ABCC6 p.Glu1400Lys
| LOVD-ABCC6: |
p.Glu1400Lys
D
|
| Predicted by SNAP2: | A: D (75%), C: D (66%), D: D (59%), F: D (91%), G: D (85%), H: D (80%), I: D (85%), K: D (91%), L: D (85%), M: D (80%), N: D (75%), P: D (95%), Q: D (80%), R: D (95%), S: D (85%), T: D (85%), V: D (85%), W: D (91%), Y: D (85%), |
| Predicted by PROVEAN: | A: D, C: D, D: N, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: N, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Multidrug resistance associated proteins as determ... Curr Drug Metab. 2007 Dec;8(8):787-802. Yu XQ, Xue CC, Wang G, Zhou SF
Multidrug resistance associated proteins as determining factors of pharmacokinetics and pharmacodynamics of drugs.
Curr Drug Metab. 2007 Dec;8(8):787-802., [PMID:18220559]
Abstract [show]
The multidrug resistance associated proteins (MRP1, MRP2, MRP3, MRP4, MRP5, MRP6, MRP7, MRP8 and MRP9) belong to the ATP-binding cassette superfamily (ABCC family) of transporters. They are expressed differentially in the liver, kidney, intestine, brain and other tissues. These transporters are localized to the apical and/or basolateral membrane of the hepatocytes, enterocytes, renal proximal tubule cells and endothelial cells of the blood-brain barrier. Several MRPs (mainly MRP1-3) are associated with tumor resistance which is often caused by an increased efflux and decreased intracellular accumulation of natural product anticancer drugs and other anticancer agents. MRPs transport a structurally diverse array of important endogenous substances and xenobiotics and their metabolites (in particular conjugates) with different substrate specificity and transport kinetics. Most MRPs are subject to induction and inhibition by a variety of compounds. Several nuclear receptors, including pregnane X receptor (PXR), liver X receptor (LXR), and farnesoid receptor (FXR) participate in the regulation of MRPs. MRPs play an important role in the absorption, distribution and elimination of various drugs in the body and thus may affect their efficacy and toxicity and cause drug-drug interactions. MRPs located in the blood-brain barrier can restrict the penetration of compounds into the central nervous system. Mutation of MRP2 causes Dubin-Johnson syndrome, while mutations in MRP6 are responsible for pseudoxanthoma elasticum. More recently, mutations in mouse Mrp6/Abcc6 gene is associated with dystrophic cardiac calcification (DCC), a disease characterized by hydroxyapatite deposition in necrotic myocytes. A single nucleotide polymorphism, 538G>A in the MRP8/ABCC11 gene, is responsible for determination of earwax type. A better understanding of the function and regulating mechanism of MRPs can help minimize and avoid drug toxicity, unfavourable drug-drug interactions, and to overcome drug resistance.
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No. Sentence Comment
406 MRP Chromosomal location Amino acid variation Nucleotide variation Location References Lys13Asn G39GC Exon1 His68Tyr C202T Exon2 Ser346Phe C1037T Exon9 Gln513Lys C1537A Exon12 Arg1297His G3890A Exon27 MRP3 17q21.3 Gly1423Arg G4267A Exon29 [241] MRP4 13q32.1 Unknown MRP5 3q27 Unknown L63L W64R 189G>C 190T>C Exon2 Exon2 [250] T364R Q378X 1091C>G 1132C>T Exon9 Exon9 [260, 261] R518X R518Q 1552 C>T 1553G>A Exon12 Exon12 [247, 262] R1141X R1138Q T1130M R1114C M1127T 3421C>T 3413G>A 3389C>T 3340C>T 3380C>T Exon24 Exon24 Exon24 Exon24 Exon24 [246, 247] R1275X 3823C>T Exon27 [246] P1346S 4036C>T Exon28 [246] MRP6 16p13.1 E1400K 4198G>A Exon29 [247] MRP7 6p12-21 Unknown MRP8 16q12.1 Unknown MRP9 16q12.1 Unknown CONCLUSIONS AND FUTURE DIRECTIONS MRPs which belong to the ABC transporter family are able to transport a remarkable array of diverse endo- and xenobiotics and their metabolites.
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ABCC6 p.Glu1400Lys 18220559:406:621
status: NEW[hide] Novel ABCC6 mutations in pseudoxanthoma elasticum. J Invest Dermatol. 2004 Mar;122(3):608-13. Chassaing N, Martin L, Mazereeuw J, Barrie L, Nizard S, Bonafe JL, Calvas P, Hovnanian A
Novel ABCC6 mutations in pseudoxanthoma elasticum.
J Invest Dermatol. 2004 Mar;122(3):608-13., [PMID:15086542]
Abstract [show]
Pseudoxanthoma elasticum (PXE) is a heritable connective tissue disorder caused by mutations in an ABC (ATP-Binding Cassette) transporter gene (ABCC6), which manifests with cutaneous, ophthalmologic, and cardiovascular findings. We studied a cohort of 19 families with PXE, and identified 16 different mutations, nine of which were novel variants. The mutation detection rate was about 77%. We found that arginine codon 518 was, with the previously described R1141X and EX23_29del, a recurrently mutated amino acid (11.5% of the mutations detected for each variant R518Q and R518X). No clear delineation of genotype/phenotype correlation was identified, and marked intra-familial variability of the disease was seen in one family. One family with pseudodominant inheritance displayed three distinct ABCC6 mutations, providing further evidence for the probable exclusive recessive transmission of PXE. These data contribute to the expanding database of ABCC6 mutations, to the description of phenotypic variability, and inheritance in PXE, and should be helpful for genetic counselling.
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24 Among these, five are missense mutations (R391G, A766D, D1238H, L1335P, E1400K), one is a nonsense mutation (W1223X), one is a small in-frame deletion of 33 bp (1088-1120del), and two are predicted to impair splicing (V74del, IVS25-3C4A).
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ABCC6 p.Glu1400Lys 15086542:24:72
status: NEW25 All new mutations but three (R391G identified in family 15, D1238H identified in family 11, and E1400K identified in families 1 and 3) fulfil the criteria described for defining nucleotide sequence variants as disease-causing (Cotton and Scriver, 1998).
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ABCC6 p.Glu1400Lys 15086542:25:96
status: NEW28 Phenotype and genotype of the patients studied Patient Origin Sex Age (y) Amino acid variation Nucleotide variation Exon Phenotype C O CV 1 France/Greece F 26 R1141X 3421C4T 24 1 0 0 E1400K 4198G4A 29 2 France F 31 V74del 220-222del 3 1 1 0 V74del 220-222del 3 3-1 Morocco F 20 E1400K 4198G4A 29 1 0 0 E1400K 4198G4A 29 3-2 M 18 E1400K 4198G4A 29 1 0 2 E1400K 4198G4A 29 4 France F 36 A999_S1403del EX23_29del 23-29 1 1 0 Splicing alteration IVS25-3C4A 5 France F 44 ?/?
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ABCC6 p.Glu1400Lys 15086542:28:183
status: NEWX
ABCC6 p.Glu1400Lys 15086542:28:278
status: NEWX
ABCC6 p.Glu1400Lys 15086542:28:302
status: NEWX
ABCC6 p.Glu1400Lys 15086542:28:329
status: NEWX
ABCC6 p.Glu1400Lys 15086542:28:353
status: NEW43 D1238H and E1400K drastically change the charge of residues located close to (D1238H) or in (E1400K) the second nucleotide binding domain (NBD2) of the molecule, where mutational analysis in ABC transporters has often been shown to lead to impaired function (Kerb et al, 2001).
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ABCC6 p.Glu1400Lys 15086542:43:11
status: NEWX
ABCC6 p.Glu1400Lys 15086542:43:93
status: NEW44 For these reasons, D1238H and E1400K were assumed to be pathogenic mutations.
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ABCC6 p.Glu1400Lys 15086542:44:30
status: NEW51 All the five novel missense mutations are located within intracellular domains of the molecule, three in the nucleotide binding domains (A766D in NBD1, L1335P and E1400K in NBD2) and two in a cytoplasmic loop (R391G, D1238H).
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ABCC6 p.Glu1400Lys 15086542:51:163
status: NEW63 Haplotypes identified in these families are different from the one associated with the same mutations in family 9 (R518Q), family 17 (R518X), and family 1 (E1400K), suggesting that they do not share a common founder with these families.
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ABCC6 p.Glu1400Lys 15086542:63:156
status: NEW67 Among the missense mutations we identified, E1400K was associated with a high intra-familial phenotypic variation in family 3, suggestive of the contribution of other factors to the phenotype severity.
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ABCC6 p.Glu1400Lys 15086542:67:44
status: NEW[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.
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64 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.
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ABCC6 p.Glu1400Lys 15459974:64:650
status: NEWX
ABCC6 p.Glu1400Lys 15459974:64:682
status: NEWX
ABCC6 p.Glu1400Lys 15459974:64:717
status: NEWX
ABCC6 p.Glu1400Lys 15459974:64:759
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.
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ABCC6 p.Glu1400Lys 15459974:72:1313
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.
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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.
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ABCC6 p.Glu1400Lys 15894595:378:300
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.
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ABCC6 p.Glu1400Lys 15894595:379:1721
status: NEW[hide] Novel clinico-molecular insights in pseudoxanthoma... Hum Mutat. 2008 Jan;29(1):205. Vanakker OM, Leroy BP, Coucke P, Bercovitch LG, Uitto J, Viljoen D, Terry SF, Van Acker P, Matthys D, Loeys B, De Paepe A
Novel clinico-molecular insights in pseudoxanthoma elasticum provide an efficient molecular screening method and a comprehensive diagnostic flowchart.
Hum Mutat. 2008 Jan;29(1):205., [PMID:18157818]
Abstract [show]
Pseudoxanthoma elasticum (PXE) is a heritable connective tissue disorder characterized by ocular, cutaneous and cardiovascular manifestations. It is caused by mutations in the ABCC6 gene (chr. 16p13.1), encoding a transmembrane transporter protein, the substrate and biological function of which are currently unknown. A comprehensive clinical and molecular study of 38 Belgian PXE probands and 21 relatives (4 affected and 17 carriers) was performed. An extensive clinical evaluation protocol was implemented with serial fundus, skin and cardiovascular evaluation. We report on 14 novel mutations in the ABCC6 gene. We observed extensive variability in severity of both cutaneous and ocular lesions. The type of skin lesion however usually remained identical throughout the evolution of the disorder, while ophthalmological progression was mainly due to functional decline. Peripheral artery disease (53%) and stroke (15%) were significantly more prevalent than in the general population (10-30% and 0.3-0.5% respectively). Interestingly, we also observed a relatively high incidence of subclinical peripheral artery disease (41%) in our carrier population. We highlight the significance of peripheral artery disease and stroke in PXE patients as well as the subclinical manifestations in carriers. Through follow-up data we gained insight into the natural history of PXE. We propose a cost- and time-efficient two-step method of ABCC6 analysis which can be used in different populations. Additionally, we created a diagnostic flowchart and attempted to define the role of molecular analysis of ABCC6 in the work-up of a PXE patient.
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83 Genotype and Phenotype of 42 Belgian PXE Patients Patient S e x Age/Clinical score at initial presentation Age/Clinical score at most recent follow-up Mutations* Allele 1 Allele 2 01-001 F 52 - S0, E2 65 - S0, E3, HT p.R1141X c.3421C>T p.R760Q c.2279G>A 02-001 M 18 - S1, E2, VR-I 18 - S1, E2, VR-I p.R1141X c.3421C>T p.R1141X c.3421C>T 03-001 F 59 - S1, E4 75 - S1, E4, HT, IC, VR-I p.R1141X c.3421C>T p.N793L c.2379C>G 04-001 F 36 - S3, E2 36 - S3, E2 p.N466Y c.1396A>T p.R1339H c.4016G>A 05-001 F 26 - S1, E4 43 - S3, E4, VR-I p.R1141X c.3421C>T p.T364M c.1091C>T 06-001 F 36 - S2, E4 44 - S2, E4, P p.A1303P c.3907G>C None found - 07-001 M 48 - S1, E2, HT 58 - S1, E4, HT p.R1141X c.3421C>T p.R1141X c.3421C>T 08-001 F 26 - S1, E0 44 - S2, E2 p.R1141X c.3421C>T p.R760Q c.2279G>A 09-001 M 49 - S0, E3, P, GIB 65 - S2, E4, P, HT, VR-I, GIB p.A1303P c.3907G>C None found - 10-001 F 46 - S1, E2 63 - S3, E4, HT, AP,VR-I p.R1141X c.3421C>T p.R1141X c.3421C>T 11-001 M 25 - S1, E2, GIB 37 - S1, E3, GIB p.R1141X c.3421C>T None found - 12-001 F 52 - S1, E4, CI, HT, VR-I 52 - S1, E4, IC, HT, VR-I p.R1141X c.3421C>T p.R1141X c.3421C>T 12-002 F 40 - S1, E2, HT, MVP, VR-I 40 - S1, E2, HT, MVP, VR-I p.R1141X c.3421C>T p.R1141X c.3421C>T 13-001 F 65 - S0, E2 80 - S0, E2, P, VR-I p.R1141X c.3421C>T p.R1141X c.3421C>T 13-002 F 57 - S3, E4 73 - S3, E4, HT, CI, VR-I p.R1141X c.3421C>T p.R1141X c.3421C>T 14-001 F 23 - S1, E2 27 - S1, E2 p.S398R c.1194C>G - c.3364delT 15-001 F 27 - S1, E2 27 - S1, E2 p.R1138W c.3412C>T p.R1221H c.3662G>A 16-001 M 51 - S2, E2 54 - S2, E2 p.R1141X c.3421C>T p.R1141X c.3421C>T 17-001 M 42 - S1, E3, IC 58 - S1, E3, IC Del23-29 - p.R518Q c.1553G>A 18-001 M 63 - S1, E4 63 - S1, E4 p.E1400K c.4198G>A None found - 19-001 F 34 - S2, E2 50 - S2, E2 p.A1303P c.3907G>C p.R1398X c.4192C>T 20-001 F 52 - S2, E2, HT, IC, GIB 68 - S2, E4, HT, IC, GIB p.R1141X c.3421C>T None found - 21-001 M 20 - S1, E2 26 - S1, E2 p.R1141X c.3421C>T p.R1141X c.3421C>T 22-001 M 53 - S2, E2, IC, AP 69 - S2, E2, HT, IC, AP p.M751K c.2252T>A p.R1164Q c.3491G>A 23-001 F 20 - S1, E2 27 - S1, E2, P, VR-I p.G666V c.1996G>T - c.1868-5T>G 24-001 M 54 - S1, E2 57 - S1, E2 p.T500P c.1498A>C p.E521D c.1563G>C 25-001 F 50 - S1, E3, HT, MI 57 - S2, E3, HT, MI p.R1141X c.3421C>T p.R1141X c.3421C>T 26-001 M 52 - S2, E4, HT 68 - S2, E4, HT, CI p.M751K c.2252T>A Del23-29 - 27-001 F 61 - S3, E4 68 - S3, E4, P, CI, AP p.R1141X c.3421C>T - c.4104delC Allele 2 28-001 F 31 - S1, E2 32 - S1, E2 - c.1674DelC p.R765W c.2293C>T Patient S e x Age/Clinical score at initial presentation Age/Clinical score at most recent follow-up Mutations* Allele 1 Allele 2 29-001 M 30 - S1, E3 32 - S1, E3 p.E125K c.373G>A p.L1025P c.3074T>C 30-001 M 65 - S0, E2, HT, CI, MI 66 - S0, E2, HT, CI, MI p.G1405S c.4213G>A None found - 31-001 F 38 - S1, E4 39 - S1, E4 p.R1141X c.3421C>T Del23-29 - 32-001 M 22 - S1, E2 36 - S1, E2 p.R1141X c.3421C>T p.R518Q c.1553G>A 33-001 F 45 - S2, E3, P 61 - S2, E3, P, VR-II p.R1141X c.3421C>T p.R1141X c.3421C>T 34-001 F 65 - S1, E4, HT 81 - S1, E4, HT, AP p.R1141X c.3421C>T p.T1301I c.3902C>T 35-001 F 62 - S2, E2 78 - S2, E2, HT - c.175_179del p.G1354R c.4060G>C 35-002 F 58 - S2, E2 74 - S2, E4 - c.175_179del p.G1354R c.4060G>C 35-003 M 67 - S2, E2 79 - S2, E3, HT, VR-I - c.175_179del p.G1354R c.4060G>C 36-001 M 53 - S1, E4 59 - S1, E4, HT, AP p.R1114H c.3341G>A p.Q1237X c.3709C>T 37-001 M 18 - S3, E2 18 - S3, E2 p.Q981H c.2943G>T - c.3507-3C>A 38-001 F 27 - S1, E2 27 - S1, E2 p.G1263R c.3787G>A - c.4182delG Table 1 represents the sex of all patients (M = male; F= female) and the age (in years - italics), respectively at initial presentation and last follow-up.
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ABCC6 p.Glu1400Lys 18157818:83:1710
status: NEW[hide] Pseudoxanthoma elasticum: a streamlined, ethnicity... Clin Transl Sci. 2010 Dec;3(6):295-8. doi: 10.1111/j.1752-8062.2010.00243.x. Larusso J, Ringpfeil F, Uitto J
Pseudoxanthoma elasticum: a streamlined, ethnicity-based mutation detection strategy.
Clin Transl Sci. 2010 Dec;3(6):295-8. doi: 10.1111/j.1752-8062.2010.00243.x., [PMID:21167005]
Abstract [show]
Pseudoxanthoma elasticum (PXE), an autosomal recessive multisystem disorder, is caused by mutations in the ABCC6 gene, and approximately 300 distinct mutations representing >1000 mutant alleles have been disclosed thus far. Few population-based studies have reported mutational hotspots in some geographic areas. In this study, we attempted to correlate recurring mutations with the individuals' ethnic origin. Specifically, we plotted our international database of 70 families from distinct or mixed ethnic backgrounds against their mutations. The frequent p.R1141X mutation was distributed widely across Europe, while deletion of exons 23-29 (del23-29) was encountered in Northern Europe and in Northern Mediterranean countries. p.R1138W may be a marker for French descent, evidenced by its presence also in French Canadians. The splice site transition mutation 3736-1G-->A was seen in the neighboring countries Greece and Turkey, whereas 2542 delG occurs only in the Japanese. Two mutations seem to be present worldwide without evidence of a founder effect, p.Q378X and p.R1339C, suggesting the presence of mutational hotspots. Knowledge of this distribution will allow us to streamline mutation screening through a targeted, stepwise approach when the ethnicity of a patient is known. This will facilitate the identification of individuals at risk, improving their care to prevent ophthalmological and vascular disease.
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67 In two patients of Greek and Turkish origin Chassaing et al.19 discovered two novel mutations, p.A766D in exon 18 and p.E1400K in exon 29.
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ABCC6 p.Glu1400Lys 21167005:67:120
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.
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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.
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ABCC6 p.Glu1400Lys 16763870:272:1544
status: NEW[hide] Heterozygosity for a single mutation in the ABCC6 ... Arch Dermatol. 2008 Mar;144(3):301-6. Martin L, Maitre F, Bonicel P, Daudon P, Verny C, Bonneau D, Le Saux O, Chassaing N
Heterozygosity for a single mutation in the ABCC6 gene may closely mimic PXE: consequences of this phenotype overlap for the definition of PXE.
Arch Dermatol. 2008 Mar;144(3):301-6., [PMID:18347285]
Abstract [show]
OBJECTIVES: To illustrate a phenotypic overlap consisting of usual, but limited, or atypical manifestations of pseudoxanthoma elasticum (PXE) between heterozygous carriers of a single ABCC6 mutation and patients diagnosed with PXE, carriers of homozygous or compound heterozygous mutations. DESIGN: Evaluation for full and typical, incomplete, mild, or overlooked PXE during a 5-year period (2001-2005) based on the following 1992 expert consensus conference items: (1) yellowish papular skin eruption, (2) dermal elastorrhexis and mineralization of elastic fibers in lesional skin, and (3) angioid streaks. Testing for ABCC6 mutations was performed in all cases after informed consent. SETTING: French multidisciplinary outpatient clinic for patients with PXE. PARTICIPANTS: Patients prospectively referred for PXE and first-degree relatives. Main Outcome Measure Prevalence of PXE with a limited or atypical phenotype and manifesting heterozygosity. RESULTS: Ninety-four patients were diagnosed as having PXE. Fifty-eight relatives were also examined, and none displayed the characteristic signs of the disease. Despite the histoclinical items and ABCC6 genotyping, we were unable to establish a definite diagnosis in 5 additional referred cases, ie, to distinguish between PXE with a limited or atypical phenotype and heterozygosity with skin and/or ophthalmologic and/or cardiovascular manifestations suggestive of PXE. CONCLUSIONS: We assume that all categories established at the 1992 consensus conference correspond to PXE, but that the 5 patients reported herein also have PXE. Homozygous, compound heterozygous, or heterozygous individuals may fulfill only some of the clinical and/or histopathologic consensus criteria of PXE. They cannot be placed into any category. Expressivity is highly variable in carriers of 1 or 2 ABCC6 mutations, and the disease manifestations overlap between both genotypes. Physicians should thus be more cautious with respect to the prognosis when faced with heterozygous relatives of a patient diagnosed with undisputable PXE. Indeed, heterozygotes may uncommonly experience severe ophthalmologic complications. Whether they may also have cardiovascular complications related to or worsened by PXE remains to be determined.
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89 ABCC6 mutation analysis showed a single c.4198C→A (p.Glu1400Lys) mutation.
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ABCC6 p.Glu1400Lys 18347285:89:60
status: NEW[hide] Parameters of oxidative stress are present in the ... Biochim Biophys Acta. 2008 Jul-Aug;1782(7-8):474-81. Epub 2008 May 10. Garcia-Fernandez MI, Gheduzzi D, Boraldi F, Paolinelli CD, Sanchez P, Valdivielso P, Morilla MJ, Quaglino D, Guerra D, Casolari S, Bercovitch L, Pasquali-Ronchetti I
Parameters of oxidative stress are present in the circulation of PXE patients.
Biochim Biophys Acta. 2008 Jul-Aug;1782(7-8):474-81. Epub 2008 May 10., [PMID:18513494]
Abstract [show]
Pseudoxanthoma elasticum (PXE) is an inherited disorder characterized by calcification of elastic fibres leading to dermatological and vascular alterations associated to premature aged features and to life threatening clinical manifestations. The severity of the disease is independent from the type of mutation in the ABCC6 gene, and it has been suggested that local and/or systemic factors may contribute to the occurrence of clinical phenotype. The redox balance in the circulation of 27 PXE patients and of 50 healthy subjects of comparable age was evaluated by measuring the advanced oxidation protein products (AOPP), the lipid peroxidation derivatives (LOOH), the circulating total antioxidant status (TAS), the thiol content and the extracellular superoxide dismutase activity (EC-SOD). Patients were diagnosed by clinical, ultrastructural and molecular findings. Compared to control subjects, PXE patients exhibited significantly lower antioxidant potential, namely circulating TAS and free thiol groups, and higher levels of parameters of oxidative damage, as LOOH and of AOPP, and of circulating EC-SOD activity. Interestingly, the ratio between oxidant and antioxidant parameters was significantly altered in PXE patients and related to various score indices. This study demonstrates, for the first time, that several parameters of oxidative stress are modified in the blood of PXE patients and that the redox balance is significantly altered compared to control subjects of comparable age. Therefore, in PXE patients the circulating impaired redox balance may contribute to the occurrence of several clinical manifestations in PXE patients, and/or to the severity of disease, thus opening new perspectives for their management.
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74 Table 1 Clinical data of patients Patients' gender/age Clinical scores Mutations Allele 1 Allele 2 M/10 S2E2 c.3413GNA (p.R1138Q) c.3413GNA (p.R1138Q) F/16 S1 c.1171ANG (p.R391G) c.1552CNT (p.R518X) F/18 S3E2V2 c.1484TNA (p.L495H) c.1484TNA (p.L495H) F/21 S2E2 c.2420GNA (p.R807Q) ND F/21 S2E2 c.184TNC (p.Y62H) c.2996_4208del (p.A999_S1403del) F/24 S2E2 c.1799GNA (p.R600H) c.2420GNA (p.R807Q) F/27 S3E2 c.184TNC (p.Y62H) c.2996_4208del (p.A999_S1403del) F/30 S2E2G1 c.2996_4208del (p.A999_S1403del) c.4198GNA (p.E1400K) F/30 S2E3 c.2996_4208del (p.A999_S1403del) c.4198GNA (p.E1400K) M/30 S2E1 c.3421CNT (p.R1141X) c.3735GNA F/32 S2 c.3421CNT (p.R1141X) c.3735GNA F/33 S3E2 c.1987GNA (p.G663S) ND F/33 S3E3 c.1609_1609delG (p.V537fsX26) c.1763_1769del ins56 F/36 S3E2V3 c.3421CNT (p.R1141X) ND F/36 S3E3V2G1 c.3421CNT (p.R1141X) c.3421CNT (p.R1141X) M/39 S1E2V2 c.1552CNT (p.R518X) c.2996_4208del (p.A999_S1403del) M/42 S1E3V2G1 c.1552CNT (p.R518X) c.2996_4208del (p.A999_S1403del) F/43 S3E3 c.1552CNT (p.R518X) c.1552CNT (p.R518X) F/44 S3E2 c.3341GNA (p.R1114H) c.3542GNA (p.G1181D) F/45 S3E3V2C1G1 c.3421CNT (p.R1141X) c.3421CNT (p.R1141X) F/48 S2E2V2 c.1553GNA (p.R518Q) ND M/51 S1E3 c.3662GNA (p.R1221H) ND F/52 S3E3V2 c.3088CNT (p.R1030X) c.3088CNT (p.R1030X) M/54 S1E2G1 c.1799GNA (p.R600H) c.3941GNA (p.R1314Q) F/56 S3E3V2 c.3662GNA (p.R1221H) ND F/60 S2E3V2C1G1 c.951CNA (p.S317R) c.3421CNT (p.R1141X) F/62 S2E3 c.1552CNT (p.R518X) c.3421CNT (p.R1141X) Scores describe the severity of clinical manifestations.
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ABCC6 p.Glu1400Lys 18513494:74:514
status: NEWX
ABCC6 p.Glu1400Lys 18513494:74:578
status: NEW[hide] Efficiency of exome sequencing for the molecular d... J Invest Dermatol. 2015 Apr;135(4):992-8. doi: 10.1038/jid.2014.421. Epub 2014 Sep 29. Hosen MJ, Van Nieuwerburgh F, Steyaert W, Deforce D, Martin L, Leftheriotis G, De Paepe A, Coucke PJ, Vanakker OM
Efficiency of exome sequencing for the molecular diagnosis of pseudoxanthoma elasticum.
J Invest Dermatol. 2015 Apr;135(4):992-8. doi: 10.1038/jid.2014.421. Epub 2014 Sep 29., [PMID:25264593]
Abstract [show]
The molecular etiology of pseudoxanthoma elasticum (PXE), an autosomal recessive connective tissue disorder, has become increasingly complex as not only mutations in ATP-binding cassette family C member 6 (ABCC6) but also ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) and gamma-glutamyl carboxylase (GGCX) can cause resembling phenotypes. Identification of modifier genes, such as vascular endothelial growth factor A, has further contributed to the molecular heterogeneity of PXE. In such heterogeneous diseases, next-generation sequencing (NGS) allows to perform mutation screening of several genes in a single reaction. We explored whole-exome sequencing (WES) as an efficient diagnostic tool to identify the causal mutations in ABCC6, GGCX, ENPP1, and vitamin K epoxide reductase complex, subunit 1 (VKORC1) in 16 PXE patients. WES identified a causal ABCC6 mutation in 30 out of 32 alleles and one GGCX mutation, whereas no causal mutations in ENPP1 or VKORC1 were detected. Exomes with insufficient reads (20 depth) for the four genes and patients with single mutations were further evaluated by Sanger sequencing (SS), but no additional mutations were found. The potential of WES compared with targeted NGS is the ease to examine target genes and the opportunity to search for novel genes when targeted analysis is negative. Together with low cost, rapid and less laborious workflow, we conclude that WES complemented with SS can provide a tiered approach to molecular diagnostics of PXE.
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89 List of mutations found by WES and SS Gene Nucleotide change Protein change Patient ID Hom/Het WES SS Known/PUR Reference ABCC6 c.C118T p.(P40S) P10 Het O O PUR ABCC6 c.998 &#fe; 2 998 &#fe; 3del TG P8 Het O O PUR ABCC6 c.T1484A p.(L495H) P7 Het O O Known Miksch et al., 2005 ABCC6 c.G1553A p.(R518Q) P11 Hom O O Known Uitto et al., 2001 ABCC6 c.G1553A p.(R518Q) P12, P13, P14 Het O O Known Uitto et al., 2001 ABCC6 c.G2263A p.(G755R) P11 Het O O Known Pfendner et al., 2007 ABCC6 c.G2294A p.(R765Q) P3 Het O O Known Le Saux et al., 2001 ABCC6 del2860_2865 P12, P13,14 Het O O PUR ABCC6 c.T2911C p.(W971R) P11 Het O O PUR ABCC6 Ex23_24del P2 Hom O O Known Ringpfeil et al., 2001 ABCC6 c.T3032C p.(L1011P) P9 Hom O O PUR ABCC6 c.C3190T p.(A1064T) P7 Het O O Known Miksch et al., 2005 ABCC6 c.G3413A p.(R1138Q) P11 Het O O Known Le Saux O, 2011 ABCC6 c.C3421T p.(R1141X) P4 Hom O O Known Bergen et al., 2000 ABCC6 c.C3421T p.(R1141X) P52 , P8, P162 Het O O Known Bergen et al., 2000 ABCC6 c.C3490T p.(R1164X) P6, P15 Hom O O Known Struk et al., 2000 ABCC6 c.G4198A p.(E1400K) P10 Het O O Known Chassaing et al., 2004 ABCC6 c.C4216A p.(Q1406K) P3 Het O O PUR GGCX c.C1321T p.(R441C) P7 Het O O PUR Het, heterozygous; Hom, homozygous; PUR, previously unreported; SS, Sanger sequencing; WES, whole-exome sequencing.
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ABCC6 p.Glu1400Lys 25264593:89:1066
status: NEW