ABCMdb

ABCD4 p.Asn141Lys

Predicted by SNAP2:	A: D (53%), C: D (63%), D: D (66%), E: D (75%), F: D (71%), G: D (59%), H: D (59%), I: D (71%), K: D (80%), L: D (75%), M: D (66%), P: D (75%), Q: D (63%), R: D (80%), S: D (53%), T: D (59%), V: D (66%), W: D (80%), Y: D (71%),
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, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D,

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Publications
[hide] Late onset of symptoms in an atypical patient with... Mol Genet Metab. 2012 Dec;107(4):664-8. doi: 10.1016/j.ymgme.2012.10.005. Epub 2012 Oct 16. Kim JC, Lee NC, Hwu PW, Chien YH, Fahiminiya S, Majewski J, Watkins D, Rosenblatt DS
Late onset of symptoms in an atypical patient with the cblJ inborn error of vitamin B12 metabolism: diagnosis and novel mutation revealed by exome sequencing.
Mol Genet Metab. 2012 Dec;107(4):664-8. doi: 10.1016/j.ymgme.2012.10.005. Epub 2012 Oct 16., [PMID:23141461]

Abstract [show]
Inborn errors of vitamin B(12) (cobalamin) metabolism are characterized by decreased production of active cobalamin cofactors and subsequent deficiencies in the activities of methionine synthase and methylmalonyl-CoA mutase. With the recent discovery of the cblJ defect in two patients with phenotypes mimicking the cblF defect, there are nine genes known to be involved in cobalamin metabolism. The new defect is caused by mutations in the ABCD4 gene, encoding an ABC transporter. At the moment, there is no clear distinction between the cblJ and cblF defects either clinically or biochemically, and both defects result in blocks in the transport of cobalamin from the lysosome to the cytoplasm. A patient was diagnosed with hyperhomocysteinemia and methylmalonic aciduria at the age of 8 years. Incorporations of both [(14)C]propionate and [(14)C]methyltetrahydrofolate in cultured fibroblasts were within reference ranges and thus too high to allow for complementation analysis. We observed decreased synthesis of both adenosylcobalamin and methylcobalamin and accumulation of unmetabolized cyanocobalamin. Exome sequencing was performed to identify causative mutation(s) and Sanger re-sequencing was performed to validate segregation of mutation in the family. By this approach, a homozygous mutation, c.423C>G, in the ABCD4 gene was identified. Here, we report the successful application of exome sequencing for diagnosis of a rare inborn error of vitamin B(12) metabolism in a patient whose unusual presentation precluded diagnosis using standard biochemical and genetic approaches. The patient represents only the third known patient with the cblJ disorder.

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Sentences [show]
No. Sentence Comment
104 The c.423C>G mutation identified in the ABCD4 gene creates an asparagine to lysine substitution, p.N141K, affecting a residue that is evolutionarily conserved down to the zebrafish (http:// genome.ucsc.edu). Login to comment
109 However, since the function of ABCD4 remains unknown, the potential impact of the p.N141K mutation on protein function cannot be predicted. Login to comment
123 (B) DNA sequencing chromatograms of the ABCD4 c.423C>G (p.N141K) mutation. Login to comment