ABCD4 p.Glu368Lys
Predicted by SNAP2: | A: N (78%), C: N (66%), D: N (82%), F: N (57%), G: N (61%), H: N (82%), I: N (72%), K: N (82%), L: N (66%), M: N (66%), N: N (82%), P: N (61%), Q: N (87%), R: N (66%), S: N (82%), T: N (82%), V: N (78%), W: D (80%), Y: N (57%), |
Predicted by PROVEAN: | A: N, C: N, D: 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, V: N, W: D, Y: N, |
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[hide] Identification of novel SNPs of ABCD1, ABCD2, ABCD... Neurogenetics. 2011 Feb;12(1):41-50. Epub 2010 Jul 27. Matsukawa T, Asheuer M, Takahashi Y, Goto J, Suzuki Y, Shimozawa N, Takano H, Onodera O, Nishizawa M, Aubourg P, Tsuji S
Identification of novel SNPs of ABCD1, ABCD2, ABCD3, and ABCD4 genes in patients with X-linked adrenoleukodystrophy (ALD) based on comprehensive resequencing and association studies with ALD phenotypes.
Neurogenetics. 2011 Feb;12(1):41-50. Epub 2010 Jul 27., [PMID:20661612]
Abstract [show]
Adrenoleukodystrophy (ALD) is an X-linked disorder affecting primarily the white matter of the central nervous system occasionally accompanied by adrenal insufficiency. Despite the discovery of the causative gene, ABCD1, no clear genotype-phenotype correlations have been established. Association studies based on single nucleotide polymorphisms (SNPs) identified by comprehensive resequencing of genes related to ABCD1 may reveal genes modifying ALD phenotypes. We analyzed 40 Japanese patients with ALD. ABCD1 and ABCD2 were analyzed using a newly developed microarray-based resequencing system. ABCD3 and ABCD4 were analyzed by direct nucleotide sequence analysis. Replication studies were conducted on an independent French ALD cohort with extreme phenotypes. All the mutations of ABCD1 were identified, and there was no correlation between the genotypes and phenotypes of ALD. SNPs identified by the comprehensive resequencing of ABCD2, ABCD3, and ABCD4 were used for association studies. There were no significant associations between these SNPs and ALD phenotypes, except for the five SNPs of ABCD4, which are in complete disequilibrium in the Japanese population. These five SNPs were significantly less frequently represented in patients with adrenomyeloneuropathy (AMN) than in controls in the Japanese population (p=0.0468), whereas there were no significant differences in patients with childhood cerebral ALD (CCALD). The replication study employing these five SNPs on an independent French ALD cohort, however, showed no significant associations with CCALD or pure AMN. This study showed that ABCD2, ABCD3, and ABCD4 are less likely the disease-modifying genes, necessitating further studies to identify genes modifying ALD phenotypes.
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No. Sentence Comment
101 Gene Fragment SNP ID Category Amino acid change ABCD3 Exon1 rs4148058 5' untranslated region Exon2 rs2147794 Intron Exon3 rs16946 Coding synonymous Exon7 rs681187 Intron Exon23 rs662813 3' untranslated region Exon23 rs337592 3' untranslated region ABCD4 5'UTR rs17782508a Upstream at the transcription start site Intron1 rs17182959 Intron Intron1 rs17158118 Intron Exon3 rs2301345a Coding synonymous L62L Exon9 rs4148077a Coding nonsynonymous A304T Exon10 rs4148078a Coding synonymous L320L Exon11 rs3742801a Coding nonsynonymous E368K Table 4 Summary of identified single nucleotide polymorphism (SNPs) of ABCD2, ABCD3, and ABCD4 in 40 adrenoleukodystrophy patients: known SNPs A total of 24 SNPs of ABCD2, ABCD3, and ABCD4 were identified in 40 ALD patients. Among them, 11 SNPs (45.8%) were novel SNPs.
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ABCD4 p.Glu368Lys 20661612:101:530
status: NEW108 Among the SNPs with suggestive association in the Japanese patients (rs17782508, rs2301345, rs4148077, rs4148078, and rs3742801), rs4148077 (A304T) substitutes a hydrophilic amino acid for a hydrophobic amino acid, and rs3742801 (E368K) substitutes a basic amino acid for an acidic amino acid.
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ABCD4 p.Glu368Lys 20661612:108:230
status: NEW[hide] Genetic architecture of vitamin B12 and folate lev... PLoS Genet. 2013 Jun;9(6):e1003530. doi: 10.1371/journal.pgen.1003530. Epub 2013 Jun 6. Grarup N, Sulem P, Sandholt CH, Thorleifsson G, Ahluwalia TS, Steinthorsdottir V, Bjarnason H, Gudbjartsson DF, Magnusson OT, Sparso T, Albrechtsen A, Kong A, Masson G, Tian G, Cao H, Nie C, Kristiansen K, Husemoen LL, Thuesen B, Li Y, Nielsen R, Linneberg A, Olafsson I, Eyjolfsson GI, Jorgensen T, Wang J, Hansen T, Thorsteinsdottir U, Stefansson K, Pedersen O
Genetic architecture of vitamin B12 and folate levels uncovered applying deeply sequenced large datasets.
PLoS Genet. 2013 Jun;9(6):e1003530. doi: 10.1371/journal.pgen.1003530. Epub 2013 Jun 6., [PMID:23754956]
Abstract [show]
Genome-wide association studies have mainly relied on common HapMap sequence variations. Recently, sequencing approaches have allowed analysis of low frequency and rare variants in conjunction with common variants, thereby improving the search for functional variants and thus the understanding of the underlying biology of human traits and diseases. Here, we used a large Icelandic whole genome sequence dataset combined with Danish exome sequence data to gain insight into the genetic architecture of serum levels of vitamin B(12) (B12) and folate. Up to 22.9 million sequence variants were analyzed in combined samples of 45,576 and 37,341 individuals with serum B(12) and folate measurements, respectively. We found six novel loci associating with serum B(12) (CD320, TCN2, ABCD4, MMAA, MMACHC) or folate levels (FOLR3) and confirmed seven loci for these traits (TCN1, FUT6, FUT2, CUBN, CLYBL, MUT, MTHFR). Conditional analyses established that four loci contain additional independent signals. Interestingly, 13 of the 18 identified variants were coding and 11 of the 13 target genes have known functions related to B(12) and folate pathways. Contrary to epidemiological studies we did not find consistent association of the variants with cardiovascular diseases, cancers or Alzheimer's disease although some variants demonstrated pleiotropic effects. Although to some degree impeded by low statistical power for some of these conditions, these data suggest that sequence variants that contribute to the population diversity in serum B(12) or folate levels do not modify the risk of developing these conditions. Yet, the study demonstrates the value of combining whole genome and exome sequencing approaches to ascertain the genetic and molecular architectures underlying quantitative trait associations.
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88 SNV name Locus Chr. Position (build 36/hg18) Annotation 1 Alleles 2 (effect/other) EAF Icelandic Danish - Inter99 Danish - Health2006 Combined Effect P Effect P Effect P N P I 2 ( P HET ) Novel loci rs2336573 CD320 19 8,273,709 G220R T/C 0.031 0.32 1.1610 251 0.22 0.0057 0.31 1.7610 28 45,575 8.4610 259 41 (0.033) rs1131603 TCN2 22 29,348,975 L376S C/T 0.055 0.19 4.3610 228 0.33 1.8610 29 0.33 5.3610 217 45,575 4.9610 249 62 (0.0050) rs3742801 ABCD4 14 73,828,759 E368K T/C 0.294 0.045 5.3610 28 0.093 7.6610 24 0.083 4.5610 25 45,571 1.7610 213 0 (0.20) rs2270655 MMAA 4 146,795,868 Q363H G/C 0.941 0.066 3.5610 25 0.30 2.8610 27 0.25 5.8610 28 45,576 2.2610 213 79 (7.1610 25 ) rs12272669 MMACHC 1 45,747,242 R206Q A/G 0.0022 0.51 3.0610 29 - - - - - - - Novel SNV associations in reported loci rs34324219 TCN1 11 59,379,954 D301Y C/A 0.881 0.21 8.8610 271 0.40 3.2610 223 0.30 3.5610 224 45,576 1.1610 2111 70 (0.001) rs7788053 3 FUT6 19 5,783,209 P124S A/G 0.254 0.046 2.1610 27 0.050 0.076 0.070 0.00072 45,575 1.7610 210 0 (0.64) Reported associated SNVs rs602662 FUT2 19 53,898,797 G258S A/G 0.596 0.16 4.1610 296 0.19 3.5610 213 0.23 1.9610 234 45,568 2.4610 2139 0 (0.14) rs1801222 CUBN 10 17,196,157 F253S G/A 0.593 0.11 1.1610 252 0.14 7.6610 28 0.17 2.9610 218 45,576 3.3610 275 0 (0.48) rs41281112 CLYBL 13 99,316,635 R259X C/T 0.948 0.17 9.6610 227 0.24 0.0013 0.29 2.5610 27 45,576 8.9610 235 0 (0.90) rs1141321 4 MUT 6 49,520,392 R532H C/T 0.627 0.061 1.4610 216 0.12 3 1.4610 25 0.11 1.4610 27 45,574 3.6610 226 0 (0.24) Association results for serum B 12 in Icelandic and Danish study samples separately and combined.
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ABCD4 p.Glu368Lys 23754956:88:468
status: NEW