ABCC6 p.Ile319Val
| LOVD-ABCC6: |
p.Ile319Val
D
|
| Predicted by SNAP2: | A: D (63%), C: D (53%), D: D (95%), E: D (91%), F: N (53%), G: D (91%), H: D (91%), K: D (95%), L: N (72%), M: D (71%), N: D (91%), P: D (95%), Q: D (91%), R: D (95%), S: D (85%), T: D (85%), V: N (87%), W: D (91%), Y: D (91%), |
| Predicted by PROVEAN: | A: N, C: D, D: D, E: D, F: N, G: D, H: D, K: D, L: N, M: N, N: D, P: D, Q: D, R: D, S: D, T: N, V: N, 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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No. Sentence Comment
153 Three of the neutral variants (K281E, I319V, and H632Q) could not be detected by SSCP or CSGE.
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ABCC6 p.Ile319Val 11536079:153:38
status: NEW155 The frequencies of K281E, I319V, and H632Q in our PXE cohort and control panel were, consequently, not assessed.
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ABCC6 p.Ile319Val 11536079:155:28
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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No. Sentence Comment
92 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.Ile319Val 12384774:92:33
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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No. Sentence Comment
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.Ile319Val 16086317:209:1150
status: NEW157 Search for MutationsWithin the Duplicated Region (50 UTR, exons 1^ 9) of ABCC6 In the first round of mutation screening (see Materials and Methods, and Supplementary Table S5), sequencing of the PCR products and comparative analysis of the sequencing reads revealed frequent polymorphisms and potential mutations (p.A78T, p.E125K, p.A158V, p.R265G, p.K281E, and p.I319V p.Q378X) (see Tables 1 and 2) that appeared in all families and initially did not cosegregate with familial haplotypes, which suggests that they are likely pseudogene polymorphisms.
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ABCC6 p.Ile319Val 16086317:157:364
status: NEW206 While some of these polymorphisms have been identified in recently characterized ABCC6 pseudogene sequences and neighboring intronic sequences [Pulkkinen et al., 2001], others (c.345112T4C, c.474113G4A, c.794136A4C, p.K281E, and p.I319V) were not found in such sequences.
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ABCC6 p.Ile319Val 16086317:206:231
status: NEW