ABCB1 p.Gly955Val
| Predicted by SNAP2: | A: N (87%), C: N (57%), D: D (71%), E: D (75%), F: D (63%), H: D (75%), I: D (53%), K: D (85%), L: D (63%), M: D (59%), N: D (59%), P: D (80%), Q: D (75%), R: D (80%), S: N (53%), T: D (53%), V: N (72%), W: D (66%), Y: D (71%), |
| Predicted by PROVEAN: | A: N, C: D, D: D, E: D, F: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: N, T: N, V: D, W: D, Y: D, |
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[hide] Molecular characterization and structural implicat... Eur J Hum Genet. 2007 Dec;15(12):1230-8. Epub 2007 Aug 29. Degiorgio D, Colombo C, Seia M, Porcaro L, Costantino L, Zazzeron L, Bordo D, Coviello DA
Molecular characterization and structural implications of 25 new ABCB4 mutations in progressive familial intrahepatic cholestasis type 3 (PFIC3).
Eur J Hum Genet. 2007 Dec;15(12):1230-8. Epub 2007 Aug 29., [PMID:17726488]
Abstract [show]
Progressive familial intrahepatic cholestasis type 3 (PFIC3) is an autosomal-recessive disorder due to mutations in the ATP-binding cassette, subfamily B, member 4 gene (ABCB4). ABCB4 is the liver-specific membrane transporter of phosphatidylcholine, a major and exclusive component of mammalian bile. The disease is characterized by early onset of cholestasis with high serum gamma-glutamyltranspeptidase activity, which progresses into cirrhosis and liver failure before adulthood. Presently, about 20 distinct ABCB4 mutations associated to PFIC3 have been described. We report the molecular characterization of 68 PFIC3 index cases enrolled in a multicenter study, which represents the largest cohort of PFIC3 patients screened for ABCB4 mutations to date. We observed 31 mutated ABCB4 alleles in 18 index cases with 29 distinct mutations, 25 of which are novel. Despite the lack of structural information on the ABCB4 protein, the elucidation of the three-dimensional structure of bacterial homolog allows the three-dimensional model of ABCB4 to be built by homology modeling and the position of the mutated amino-acids in the protein tertiary structure to be located. In a significant fraction of the cases reported in this study, the mutation should result in substantial impairment of ABCB4 floppase activity. The results of this study provide evidence of the broad allelic heterogeneity of the disease, with causative mutations spread along 14 of the 27 coding exons, but with higher prevalence on exon 17 that, as recently shown for the closely related paralogous ABCB1 gene, could contain an evolutionary marker for mammalian ABCB4 genes in the seventh transmembrane segment.
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No. Sentence Comment
123 Previous mutagenesis and biochemical studies carried out on human ABCB1 have assessed that Ala841, part of TM9, structurally equivalent to Ala840 in ABCB4, is involved in drug binding24,25 and interferes with the ability of the two structural modules (TMDs and NBDs) to form correct interactions.25 Furthermore, the position Gly954 was already described as ABCB1 mutant G955V that shows altered drug-stimulated ATPase activities.26 (c) The remaining four novel missense mutations described here (green bars, Figure 2) are affected residues conserved only in mammals ABCB4 (category named C in Table 3).
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ABCB1 p.Gly955Val 17726488:123:370
status: NEW