ABCD4 p.Tyr319Cys
ClinVar: |
c.956A>G
,
p.Tyr319Cys
D
, Pathogenic
|
Predicted by SNAP2: | A: D (85%), C: D (91%), D: D (95%), E: D (95%), F: D (91%), G: D (95%), H: D (91%), I: D (91%), K: D (95%), L: D (91%), M: D (91%), N: D (91%), P: D (95%), Q: D (91%), R: D (91%), S: D (85%), T: D (95%), V: D (91%), W: D (95%), |
Predicted by PROVEAN: | A: D, C: D, D: 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, |
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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
40 Subject 1 carried a missense mutation, c.956A>G (p.Tyr319Cys) (NM_005050.3), predicted to be probably damaging with a score of 0.984 using the PolyPhen-2 program5, and a dinucleotide insertion, c.1746_1747insCT (p.Glu583Leufs*9), resulting in a frameshift and the introduction of a premature stop codon leading to removal of 14 amino acids from the C terminus.
X
ABCD4 p.Tyr319Cys 22922874:40:51
status: NEW71 Among the four mutations detected in our affected subjects, two (encoding p.Asp143_Ser181del and p.Tyr319Cys) occur in the predicted transmembrane domain, whereas the other two (encoding p.Gly443_ Ser485del and p.Glu583Leufs*9) are located in the predicted NBD11.
X
ABCD4 p.Tyr319Cys 22922874:71:99
status: NEW82 The position of the p.Tyr319Cys and p.Glu583Leufs*9 alterations (detected in subject 1) are represented with a red dot, and the polypeptide fragments deleted in the p.Asp143_Ser181del and p.Gly443_Ser485del protein products (detected in subject 2) are highlighted in red.
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ABCD4 p.Tyr319Cys 22922874:82:22
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.Tyr319Cys 22922874:86:22
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.Tyr319Cys 22922874:89:150
status: NEW75 Among the four mutations detected in our affected subjects, two (encoding p.Asp143_Ser181del and p.Tyr319Cys) occur in the predicted transmembrane domain, whereas the other two (encoding p.Gly443_ Ser485del and p.Glu583Leufs*9) are located in the predicted NBD11.
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ABCD4 p.Tyr319Cys 22922874:75:99
status: NEW93 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 206 189 293 313 330 276 b 25 20 15 10 5 0 Percentage of total Cbl AdoCbI MeCbI V e c t o r o n l y A B C D 4 - p .
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ABCD4 p.Tyr319Cys 22922874:93:150
status: NEW