ABCC6 p.Asn411Lys
| ClinVar: |
c.1233T>C
,
p.Asn411=
N
, Likely benign
|
| LOVD-ABCC6: |
p.Asn411Lys
D
|
| Predicted by SNAP2: | A: D (95%), C: D (95%), D: D (95%), E: D (95%), F: D (95%), G: D (95%), H: D (95%), I: D (95%), K: N (61%), L: D (95%), M: D (95%), P: D (95%), Q: D (95%), R: D (95%), S: D (95%), T: D (91%), V: D (95%), 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, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] A spectrum of ABCC6 mutations is responsible for p... Am J Hum Genet. 2001 Oct;69(4):749-64. Epub 2001 Aug 31. Le Saux O, Beck K, Sachsinger C, Silvestri C, Treiber C, Goring HH, Johnson EW, De Paepe A, Pope FM, Pasquali-Ronchetti I, Bercovitch L, Marais AS, Viljoen DL, Terry SF, Boyd CD
A spectrum of ABCC6 mutations is responsible for pseudoxanthoma elasticum.
Am J Hum Genet. 2001 Oct;69(4):749-64. Epub 2001 Aug 31., [PMID:11536079]
Abstract [show]
To better understand the pathogenetics of pseudoxanthoma elasticum (PXE), we performed a mutational analysis of ATP-binding cassette subfamily C member 6 (ABCC6) in 122 unrelated patients with PXE, the largest cohort of patients yet studied. Thirty-six mutations were characterized, and, among these, 28 were novel variants (for a total of 43 PXE mutations known to date). Twenty-one alleles were missense variants, six were small insertions or deletions, five were nonsense, two were alleles likely to result in aberrant mRNA splicing, and two were large deletions involving ABCC6. Although most mutations appeared to be unique variants, two disease-causing alleles occurred frequently in apparently unrelated individuals. R1141X was found in our patient cohort at a frequency of 18.8% and was preponderant in European patients. ABCC6del23-29 occurred at a frequency of 12.9% and was prevalent in patients from the United States. These results suggested that R1141X and ABCC6del23-29 might have been derived regionally from founder alleles. Putative disease-causing mutations were identified in approximately 64% of the 244 chromosomes studied, and 85.2% of the 122 patients were found to have at least one disease-causing allele. Our results suggest that a fraction of the undetected mutant alleles could be either genomic rearrangements or mutations occurring in noncoding regions of the ABCC6 gene. The distribution pattern of ABCC6 mutations revealed a cluster of disease-causing variants within exons encoding a large C-terminal cytoplasmic loop and in the C-terminal nucleotide-binding domain (NBD2). We discuss the potential structural and functional significance of this mutation pattern within the context of the complex relationship between the PXE phenotype and the function of ABCC6.
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85 PXE Mutations The most-prevalent mutations detected in the ABCC6 gene were missense substitutions (21 [58.3%] mutations, Table 1 ABCC6 Mutations in a Cohort of Patients with PXE CHANGE IN STATUS a ORIGIN(S)b EXON(S)c REFERENCE(S)Amino Acid Nucleotide … 179-195del ht Belgium 2 Present study … 938-939insT ch, ht SA, UK 8 Present study N411K 1233TrG ht US 10 Present study A455P 1363GrC Nd Nd 11 Uitto et al. (2001) R518Q 1553GrA ch, ht Belgium 12 Present study, Uitto et al. (2001) F568S 1703TrC ch US 13 Present study … ABCC6del15 hm SA 15 Present study … 1944del22 ht Holland 16 Bergen et al. (2000) … 1995delG ht Germany 16 Present study L673P 2018TrC ch SA 16 Present study R765Q 2294GrA ht Germany 18 Present study Y768X 2304CrA ch, ht SA 18 Present study … 2322delC ht US 18 Present study … 2542delG Nd Nd 19 Uitto et al. (2001) … IVS21ϩ1GrT ch US, Germany i-21 Present study, Uitto et al. (2001) R1030X 3088CrT ht SA, UK 23 Present study R1114P 3341GrC hm UK 24 Present study S1121W 3362CrG ch Germany 24 Present study R1138W 3412CrT hm Nd 24 Ringpfeil et al. (2000) R1138P 3413GrC ch Germany 24 Present study R1138Q 3413GrA ch UK, US 24 Present study, Ringpfeil et al. (2000) R1141X 3421CrT All All 24 Present study and othersd R1164X 3490CrT ch Germany, UK 24 Ringpfeil et al. (2001) G1203D 3608GrA ch Germany 25 Present study … IVS26-1GrA ch Belgium i-26 Present study, Ringpfeil et al. (2000, 2001) Q1237X 3709CrT ch Belgium 26 Present study … 3775delT ht, hm SA, US, Holland 27 Present study, Bergen et al. (2000) V1298F 3892GrT ht US 28 Present study T1301I 3902CrT ch Belgium 28 Present study G1302R 3904GrA hm US 28 Present study A1303P 3907GrC ch Belgium 28 Present study R1314W 3940CrT hm US 28 Present study R1314Q 3941GrA ch Germany 28 Present study G1321S 3961GrA ht US 28 Present study R1339C 4015CrT All SA, US 28 Present study, Struk et al. (2000) Q1347H 4041GrC hm US 28 Present study D1361N 4081GrA ch Germany 29 Present study … 4104delC ch Belgium 29 Present study R1398X 4192CrT ch Belgium 29 Present study … ABCC6del23-29 ch US 23-29 Present study, Ringpfeil et al. (2001) … 4220insAGAA ht Holland 30 Bergen et al. (2000) I1424T 4271TrC ht US 30 Present study … ABCC6del ht Holland all Bergen et al. (2000) a Nd p not determined; hm p homozygote; ht p heterozygote; ch p compound heterozygote.
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ABCC6 p.Asn411Lys 11536079:85:351
status: NEW94 Although most of the mutations reported here appear to be unique, a few disease-causing variants have been found to occur frequently in apparently unrelated individuals; R1141X was found at Table 2 Frequencies of Mutant Alleles Found in a Cohort of 101 Unrelated Patients with PXE MUTATION a OVERALL EUROPE UNITED STATES No. of Alleles Frequency (%) No. of Alleles Frequency (%) No. of Alleles Frequency (%) R1141X 38 18.8 33 28.4 3 4.1 ABCC6del23-29 26 12.9 5 4.3 21 28.4 IVS21ϩ1GrT 7 3.5 4 3.4 3 4.1 G1302R 4 2.0 0 .0 4 5.4 A1303P 4 2.0 3 2.6 1 1.4 R1314W 3 1.5 0 .0 3 4.1 R518Q* 3 1.5 1 .9 1 1.4 3775delT* 3 1.5 2 1.7 0 .0 R1138Q 2 1.0 1 .9 1 1.4 V1298F 2 1.0 0 .0 2 2.7 R1339C 2 1.0 0 .0 2 2.7 Q1347H 2 1.0 0 .0 2 2.7 4104delC* 2 1.0 1 .9 0 .0 179-195del 1 .5 1 .9 0 .0 938-939insT* 1 .5 0 .0 0 .0 N411K 1 .5 0 .0 1 1.4 F568S 1 .5 0 .0 1 1.4 1995delG 1 .5 1 .9 0 .0 R765Q 1 .5 1 .9 0 .0 2322delC 1 .5 0 .0 1 1.4 R1030X* 1 .5 0 .0 0 .0 R1114P 1 .5 1 .9 0 .0 S1121W 1 .5 1 .9 0 .0 R1138P 1 .5 1 .9 0 .0 G1203D 1 .5 1 .9 0 .0 IVS26-1GrA 1 .5 1 .9 0 .0 Q1237X 1 .5 1 .9 0 .0 W1241C 1 .5 1 .9 0 .0 T1301I 1 .5 1 .9 0 .0 R1314Q 1 .5 1 .9 0 .0 D1361N 1 .5 1 .9 0 .0 R1398X 1 .5 1 .9 0 .0 G1321S 1 .5 0 .0 1 1.4 I1424T 1 .5 0 .0 1 1.4 ?
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ABCC6 p.Asn411Lys 11536079:94:811
status: NEW[hide] ABCC6/MRP6 mutations: further insight into the mol... Eur J Hum Genet. 2003 Mar;11(3):215-24. Hu X, Plomp A, Wijnholds J, Ten Brink J, van Soest S, van den Born LI, Leys A, Peek R, de Jong PT, Bergen AA
ABCC6/MRP6 mutations: further insight into the molecular pathology of pseudoxanthoma elasticum.
Eur J Hum Genet. 2003 Mar;11(3):215-24., [PMID:12673275]
Abstract [show]
Pseudoxanthoma elasticum (PXE) is a hereditary disease characterized by progressive dystrophic mineralization of the elastic fibres. PXE patients frequently present with skin lesions and visual acuity loss. Recently, we and others showed that PXE is caused by mutations in the ABCC6/MRP6 gene. However, the molecular pathology of PXE is complicated by yet unknown factors causing the variable clinical expression of the disease. In addition, the presence of ABCC6/MRP6 pseudogenes and multiple ABCC6/MRP6-associated deletions complicate interpretation of molecular genetic studies. In this study, we present the mutation spectrum of ABCC6/MRP6 in 59 PXE patients from the Netherlands. We detected 17 different mutations in 65 alleles. The majority of mutations occurred in the NBF1 (nucleotide binding fold) domain, in the eighth cytoplasmatic loop between the 15th and 16th transmembrane regions, and in NBF2 of the predicted ABCC6/MRP6 protein. The R1141X mutation was by far the most common mutation identified in 19 (32.2%) patients. The second most frequent mutation, an intragenic deletion from exon 23 to exon 29 in ABCC6/MRP6, was detected in 11 (18.6%) of the patients. Our data include 11 novel ABCC6/MRP6 mutations, as well as additional segregation data relevant to the molecular pathology of PXE in a limited number of patients and families. The consequences of our data for the molecular pathology of PXE are discussed.
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38 Table 2 Summary of ABCC6/MRP6 mutations associated with PXE known today: our data combined with those of the literature Mutation Protein alteration Nucleotide substitution Location Reference Nonsense Q378X 1132C > T Exon 9 19,20 R518X 1552C > T Exon 2 41 Q749X 2247C > T Exon 17 This study Y768X 2304C > A Exon 18 22 R1030X 3088C > T Exon 23 22 R1141X 3421C > T Exon 24 12,20,22,38,39, this study R1164X 3490C > T Exon 24 12,41 Q1237X 3709C > T Exon 26 22 R1398X 4192C >T Exon 29 22 T364R Missense N411K 1091C > G Exon 9 20 A455P 1233T > G Exon 10 22 R518Q 1363G > C Exon 11 38 F568S 1553G > A Exon 12 22,38 L673P 1703T > C Exon 13 22 R765Q 2018T > C Exon 16 22 R1114P 2294G > A Exon 18 22, this study R1114H 3341G > C Exon 24 22 S1121W 3341G > A Exon 24 This study T1130M 3362C > G Exon 24 22 R1138W 3390C > T Exon 24 This study R1138Q 3412C > T Exon 24 12 R1138P 3413G > A Exon 24 12,22 G1203D 3413G > C Exon 24 22 R1221C 3608G > A Exon 25 22 V1298F 3663C > T Exon 26 This study T1301I 3892G > T Exon 28 22 G1302R 3902C > T Exon 28 22 A1303P 3904G > A Exon 28 22, this study R1314W 3907G > C Exon 28 22, this study R1314Q 3940C > T Exon 28 22 G1321S 3941G > A Exon 28 22 R1339C 3961G > A Exon 28 22 Q1347H 4015C > T Exon 28 22,39 G1354R 4041G > C Exon 28 22 D1361N 4060G > C Exon 29 20,38 K1394N 4081G > A Exon 29 22 I1424T 4182G > T Exon 29 This study R1459C 4271T > C Exon 30 22 4377C > T Exon 30 This study Frameshift IVS17-12delT T Intron 17 This study IVS21+1G>T Intron 21 22,38 IVS26-1G>A Intron 26 12,21,22 179del 9 Exon 2 20 179-195del Exon 2 22 960del C Exon 8 41 1944del22 Exon 16 This study 1995delG Exon 16 22 2322delC Exon 18 22 2542delG Exon 19 41 3775delT Exon 27 This study 4104delC Exon 29 22 4182delG Exon 29 This study 938-939insT Exon 8 22 4220insAGAA Exon 30 This study Large deletion Exons 23-29 21, This study Exon 15 22 ABCC1, ABCC6 41, this study Mutation types The mutation types found in this study are summarized in Table 1.
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ABCC6 p.Asn411Lys 12673275:38:498
status: NEW[hide] Pseudoxanthoma elasticum: a clinical, histopatholo... Surv Ophthalmol. 2003 Jul-Aug;48(4):424-38. Hu X, Plomp AS, van Soest S, Wijnholds J, de Jong PT, Bergen AA
Pseudoxanthoma elasticum: a clinical, histopathological, and molecular update.
Surv Ophthalmol. 2003 Jul-Aug;48(4):424-38., [PMID:12850230]
Abstract [show]
Pseudoxanthoma elasticum is an autosomally inherited disorder that is associated with the accumulation of mineralized and fragmented elastic fibers in the skin, Bruch's membrane in the retina, and vessel walls. The ophthalmic and dermatologic expression of pseudoxanthoma elasticum and its vascular complications are heterogeneous, with considerable variation in phenotype, progression, and mode of inheritance. Using linkage analysis and mutation detection techniques, mutations in the ABCC6 gene were recently implicated in the etiology of pseudoxanthoma elasticum. ABCC6 encodes the sixth member of the ATP-binding cassette transporter and multidrug resistance protein family (MRP6). In humans, this transmembrane protein is highly expressed in the liver and kidney. Lower expression was found in tissues affected by pseudoxanthoma elasticum, including skin, retina, and vessel walls. So far, the substrates transported by the ABCC6 protein and its physiological role in the etiology of pseudoxanthoma elasticum are not known. A functional transport study of rat MRP6 suggests that small peptides such as the endothelin receptor antagonist BQ123 are transported by MRP6. Similar molecules transported by ABCC6 in humans may be essential for extracellular matrix deposition or turnover of connective tissue at specific sites in the body. One of these sites is Bruch's membrane. This review is an update on etiology of pseudoxanthoma elasticum, including its clinical and genetic features, pathogenesis, and biomolecular basis.
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193 TABLE 3 Summary of ABCC6 Mutations in PXE Patients Mutation Protein Alteration Nucleotide Substitution Location Reference Nonsense Q378X 1132C Ͼ T Exon 9 16,107 R518X 1552C Ͼ T Exon 12 88 Y768X 2304C Ͼ A Exon 18 67 R1030X 3088C Ͼ T Exon 23 67 R1141X 3421C Ͼ T Exon 24 12,45,67,107,111,112,133 R1164X 3490C Ͼ T Exon 24 88,112 Q1237X 3709C Ͼ T Exon 26 67 R1398X 4192C Ͼ T Exon 29 67 Missense T364R 1091C Ͼ G Exon 9 107 N411K 1233T Ͼ G Exon 10 67 A455P 1363G Ͼ C Exon 11 142 R518Q 1553G Ͼ A Exon 12 67,142 F568S 1703T Ͼ C Exon 13 67 L673P 2018T Ͼ C Exon 16 67 R765Q 2294G Ͼ A Exon 18 67 R1114P 3341G Ͼ C Exon 24 67 S1121W 3362C Ͼ G Exon 24 67 R1138W 3412C Ͼ T Exon 24 111 R1138Q 3413G Ͼ A Exon 24 67,111 R1138P 3413G Ͼ C Exon 24 67 G1203D 3608G Ͼ A Exon 25 67 V1298F 3892G Ͼ T Exon 28 67 T13011 3902C Ͼ T Exon 28 67 G1302R 3904G Ͼ A Exon 28 67 A1303P 3907G Ͼ C Exon 28 67 R1314W 3940C Ͼ T Exon 28 67 R1314Q 3941G Ͼ A Exon 28 67 G1321S 3961G Ͼ A Exon 28 67 R1339C 4015C Ͼ T Exon 28 67,133 Q1347H 4041G Ͼ C Exon 28 67 G1354R 4060G Ͼ C Exon 29 107,142 D1361N 4081G Ͼ A Exon 29 67 11424T 4271T Ͼ C Exon 30 67 Frameshift Splicing IVS21 ϩ 1G ϾT Intron 21 67,142 IVS26-1G ϾA Intron 26 67,111,112 Deletion 179del9 Exon 2 107 179-195del Exon 2 67 960delC Exon 8 88 1944del22 Exon 16 12 1995delG Exon 16 67 2322delC Exon 18 67 2542delG Exon 19 67 3775delT Exon 27 12,67 4101delC Exon 29 67 Insertion 938-939insT Exon 8 67 4220insAGAA Exon 30 12 Intragenic deletion Exon 23-29 67,112 Exon 15 67 Intergenic deletion ABCC6 12,88 LOCAL RETINAL TRANSPORT FUNCTION OF ABCC6 ABCC6 Expression in the Retina Bergen et al detected ABCC6 expression in various tissues in man.12 Low expression levels of ABCC6 were observed in the retina as well as other tissues usually affected by PXE, including skin and vessel wall.
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ABCC6 p.Asn411Lys 12850230:193:471
status: NEW[hide] Heterozygous carriers of Pseudoxanthoma elasticum ... J Neurol. 2003 Aug;250(8):983-6. Morcher M, Hausser I, Brandt T, Grond-Ginsbach C
Heterozygous carriers of Pseudoxanthoma elasticum were not found among patients with cervical artery dissections.
J Neurol. 2003 Aug;250(8):983-6., [PMID:12928920]
Abstract [show]
In this study of patients with spontaneous cervical artery dissections (sCAD) we searched for mutations in ABCC6, the candidate gene for Pseudoxanthoma elasticum (PXE). Genomic DNA samples from 12 sCAD patients with pronounced electron microscopic alterations in their dermal connective tissue and from 2 patients with PXE were analysed. One patient with PXE was compound heterozygous for two missense point mutations, in the second patient with PXE we did not find changes in the ABCC6 gene. We observed several missense mutations (H623Q, R3190W and R1268Q) in the patients with sCAD, but these mutations were not disease specific,since they were also detected in a series of 25 healthy control subjects.The finding of several sequence variants in sCAD patients and of disease causing mutations in one of the PXE patients suggests that our strategy of mutation search is reliable. Since we did not find disease causing mutations in our series of patients with sCAD we suggest that ABCC6 is not a candidate gene for sCAD.
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53 A missense mutation (N411K) at this same nucleotide position was described as disease causing in a patient with PXE [13].The analysis of 25 control subjects revealed that none of the sequence variants found in the group of sCAD patients was specific, as each mutation was also detected among control subjects.Two of the missense mutations (H623Q and R1268Q) had already been found in healthy subjects [13, 18].
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ABCC6 p.Asn411Lys 12928920:53:21
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.Asn411Lys 15459974:64:467
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.Asn411Lys 15459974:72:270
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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No. Sentence Comment
379 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.Asn411Lys 15894595:379:229
status: NEW