ABCD4 p.Asp548Asn
| Predicted by SNAP2: | A: D (85%), C: D (85%), E: D (85%), F: D (95%), G: D (91%), H: D (91%), I: D (91%), K: D (95%), L: D (95%), M: D (91%), N: D (91%), P: D (95%), Q: D (91%), R: D (91%), S: D (85%), T: D (91%), V: D (91%), W: D (95%), Y: D (95%), |
| Predicted by PROVEAN: | A: D, C: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Mutations in ABCD4 cause a new inborn error of vit... Nat Genet. 2012 Oct;44(10):1152-5. doi: 10.1038/ng.2386. Epub 2012 Aug 26. Coelho D, Kim JC, Miousse IR, Fung S, du Moulin M, Buers I, Suormala T, Burda P, Frapolli M, Stucki M, Nurnberg P, Thiele H, Robenek H, Hohne W, Longo N, Pasquali M, Mengel E, Watkins D, Shoubridge EA, Majewski J, Rosenblatt DS, Fowler B, Rutsch F, Baumgartner MR
Mutations in ABCD4 cause a new inborn error of vitamin B(12) metabolism.
Nat Genet. 2012 Oct;44(10):1152-5. doi: 10.1038/ng.2386. Epub 2012 Aug 26., [PMID:22922874]
Abstract [show]
Inherited disorders of vitamin B(12) (cobalamin) have provided important clues to how this vitamin, which is essential for hematological and neurological function, is transported and metabolized. We describe a new disease that results in failure to release vitamin B(12) from lysosomes, which mimics the cblF defect caused by LMBRD1 mutations. Using microcell-mediated chromosome transfer and exome sequencing, we identified causal mutations in ABCD4, a gene that codes for an ABC transporter, which was previously thought to have peroxisomal localization and function. Our results show that ABCD4 colocalizes with the lysosomal proteins LAMP1 and LMBD1, the latter of which is deficient in the cblF defect. Furthermore, we show that mutations altering the putative ATPase domain of ABCD4 affect its function, suggesting that the ATPase activity of ABCD4 may be involved in intracellular processing of vitamin B(12).
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No. Sentence Comment
72 Expression of an ABCD4 construct -encoding a mutant Walker B motif (p.Asp548Asn) in cells from subject 1 led to very low levels of Cbl cofactor synthesis (Fig. 4b; P < 0.00001 for AdoCbl and 0.0001 for MeCbl synthesis compared with wild-type ABCD4 construct), indicating that this Walker B motif aspartate is necessary for ABCD4 function.
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ABCD4 p.Asp548Asn 22922874:72:70
status: NEW86 Mutant alleles encoding changes to highly conserved amino-acid residues known to be involved in ATPase activity, for example, p.Lys427Leu in the Walker A site, p.Asp548Asn in the Walker B site and p.Glu549Gln in the putative catalytic domain of ABCD4, were transfected transiently into immortalized fibroblasts from subject 1 by electroporation and were assayed for rescue of AdoCbl and MeCbl synthesis.
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ABCD4 p.Asp548Asn 22922874:86:162
status: NEW89 a Intralysosomal Membrane Cytosolic H2N 37 54 81 98 Asp143 Gly443 p.Gly443_Ser485del Ser485 536 421 ATP binding (Walker B) COOH 606 p.Glu583Leufs*9 p.Tyr319Cys 35 30 ATP binding (Walker A) p.Asp143_Ser181del 160 177 Ser181 206 189 293 313 330276 b 25 20 15 10 5 0 PercentageoftotalCbl AdoCbI MeCbI Vectoronly ABC D 4-p.Lys427Leu ABC D 4-p.G lu549G ln ABC D 4-p.Asp548Asn ABC D 4-w t Figure 5 Subcellular localization of ABCD4 detected by fluorescence and confocal microscopy.
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ABCD4 p.Asp548Asn 22922874:89:361
status: NEW76 Expression of an ABCD4 construct -encoding a mutant Walker B motif (p.Asp548Asn) in cells from subject 1 led to very low levels of Cbl cofactor synthesis (Fig. 4b; P < 0.00001 for AdoCbl and 0.0001 for MeCbl synthesis compared with wild-type ABCD4 construct), indicating that this Walker B motif aspartate is necessary for ABCD4 function.
X
ABCD4 p.Asp548Asn 22922874:76:70
status: NEW90 Mutant alleles encoding changes to highly conserved amino-acid residues known to be involved in ATPase activity, for example, p.Lys427Leu in the Walker A site, p.Asp548Asn in the Walker B site and p.Glu549Gln in the putative catalytic domain of ABCD4, were transfected transiently into immortalized fibroblasts from subject 1 by electroporation and were assayed for rescue of AdoCbl and MeCbl synthesis.
X
ABCD4 p.Asp548Asn 22922874:90:162
status: NEW