ABCC6 p.Val614Ala
| LOVD-ABCC6: |
p.Val614Ala
D
|
| Predicted by SNAP2: | A: N (72%), C: N (82%), D: N (61%), E: N (82%), F: N (66%), G: N (72%), H: N (66%), I: N (78%), K: N (82%), L: N (82%), M: N (78%), N: N (82%), P: N (61%), Q: N (82%), R: N (72%), S: N (87%), T: N (87%), W: D (66%), Y: N (72%), |
| Predicted by PROVEAN: | A: N, C: N, D: N, E: N, F: N, G: N, H: N, I: N, K: N, L: N, M: N, N: N, P: N, Q: N, R: N, S: N, T: N, W: N, Y: N, |
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[hide] Pseudoxanthoma elasticum: Point mutations in the A... Hum Mutat. 2001;18(1):85. Meloni I, Rubegni P, De Aloe G, Bruttini M, Pianigiani E, Cusano R, Seri M, Mondillo S, Federico A, Bardelli AM, Andreassi L, Fimiani M, Renieri A
Pseudoxanthoma elasticum: Point mutations in the ABCC6 gene and a large deletion including also ABCC1 and MYH11.
Hum Mutat. 2001;18(1):85., [PMID:11439001]
Abstract [show]
Pseudoxanthoma elasticum (PXE) is a mendelian disorder characterized by calcification of elastic fibers in skin, arteries, and retina. It results in dermal lesions, arterial insufficiency and retinal hemorrhages, leading to macular degeneration. PXE is transmitted either as an autosomal dominant or recessive trait and several sporadic cases have been observed. Mutations in the ABCC6 gene have been identified very recently in patients. Here, we report on a large Italian family affected by pseudoxanthoma elasticum for which linkage analysis had pointed to a region encompassing markers D16S3069-D16S405-D16S3103; hemizygosity of marker D16S405 allowed us to detect a submicroscopic deletion of at least 900 kb involving ABCC6, ABCC1, and MYH11. Mutation analysis on the other allele of the family, as well as on two additional sporadic cases, revealed nonsense (Y227X, R518X, R1164X) and frame-shift (c.960delC) mutations in ABCC6 (MRP6) further confirming the role of this multi-drug resistance gene in the etiology of pseudoxanthoma elasticum. Furthermore, clinical re-examination of members of the family harboring the deletion led to the detection of additional features, potentially caused by the deletion of the MYH11 gene. In the course of the analysis five nonpathogenic variants were found in ABCC6: 1233T>C, 1245G>A, 1838 T>G (V614A), 1890C>G, and 3506+83C>A. Hum Mutat 18:85, 2001.
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8 In the course of the analysis five nonpathogenic variants were found in ABCC6: 1233T>C, 1245G>A, 1838 T>G (V614A), 1890C>G, and 3506+83C>A.
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ABCC6 p.Val614Ala 11439001:8:107
status: NEW95 Mutations and variants in ABCC6 nt change Mutations 681 C ->G 960delC 1552 C ->T 3490 C ->T Non pathogenic variants 1233 T ->C 1245 G ->A 1838 T->G 1890 C->G c.3506+83 C ->A protein change Y227X frame-shift from I320 R518X R1164X N411N N415N V614A T630T _ exon 7 11 exon 8 family exon 12 11 exon 24 12 exon 10 11 exon 10 11 exon 14 11, 12 exon patient 11 11 12 exon 14 exon 24 11 11, 12 11, 12 Re-evaluation of the phenotype in the family with the large deletion did not reveal significant additional manifestations, suggesting that heterozygous ABCC1 and MYH11 deletion does not give rise to an obvious phenotype.
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ABCC6 p.Val614Ala 11439001:95:242
status: NEW[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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129 Premature termination mutations frequently result in the nonsense-mediated decay (NMD) of mutant mRNA products and significantly reduce mutant transcript levels (Maquat 1996; Nagy and Table 3 Missense Neutral Variants Identified in the ABCC6 Gene in a Cohort of 122 Patients CHANGE IN STATUS a ORIGIN(S)b EXON(S) NO. OF ALLELES/ PXE CHROMOSOMES NO. OF ALLELES/ CONTROL CHROMOSOMES c Amino Acid Nucleotide G61D 182GrA ht SA 2 1/244 0/200 G207R 619GrA ht Belgium 6 1/244 0/200 R265G 793ArG ht Belgium 7 1/244 0/200 K281Ed 841ArG ht, hm SA 8 5/8d Nd I319Vd 955ArG ht, hm SA 8 5/8d Nd N497K 1489CrA ht Belgium 12 1/244 0/200 V614A 1841TrC ht, hm All 14 200/244 163/200 H632Qd 1896CrA ht, hm SA, Belgium 15 17/24d Nd L953H 2858TrA ht US 22 1/244 0/200 W1241C 3723GrC ht Germany 26 1/244 0/200 R1268Q 3803GrA ht All 27 23/244 31/200 a ht p heterozygote; hm p homozygote.
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ABCC6 p.Val614Ala 11536079:129:624
status: NEW156 Most of the neutral variants were unique; however, two of these alleles (V614A and R1268Q) were found at 81.9% and 9.4%, respectively, in the cohort of patients with PXE.
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ABCC6 p.Val614Ala 11536079:156:73
status: NEW[hide] Evidence for a founder effect for pseudoxanthoma e... Hum Genet. 2002 Oct;111(4-5):331-8. Epub 2002 Sep 7. Le Saux O, Beck K, Sachsinger C, Treiber C, Goring HH, Curry K, Johnson EW, Bercovitch L, Marais AS, Terry SF, Viljoen DL, Boyd CD
Evidence for a founder effect for pseudoxanthoma elasticum in the Afrikaner population of South Africa.
Hum Genet. 2002 Oct;111(4-5):331-8. Epub 2002 Sep 7., [PMID:12384774]
Abstract [show]
Pseudoxanthoma elasticum (PXE) is a heritable elastic tissue disorder recently shown to be attributable to mutations in the ABCC6 ( MRP6) gene. Whereas PXE has been identified in all ethnic groups studied to date, the prevalence of this disease in various populations is uncertain, although often assumed to be similar. A notable exception however is the prevalence of PXE among South African Afrikaners. A previous report has suggested that a founder effect may explain the higher prevalence of PXE in Afrikaners, a European-derived population that first settled in South Africa in the 17th century. To investigate this hypothesis, we performed haplotype and mutational analysis of DNA from 24 South African families of Afrikaner, British and Indian descent. Among the 17 Afrikaner families studied, three common haplotypes and six different disease-causing variants were identified. Three of these mutant alleles were missense variants, two were nonsense mutations and one was a single base-pair insertion. The most common variant accounted for 53% of the PXE alleles, whereas other mutant alleles appeared at lower frequencies ranging from 3% to 12%. Haplotype analysis of the Afrikaner families showed that the three most frequent mutations were identical-by-descent, indicating a founder origin of PXE in this population.
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89 335 Table 3 Silent and neutral variants identified in the ABCC6 gene in a cohort of 24 South African patients with PXE (hm homozygote, ht heterozygote, aa amino acid changes, nt nucleotide changes, i- the intron in which the variant is located, No. of alleles number of variants found in the 48 PXE chromosomes analysed in this study aVariants identified by sequencing only; variants identified in either or both ABCC6 pseudogenes have not been indicated in this table aa nt Status Exon Origin No. of alleles G61D 182G→A ht 2 Afrikaner 1 T215T 645G→A ht 6 Afrikaner 2 K281Ea 841A→G ht, hm 8 Afrikaner, UK 2 T285Ta 855C→T ht, hm 8 Afrikaner, UK 2 I319Va 955A→G ht, hm 8 Afrikaner, UK 2 N411N 1233T→C ht, hm 10 Afrikaner, UK 20 V415V 1245G→A ht, hm 10 All 20 none IVS11+73G→C ht i-11 Afrikaner, UK 2 none IVS11-45C→A ht i-11 UK 1 none IVS11-41A→G ht, hm i-11 Afrikaner, UK 5 none IVS11-22C→A ht i-11 Afrikaner 1 V614A 1841T→C ht, hm 14 All 16 T630Ta 1890C→G ht, hm 15 Afrikaner, UK 11 H632Qa 1896C→A ht, hm 15 Afrikaner, UK 11 A830A 2490C→T ht, hm 19 Afrikaner, UK 6 none IVS21+30G→A ht i-21 UK 2 P945P 2835C→T ht, hm 22 Indian, UK 3 none IVS22-5delTCCC-8 ht i-22 UK 1 none IVS24-16T→C ht i-24 UK 1 none IVS24-3C→T ht i-24 AFK 1 none IVS25+55T→C ht i-25 Afrikaner, UK 8 none IVS25+90G→A ht, hm i-25 All 21 R1268Q 3803G→A ht, hm 27 Afrikaner, UK 4 none IVS27-6G→A ht i-27 Afrikaner 1 none IVS28+49C→T ht, hm i-28 Afrikaner 18 I1350L 4048A→C ht 29 UK 1 none 3` UTR+17G→A ht 3`UTR Afrikaner 2 Silent and neutral variants of ABCC6 An additional 27 variants, assumed to be neutral or silent, were identified in the course of the ABCC6 screening of our cohort of 24 South African PXE individuals (Table 3).
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ABCC6 p.Val614Ala 12384774:89:987
status: NEW92 Six other variants (G61D, K281E, I319V, V614A, H632Q and R1268Q) resulted in amino acid changes but appeared not to segregate with the disease in PXE pedigrees and were therefore likely to be neutral.
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ABCC6 p.Val614Ala 12384774:92:40
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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159 Table 4 Polymorphic sequence changes identified in ABCC6 Nucleotide Amino acid Location Estimated frequency (%) CA(18) F Intron4 68 V415V 1245G>A 10 33 V614A 1841T>C 14 52 T630T 1890C>G 15 22 H632Q 1896C>A 15 24 A830G 2490C>G 19 25 P945P 2846C>T 22 50 L968L 2904G>A 22 20 Int(22) F Intron22 50 R1268Q 3808G>A 27 38 The definition of disease-associated alleles essentially follows the criteria described by Le Saux et al.22 In summary, sequence variants predicted to result in nonsense or splice-site changes were considered to be disease-associated alleles if they are absent in DNA of a panel of at least 100 controls.
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ABCC6 p.Val614Ala 12673275:159:152
status: NEW[hide] Molecular genetics of pseudoxanthoma elasticum: ty... Hum Mutat. 2005 Sep;26(3):235-48. Miksch S, Lumsden A, Guenther UP, Foernzler D, Christen-Zach S, Daugherty C, Ramesar RK, Lebwohl M, Hohl D, Neldner KH, Lindpaintner K, Richards RI, Struk B
Molecular genetics of pseudoxanthoma elasticum: type and frequency of mutations in ABCC6.
Hum Mutat. 2005 Sep;26(3):235-48., [PMID:16086317]
Abstract [show]
Pseudoxanthoma elasticum (PXE) is a systemic heritable disorder that affects the elastic tissue in the skin, eye, and cardiovascular system. Mutations in the ABCC6 gene cause PXE. We performed a mutation screen in ABCC6 using haplotype analysis in conjunction with direct sequencing to achieve a mutation detection rate of 97%. This screen consisted of 170 PXE chromosomes in 81 families, and detected 59 distinct mutations (32 missense, eight nonsense, and six likely splice-site point mutations; one small insertion; and seven small and five large deletions). Forty-three of these mutations are novel variants, which increases the total number of PXE mutations to 121. While most mutations are rare, three nonsense mutations, a splice donor site mutation, and the large deletion comprising exons 23-29 (c.2996_4208del) were identified as relatively frequent PXE mutations at 26%, 5%, 3.5%, 3%, and 11%, respectively. Chromosomal haplotyping with two proximal and two distal polymorphic markers flanking ABCC6 demonstrated that most chromosomes that carry these relatively frequent PXE mutations have related haplotypes specific for these mutations, which suggests that these chromosomes originate from single founder mutations. The types of mutations found support loss-of-function as the molecular mechanism for the PXE phenotype. In 76 of the 81 families, the affected individuals were either homozygous for the same mutation or compound heterozygous for two mutations. In the remaining five families with one uncovered mutation, affected showed allelic compound heterozygosity for the cosegregating PXE haplotype. This demonstrates pseudo-dominance as the relevant inheritance mechanism, since disease transmission to the next generation always requires one mutant allelic variant from each parent. In contrast to other previous clinical and molecular claims, our results show evidence only for recessive PXE. This has profound consequences for the genetic counseling of families with PXE.
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209 Type and Frequency of Polymorphisms in ABCC6 Identi'ed in170 Chromosomes of 81 PXE Familiesà Exon/ Intron Nucleotide substitution Amino acid change Location Frequency (] of families) Referencea E 03 c.232G4A p.A78T ABCC6-C2 81 This study, (C,H) IVS 03 c.345112T4C Intron duplication 81 This study IVS 03 c.345126C4T Intron 1 This study IVS 03 c.346À6G4A Intron 10 This study, (C) E 04 c.373G4A p.E125K ABCC6-C1 81 This study, (C) E 04 c.473C4T p.A158V ABCC6-C2 81 This study, (C) IVS 04 c.474113 G4A Intron duplication 2 This study IVS 04 c.474143C4T Intron duplication 80 This study, (C) IVS 04 c.475À76A4C Intron duplication 81 This study IVS 04 c.475À45C4T Intron 3 This study IVS 04 c.475À22T4C Intron duplication 80 This study, (C) E 05 c.549G4A L183L ABCC6 2 This study, (E) IVS 05 c.600123C4T Intron 1 This study E 06 c.645G4A T215T ABCC6 8 This study, (C) IVS 06 c.662112C4T Intron 1 This study, (C) E 07 c.793A4G R265G ABCC6-C1 81 This study, (C,H) IVS 07 c.794136A4C Intron duplication 81 This study, (C) E 08 c.841A4G K281E ABCC6-Cx 81 This study, (H) E 08 c.855C4T T285T ABCC6-C1 81 This study, (C) E 08 c.955A4G I319V ABCC6-Cx 81 This study, (H) E 09 c.1077A4G S359S ABCC6, ABCC6-C1 1 This study, (C,H) E 09 c.1132C4T Q378X ABCC6-C1 81 This study, (C,H) E 09 c.1141T4C L381L ABCC6, ABCC6-C1 81 This study, (C,H) IVS 09 c.117616C4T No SSM Intron 1 This study E 10 c.1233T4C N411N ABCC6 1 This study, (B,L) E 10 c.1245G4A V415V ABCC6 Frequent This study, (B,L) IVS 10 c.133817C4G Intron Frequent This study IVS 10 c.1338120C4G Intron Frequent This study IVS 10 c.1338162G4C Intron Frequent This study IVS 11 c.1432À41A4G Intron Frequent This study, (E) E 12 c.1540G4A V514I ABCC6 1 This study IVS 12 c.1635147C4T Intron Frequent This study E 14 c.1841T4C V614A ABCC6 Frequent This study, (B,E) IVS 14 c.1868À57G4A Intron 3 This study E 15 c.1890C4G T630T ABCC6 Frequent This study, (B,L) E 15 c.1896C4A H632Q ABCC6 Frequent This study, (C,G) E 17 c.2171G4A R724K ABCC6 2 This study E 17 c.2175A4T V725V ABCC6 2 This study E 17 c.2224A4G I742V ABCC6 2 This study E 19 c.2490C4T A830A ABCC6 Frequent This study, (E) E 22 c.2820T4G R940R ABCC6 1 This study E 22 c.2835C4T P945P ABCC6 8 This study, (J) E 22 c.2836C4A L946I ABCC6 3 This study E 22 c.2904G4A L968L ABCC6 1 This study, (J) E 23 c.3190C4T R1064W ABCC6 2 This study IVS 24 c.3507À16T4C No SSM Intron 4 This study IVS 24 c.3507À3C4T No SSM Intron 3 This study E 27 c.3803G4A R1268Q ABCC6 Frequent This study, (C,M) IVS 27 c.3883À24G4A Intron 1 This study IVS 28 c.4041149C4T Intron Frequent This study, (E) IVS 28 c.4042À30C4T Intron Frequent This study IVS 29 c.420819G4A Intron 2 This study E 30 c.4305C4T G1435G ABCC6 1 This study IVS 30 c.4405À31G4A Intron Frequent This study 30 UTR c.4512117G4A UTR 5 This study, (E) 30 UTR c.4512138G4A UTR 1 This study ÃDNA mutation numbering is based on the ABCC6 cDNA sequence (GenBank accession no. AF076622.1) and 11 corresponds to the A of the ATG translation initiation codon of the reference sequence.
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ABCC6 p.Val614Ala 16086317:209:1796
status: NEW199 Coding sequence SNPs were considered as neutral (non-disease-causing) when they resulted in a synonymous amino acid substitution or a nonsynonymous substitution that did not cosegregate with the disease haplotype and phenotype (p.V614A, p.R724K, p.I742V, p.L946I, p.R1064W, and p.R1268Q) or did cosegregate with other PXE mutations in linkage disequilibrium in individual families (p.V514I, p.H632Q, and p.R1268Q).
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ABCC6 p.Val614Ala 16086317:199:230
status: NEW[hide] Spectrum of genetic variation at the ABCC6 locus i... J Dermatol Sci. 2009 Jun;54(3):198-204. Epub 2009 Mar 31. Ramsay M, Greenberg T, Lombard Z, Labrum R, Lubbe S, Aron S, Marais AS, Terry S, Bercovitch L, Viljoen D
Spectrum of genetic variation at the ABCC6 locus in South Africans: Pseudoxanthoma elasticum patients and healthy individuals.
J Dermatol Sci. 2009 Jun;54(3):198-204. Epub 2009 Mar 31., [PMID:19339160]
Abstract [show]
BACKGROUND: Pseudoxanthoma elasticum (PXE) is an autosomal recessive metabolic disorder with ectopic mineralization in the skin, eyes and cardiovascular system. PXE is caused by mutations in ABCC6. OBJECTIVE: To examine 54 unrelated South African PXE patients for ABCC6 PXE causing mutations. METHODS: Patients were screened for mutations in ABCC6 using two strategies. The first involved a comprehensive screening of all the ABCC6 exons and flanking regions by dHPLC or sequencing whereas the second involved screening patients only for the common PXE mutations. The ABCC6 gene was screened in ten white and ten black healthy unrelated South Africans in order to examine the level of common non-PXE associated variation. RESULTS: The Afrikaner founder mutation, R1339C, was present in 0.41 of white ABCC6 PXE alleles, confirming the founder effect and its presence in both Afrikaans- (34/63 PXE alleles) and English-speakers (4/28). Eleven mutations were detected in the white patients (of European origin), including two nonsense mutations, 6 missense mutations, two frameshift mutations and a large deletion mutation. The five "Coloured" patients (of mixed Khoisan, Malay, European and African origin) included three compound heterozygotes with R1339C as one of the mutations. The three black patients (sub-Saharan African origin) were all apparent homozygotes for the R1314W mutation. Blacks showed a trend towards a higher degree of neurtral variation (18 variants) when compared to whites (12 variants). CONCLUSION: Delineation of the ABCC6 mutation profile in South African PXE patients will be used as a guide for molecular genetic testing in a clinical setting and for genetic counselling.
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149 998+13C>T - Intron - 1 - This study E 10 c.1233T>C N411N CL3 1 2 1 [32,35] rs9930886 E 10 c.1245G>A V415V CL4 - 2 - [32,35] rs9940825 E 10 c.1249G>A V417M CL4 5 - - This study IVS 10 c.1338+7C>G - Intron - 5 - [32] rs9940089 E 11 c.1344G>A L448L EL5 - 2 - This study IVS 11 c.1432-41A>C - Intron 3 1 2 [7,32] rs2239322 IVS 11 c.1432-45C>T - Intron - - 2 [11] No rs number IVS 11 c.1432-48G>A - Intron 7 - 8 dbSNP rs7193932 E 12 c.1494G>A K499K CL4 - - 1 This study IVS 12 c.1635+48C>T** - Intron 7 - - [32] ENSSNP11084760 E 14 c.1841T>C V614A CL5 15 2 3 [7,32,35] rs12931472 E 15 c.1890C>G T630T CL5 6 3 1 [32,35] rs8058696 E 16 c.1896C>A H632Q CL5 - 3 1 [31,32,36] rs8058694 E 17 c.2171G>A*** R724L NBF1 - 1 - [32] No rs number E 17 c.2175A>T V725V NBF1 - 2 - [32] No rs number E 17 c.2224A>G I742V NBF1 - 1 - [32] No rs number E 18 c.2400A>G G800G NBF1 1 2 - dbSNP rs7500834 E 19 c.2490C>T A830A CL6 3 - - [7,32] rs9924755 E 19 c.2542A>G M848V CL6 1 3 - dbSNP rs6416668 E 22 c.2835C>T P945P TS12 1 2 1 [32,37] rs2856585 E 22 c.2836C>A L946I TS12 1 - - This studya IVS 24 c.3507-16T>C - Intron 3 2 - [11,32] rs3213471 a L946I was previously identified as a pathogenic mutation by Morcher et al. [38], in this study bioinformatic analysis of the variant did not support a functional effect of the variant on the protein.
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ABCC6 p.Val614Ala 19339160:149:537
status: NEW180 V614A was the most prevalent variant, observed in PXE patients (15/24) but also found in both black and white healthy South Africans.
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ABCC6 p.Val614Ala 19339160:180:0
status: NEW[hide] Novel mutations of ABCC6 gene in Japanese patients... Biochem Biophys Res Commun. 2009 Mar 13;380(3):548-53. Epub 2009 Jan 25. Sato N, Nakayama T, Mizutani Y, Yuzawa M
Novel mutations of ABCC6 gene in Japanese patients with Angioid streaks.
Biochem Biophys Res Commun. 2009 Mar 13;380(3):548-53. Epub 2009 Jan 25., 2009-03-13 [PMID:19284998]
Abstract [show]
Angioid streaks (AS) are eye abnormalities caused by breaks in Bruch's membrane. The condition is often associated with pseudoxanthoma elasticum (PXE). The ATP-binding cassette, sub-family C (CFTR/MRP), member 6 (ABCC6) is reported to be the causal gene for PXE, although there have been no reports on whether the ABCC6 gene is the causal gene for AS. The aims of this study are to isolate the causal mutations for AS using a haplotype-based case-control study. We genotyped 54 Japanese AS patients and 150 controls for 5 single-nucleotide polymorphisms (SNPs). A simple association study using each SNP and a haplotype-based case-control study were performed. Twelve patients with special haplotypes for AS were selected, and were then subjected to gene sequencing. Six variants were successfully identified as causal mutations for AS (p.R419Q, p.E422K, c.2542delG, Del_Exon23, c.3774-3775insC and p.E1427K), and 4 of these were novel. This method can be applied to both identifying susceptibility variants of multifactorial diseases and isolating mutations in single-gene diseases.
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84 We identified 8 nonsynonymous variants and a deletion variant in the exon regions; p.R419Q (Exon10), p.S587C (exon13), p.V614A (Exon14), p.H632Q (Exon15), c.2542delG (Exon19), p.A950V (Exon22), p.R1268Q (Exon27) and p.E1427K (Exon30).
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ABCC6 p.Val614Ala 19284998:84:121
status: NEW104 Disease-causing mutations The homozygous p.R419Q and the homozygous p.R1268Q were found in 2 subjects with the homozygous GTGG/GTGG diplotype. The homozygous c.2542delG and the homozygous p.H632Q or homozygous p.V614A were found in each subject with the homozygous ATGA/ATGA diplotype. The homozygous Del_Exon23 was found in 2 subjects with the homozygous GTGA/GTGA diplotype.
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ABCC6 p.Val614Ala 19284998:104:212
status: NEW106 The heterozygous p.E1427K and p.V614A or p.H632Q or p.R1268Q were found in a subject with the heterozygous GTAA/ATGG diplotype. The heterozygous c.2542delG and p.V614A or p.H632Q were found in a subject with the heterozygous GTAA/ACAA diplotype. The heterozygous p.S587C was found in a subject with the heterozygous GTGA/GCGA diplotype, and the heterozygous p.A950V was found in a subject with the heterozygous GTAA/GCAA diplotype.
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ABCC6 p.Val614Ala 19284998:106:32
status: NEWX
ABCC6 p.Val614Ala 19284998:106:162
status: NEW109 Consequently, p.S587C (exon13), p.V614A (Exon14), p.H632Q (Exon15), p.A950V (Exon22) and p.R1268Q (Exon27) were excluded from among the disease-causing mutations because they were seen in the control group.
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ABCC6 p.Val614Ala 19284998:109:34
status: NEW110 Of the 9 variants, p.V614A, p.H632Q and p.R1268Q were previously reported as non-causal variants for PXE. Although c.2542delG (Exon19) was seen in the control group, this is defined as the disease-causing mutation because it yields a premature stop codon.
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ABCC6 p.Val614Ala 19284998:110:21
status: NEW157 Exon Mutation AS Control Decision Wild/Wild Wild/Mut Mut/Mut Wild/Wild Wild/Mut Mut/Mut Undetermine 10 c.1256G>A (p.R419Q) 45 3 6 150 0 0 0 * 10 c.1264G>A (p.E422K) 53 1 0 150 0 0 0 * 10 c.1283A>G (p.N428S) 54 0 0 148 2 0 0 # 10 c.1312G>A (p.V438M) 54 0 0 149 1 0 0 # 13 c.1760C>G (p.S587C) 53 1 0 149 1 0 0 # 14 c.1841T>C (p.V614A) 40 12 2 89 56 5 0 $ 15 c.1896C>A (p.H632Q) 30 15 9 90 55 5 0 $ 19 c.2542delG 34 13 7 149 1 0 0 * 22 c.2849C>T (p.A950V) 53 1 0 149 1 0 0 # 23 Del_Exon23 52 0 2 150 0 0 0 * 27 c.3803G>A (p.R1268Q) 29 16 9 105 42 3 0 $ 27 c.3774-3775insertC 53 1 0 147 0 0 3 * 30 c.4279G>A (p.E1427K) 53 1 0 150 0 0 0 * For ABCC6 proteins, the designations for the mutations refer to the position of the amino acid substitution, where amino acid terminus. Nonsynonymous variants were shown by the amino acid numbers started by the strat codon methionine. The cDNA base numbers refer to the nucleotide in the cDNA, where nucleotide 1 is the A of the first ATG. * Causal mutation definitely.
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ABCC6 p.Val614Ala 19284998:157:326
status: NEW