ABCD4 p.Glu549Gln
Predicted by SNAP2: | A: D (85%), C: D (85%), D: D (85%), F: D (91%), G: D (91%), H: D (91%), I: D (91%), K: D (91%), L: D (91%), M: D (91%), N: D (91%), P: D (95%), Q: D (91%), R: D (95%), S: D (91%), T: D (91%), V: D (91%), W: D (95%), Y: D (91%), |
Predicted by PROVEAN: | A: D, C: D, D: 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
73 Moreover, expression of constructs with selective changes affecting the Walker A motif (p.Lys427Leu) and the putative catalytic site (p.Glu549Gln) also led to reduced synthesis of both Cbl cofactors (Fig. 4b; p.Lys427Leu: P = 0.003 for AdoCbl and 0.007 for MeCbl synthesis; p.Glu549Gln: P = 0.001 for AdoCbl and 0.0021 for MeCbl synthesis).
X
ABCD4 p.Glu549Gln 22922874:73:136
status: NEWX
ABCD4 p.Glu549Gln 22922874:73:276
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.
X
ABCD4 p.Glu549Gln 22922874:86:199
status: NEW77 Moreover, expression of constructs with selective changes affecting the Walker A motif (p.Lys427Leu) and the putative catalytic site (p.Glu549Gln) also led to reduced synthesis of both Cbl cofactors (Fig. 4b; p.Lys427Leu: P = 0.003 for AdoCbl and 0.007 for MeCbl synthesis; p.Glu549Gln: P = 0.001 for AdoCbl and 0.0021 for MeCbl synthesis).
X
ABCD4 p.Glu549Gln 22922874:77:136
status: NEWX
ABCD4 p.Glu549Gln 22922874:77:276
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.Glu549Gln 22922874:90:199
status: NEW