 3 Nd F, G 18 c.2278C>T p.R760W ht 2 Nd B, F, G Change in Number of Allelic frequency Exona nucleotideb Amino acid Statusc families in blood donorsd Referenceg 18 c.2294G>A p.R765Q ht 2 Nd A, F, G, H 19 c.2552T>C p.L851P ht 1 Nd F i-21 c.2787+1G>T altered splicing ht 7 Nd B, C, F, I, J 22 c.2835_2850del16 p.P946fsX17 ht 1 Nd F 22 c.2855T>G p.F952C ht 1 Nd F 23 c.3145T>G p.S1049A ht 1 0 / 200 This study 23 c.3188T>G p.L1063R ht 1 0 / 200 This study 24 c.3340C>T p.R1114C ht 1 Nd B, K, G, L 24 c.3341G>A p.R1114H ht 1 Nd G, H, L, M 24 c.3389C>T p.T1130M ht 1 Nd B, D, G, H, K, L, M, N 24 c.3413G>A p.R1138Q ht 1 Nd A, B, D, J, K, L, N 24 c.3412C>T p.R1138W ht 1 Nd N 24 c.3421C>T p.R1141X hm, ht 26 Nd B, G, J, K, L, M, N, O, P, Q, R, S i-24 c.3505_3506+2delA GGT altered splicing ht 1 0 / 200 This study i-24 c.3507-3C>T altered splicing ht 2 Nd B 26 c.3715T>C p.Y1239H ht 1 Nd L 26 c.3723G>C p.W1241C ht 1 Nd A, L i-26 c.3736-1G>A altered splicing ht 1 Nd B, L, N 27 c.3775delT p.W1259fsX13 ht 1 Nd B, J, L, O i-27 c.3883-6G>A altered splicing ht 1 Nd B 28 c.3902C>T p.T1301I ht 1 Nd A, G, L 28 c.3932G>A p.G1311E ht 1 Nd L 28 c.3940C>T p.R1314W ht 1 Nd A, G, L 28 c.3941G>A p.R1314Q ht 1 Nd A, B, G, L 29 c.4182delG p.N1394fsX8 ht 2 Nd G, H, L 30 c.4209C>A p.S1403R ht 1 Nd F 31 c.4434delA p.R1479fsX25 hm 1 Nd F 23-29 Ex23_Ex29del p.A999_S1403del ht 5 Nd A, B, D, E, G, H, O, R a The exon that contains the ABCC6 sequence variation.
X
ABCC6 p.Arg1114Cys 16835894:82:1192
status: NEW89 Genotypes and phenotypes of the PXE patients analyzed in this study Phenotype Genotypeb No.a Sex, Age Age on diagnosis Organ involvement Mutations 1 M 36 11 E, S, G p.R1141X p.R1141X 2 F 44 39 E, S, G, A p.R1141X Ex23_Ex29del 3 F 41 7 E, S p.R1141X p.R1141X 4 F 46 19 E, S, A p.R1141X p.R1141X 5 F 59 55 E, S, A c.37-1G>A c.37-1G>A 6c F 63 16 E, S, H, V, A Ex23_Ex29del c.4182delG 7 F 24 15 E, S c.4434delA c.4434delA 8 M 60 23 E, S p.Q378X p.R1141X 9 F 79 65 E, S, A c.2787+1G>T p.R1141X 10 F 55 35 E, S, G, H, V, A p.Q378X c.2787+1G>T 11 F 47 14 S c.1995delG c.2787+1G>T 12c F 36 24 E, S c.2787+1G>T c.4182delG 13 F 56 8 E, S p.R1141X c.3507-3C>T 14 M 72 55 E, S, H, V p.R1141X 15 F 69 51 E, S c.1995delG p.R765Q 16 F 19 11 S p.R760W p.R1141X 17c F 59 50 E, S, H, V, A p.R1141X p.G1311E 18c M 54 32 E, S p.R1141X p.Y1239H 19-1 M 63 53 E, H p.L252F p.V415A p.R765Q 19-2 F 58 48 E, S p.L252F p.V415A p.R765Q 20 M 54 44 E, S, V, A c.3775delT c.346-6G>A 21 M 52 43 E, S, A p.R1141X c.3883-6G>A 22-1 M 47 36 E, S, G, H, V p.R518X 22-2 M 45 34 E, S, H p.R518X 23 F 35 22 E, S, A p.W38S 24 F 40 30 E c.346-6G>A 25-1 M 58 46 E, S, A p.R1141X c.3883-6G>A 25-2 M 19 10 S p.R1141X c.3883-6G>A 26-1 F 46 18 E, S, V p.R487Q c.3883-6G>A 27c F 62 30 E, S, A p.Q378X p.R1114H 28 F 59 49 E, A p.R1314Q c.3507-3C>T 29c F 30 10 E, S c.1995delG p.R1114C 30 M 67 52 E p.L1063R p.R1141X 31 F 50 46 E, S, V p.M751K p.R1141X 32 F 27 24 S Ex23_Ex29del 33c F 34 19 E, S Ex23_Ex29del p.T1130M 34 F 33 19 E, S c.2787+1G>T p.W1241C 35 M 47 15 E, S, G, H, V, A Ex23_Ex29del 36 M 72 63 E, S p.S1049A c.3736-1G>A p.S1403R 37 F 34 16 E, S c.2787+1G>T 38 F 42 8 E, S, V p.R1141X p.R1314W 39 F 37 20 E, S p.N497K 40 F 54 33 E, S, V, A p.M751K p.R1141X 41 M 53 49 E, S, G, H, V p.R1141X 42-1 F 52 38 E, S p.R391G p.R1141X 42-2 F 43 28 E, S p.R391G p.R1141X 43 F 64 58 S, A 44-1 F 51 27 E, S, A p.R1141X 44-2 F 18 9 E, S 44-3 F 54 26 E, S, V, A p.R1141X 45-1 F 64 49 E, S, G, V p.R1138Q 45-2 F 62 48 E, S, A p.R1138Q 46 M 56 25 E, S, V p.R1141X p.T1301I 47 F 34 23 E, S p.R760W c.2787+1G>T 48 M 47 24 E, S, V, A c.2835_2850del16 p.F952C p.R1141X 49 F 28 11 E, S, G, V p.M751K p.R1141X 50 F 39 25 E, S, V p.L851P p.R1141X c.3505_3506+2 delAGGT 51 F 61 16 E, S, H, A p.Q378X p.R1141X 52-1 F 40 20 E, S p.R1138W p.R1141X 52-2 F 43 23 E, S p.R1138W p.R1141X 53 M 68 66 E, H, V, G, A c.1574_1575insG p.R1141X F = female, M = male, wt = wild-type, hm = homozygote, ht = heterozygote, cht = compound heterozygote, nd = not determined, MSM = microsatellite marker, E = eyes, S = skin, G = gastrointestinum, H = heart, V = vascular tissue and A = arterial hypertension.
X
ABCC6 p.Arg1114Cys 16835894:89:1329
status: NEW