ABCB4 p.Ala364Val
| Predicted by SNAP2: | C: N (61%), D: D (80%), E: D (80%), F: D (75%), G: N (78%), H: D (71%), I: D (59%), K: D (75%), L: D (66%), M: D (63%), N: D (66%), P: D (80%), Q: D (71%), R: D (75%), S: N (57%), T: N (53%), V: D (66%), W: D (71%), Y: D (75%), |
| Predicted by PROVEAN: | 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, 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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18 The two TMDs contain specific sites for substrate binding and translocation, whereas the two NBDs, which display a high degree of sequence similarity with the equivalent domain of ABC transporters, couple the energy obtained from ATP hydrolysis to substrate transport.8 The ICDs are deemed to be involved in mediating the coupling between NBD conformational changes and the reorientation of TM helices concomitant with substrate extrusion.9 The ABCB1 gene, one of the most extensively studied ABC transporters, is responsible for the human multidrug resistance phenotype that is a rapidly growing obstacle to the treatment of numerous infectious diseases, including human immunodeficiency10 and malaria.11 The properties of this transporter are also exploited in cancer pharmacological therapy where ABCB1 translocates the chemotherapeutic drugs and other molecules with a broad but defined specificity.12 A gene duplication of ABCB1 and additional mutations selected as advantageous have created in mammals the T715I G723E L724AfsX744 A737V G954S G762X T775M G126E S320F A840D OUT IN Linker region F357L L701P A364V NBD-NH2 terminal NBD-COOH terminal A1193T NH2 COOH 1 2 54 6 7 8 129 11 10 EC2EC1 ICD2 A250P Y279X A286V ICD1 R159X T175A ICD3 EC3 EC4 EC6EC5 ICD4 ICD6 ICD5 E888X Y403H V475A A511T E558K R590Q T593A M630V 3 S379KfsX413 P726T Figure 1 (a) Localization of the 29 mutations identified in this study in the ABCB4 protein, schematically represented in its domains.
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ABCB4 p.Ala364Val 17726488:18:1111
status: NEW110 Apart M630, located in the NBD, the remaining mutations involve either the helical loops (A250, A286, F357, A364) or TM segments (G126, P726, A840, G954; Figure 1b); the ...122_GLGAGVLVA_130... ...434_GLGAGVLVA_442... ...119_GLGGGVLVA_127... ...119_GLGGGVLLA_127... ...276_GLGAGVLVA_284... ...10_GLGGGVLIA_18.... ...120_GIGAGVLVA_128... ....73_GLMILRGIT_81.... ....73_GLMILRGIT_81.... ....73_GLMFVRGLS_81.... ...69_IFVIVRPPI_77.... Hs_ABCB4 Pt_ABCB4 Mm_ABCB4 Rn_ABCB4 Bt_ABCB4 Md_ABCB4 Hs_ABCB1 Esch-coli_Msba Salm-typh_Msba Vibrio-ch_Msba Staph-au_Sav1866 246_LAAYAKAGA_254... 558_LAAYAKAGA_566... 243_LAAYAKAGA_251... 243_LAAYAKAGA_251... 400_LAAYAKAGA_408... 134_LAAYAKAGA_142... 244_LLAYAKAGA_252... 197_QNTMGQVTT_205... 197_QNTMGQVTT_205... 197_QTAMGHVTS_205... 193_SQALAEVQG_201... 282_HLENAKEIG_290... 594_HLENAKEIG_602... 279_HLENAKKIG_287... 279_HLENAKKIG_287... 436_HLENAKRIG_444... 170_HLENAKKIG_178... 280_NLEEAKRIG_288... 233_VSNRMRLQG_241... 233_VSNKMRLQG_241... 233_VSNSMRQQT_241... 229_KNTNFLTRA_237... 353_CIDAFANARGAAYVIF_368.... 665_CIDAFANARGAAYVIF_680.... 350_CIDAFANARGAAYVIF_365.... 350_CIDAFPNARGAAYVIF_365.... 507_CIDAFANARGAAYAIF_522.... 241_CIDSFANARGAAYAIF_256.... 351_SIEAFANARGAAYEIF_366.... 304_VNAQFQRGMAACQTLF_319.... 304_VNAQFQRGMAACQTLF_319.... 304_VTSEFQRGMAACQTLF_319.... 300_SFTTLTQSFASMDRVF_315.... G126E A250P A286V F357L A364V 399_VHFSYPSRA_407.... 711_VHFSYPSRA_719.... 396_VHFSYPSRA_404.... 396_VHFSYPSRA_404.... 553_VHFSYPARP_561.... 287_VHFSYPSRA_295.... 397_VHFSYPSRK_405.... 347_VTFTYPGR-_354.... 347_VTFTYPGR-_354.... 347_VTFTYQGK-_354.... 345_VSFQYNDN-_352.... 471_IIGVVSQEP_479.... 783_IIGVVSQEP_791.... 468_IIGVVSQEP_476.... 468_FIGVVSQEP_476.... 625_IIGVVSQEP_633.... 359_IIGVVSQEP_367.... 469_IIGVVSQEP_477.... 418_QVALVSQNV_426.... 418_QVALVSQNV_426.... 418_HFALVSQNV_426.... 416_QIGLVQQDN_424.... V475A Hs_ABCB4 Pt_ABCB4 Mm_ABCB4 Rn_ABCB4 Bt_ABCB4 Md_ABCB4 Hs_ABCB1 Esch-coli_Msba Salm-typh_Msba Vibrio-ch_Msba Staph-au_Sav1866 ...507_KEANAYEFI_515... ...819_KEANAYEFI_827... ...504_KEANAYDFI_512... ...504_KEANAYDFI_512... ...661_KEANAYEFI_669... ...395_KDANAYEFI_403... ...505_KEANAYDFI_513... ...455_RMAYAMDFI_463... ...455_RMAYAMDFI_463... ...455_RQAHAMEFI_463... ..452_KMANAHDFI_460... A511T 554_LLLDEATSA_562... 866_LLLDEATSA_874... 551_LLLDEATSA_559... 551_LLLDEATSA_559... 708_LLLDEATSA_716... 442_LLLDEATSA_450... 552_LLLDEATSA_560... 502_LILDEATSA_510... 502_LILDEATSA_510... 502_LILDEATSA_510... 499_LILDEATSA_507... E558K 586_VIAHRLSTVRNA_597... 898_VIAHRLSTVRNA_909... 583_VIAHRLSTIRNA_594... 583_VIAHRLSTVRNA_594... 740_VIAHRLSTIRNA_751... 474_VIAHRLSTIRNA_485... 584_VIAHRLSTVRNA_595... 534_VIAHRLSTIEKA_545... 534_VIAHRLSTIEQA_545... 534_VIAHRLSTIEQA_545... 531_IVAHRLSTITHA_542... 626_KLVNMQTSG_634.. 938_KLVNMQTSG_946.. 623_RLVNMQTAG_631.. 623_RLVNMQTSG_631.. 780_RLVNTQISG_788.. 514_KLVNMQYIF_522... 624_KLVTMQTAG_632.. 574_QLHKMQFGQ_582.. 574_QLHKMQFGQ_582.. 574_QLHRIQFGE_582.. 570_HLYSIQN--_576.. 697_FLKVLKLNKTEWPYFVVGTVCAIANGGLQPAFSVIFSEIIAIF_739.
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ABCB4 p.Ala364Val 17726488:110:1362
status: NEW84 There are no PFIC3 epidemiologic data available to date; however, knowing that the number of newborns in Italy has been on average 500 000/year in the last 14 years (http://demo.istat.it/), since we observed 18 patients with ABCB4-mutated alleles born within a 14-year period (with Table 2 Mutations identified in ABCB4 Type of mutationb Exons cDNA locusa Missense Frameshift or nonsense ABCB4-predicted domain GenBank accession numberc Exon 6 c.377G4A G126E TM2 DQ861346 Exon 6 c.523A4G T175A ICD1 Exon 6 c.475C4T R159X ICD1 DQ861347 Exon 8 c.748G4C A250P ICD2 DQ861349 Exon 9 c.837T4A Y279X ICD2 DQ861348 Exon 9 c.857C4T A286V ICD2 DQ861350 Exon 9 c.959C4T S320F TM5 Exon 10 c.1069T4C F357L ICD3 DQ861351 Exon 10 c.1091C4T A364V ICD3 DQ861352 Exon 11 c.1135_1136insAA S379KfsX413 ICD3 DQ861353 Exon 11 c.1207T4C Y403H NBD-NH2 A-loop EF035007 Exon 13 c.1424T4C V475A NBD-NH2 ter DQ861354 Exon 13 c.1531G4A A511T NBD-NH2 ter DQ861355 Exon 14 c.1672G4A E558K NBD-NH2 ter DQ861356 Exon 15 c.1769G4A R590Q NBD-NH2 ter Exon 15 c.1777A4G T593A NBD-NH2 ter DQ861357 Exon 15 c.1888A4G M630V NBD-NH2 ter DQ861358 Exon 17 c.2102T4C L701P Linker region DQ861359 Exon 17 c.2144C4T T715I TM7 DQ861360 Exon 17 c.2168G4A G723E TM7 DQ861361 Exon 17 c.2169_2170insG L724AfsX744 TM7 DQ861362 Exon 17 c.2176C4A P726T TM7 DQ861363 Exon 17 c.2210C4T A737V EC4 DQ861364 Exon 18 c.2284G4T G762X TM8 DQ861365 Exon 19 c.2324C4T T775M TM8 Exon 21 c.2519C4A A840D TM9 DQ861366 Exon 21 c.2662G4T E888X ICD5 DQ861367 Exon 23 c.2860G4A G954S TM11 DQ861368 Exon 27 c.3577G4A A1193T NBD-COOH ter DQ861369 a cDNA sequence is based on reference sequence GenBank NM_018849.
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ABCB4 p.Ala364Val 17726488:84:725
status: NEW132 The structural or functional relevance of the remaining seven amino-acid substitutions (p.A250P, p.A286V, p.F357L, p.A364V, p.M630V, p.T715I and p.A737V) is less clear and the induced effect on ABCB4 is less evident.
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ABCB4 p.Ala364Val 17726488:132:117
status: NEW[hide] Clinical features and genotype-phenotype correlati... J Pediatr Gastroenterol Nutr. 2011 Jan;52(1):73-83. Colombo C, Vajro P, Degiorgio D, Coviello DA, Costantino L, Tornillo L, Motta V, Consonni D, Maggiore G
Clinical features and genotype-phenotype correlations in children with progressive familial intrahepatic cholestasis type 3 related to ABCB4 mutations.
J Pediatr Gastroenterol Nutr. 2011 Jan;52(1):73-83., [PMID:21119540]
Abstract [show]
OBJECTIVES: The aim of the study was to estimate the frequency of ABCB4 mutations among children with chronic intrahepatic cholestasis with elevated gamma-glutamyl-transpeptidase (gamma-GT) activity and to characterize the genotypes with respect to severity of symptoms, response to ursodeoxycholic acid therapy, and outcome. PATIENTS AND METHODS: Molecular analysis of ABCB4 in 133 Italian children was performed, and ABCB4 mutations were classified as disease-causing mutations or benign substitutions according to the prediction algorithm PolyPhen. RESULTS: : Twenty-eight patients were identified carrying 31 mutations (20 disease causing). Twenty patients carried 2 mutated alleles and 8 only 1. At presentation (1-204 months), 20 children were symptomatic with jaundice and/or pruritus, whereas in 8 biochemical cholestasis was a fortuitous finding. Cirrhosis developed in 15 and 6 progressed to terminal liver failure. Disease-causing mutations on both alleles were found to be associated with reduced liver expression of ABCB4 protein, lack of response to ursodeoxycholic acid therapy, and progression to cirrhosis and end-stage liver disease, whereas mild genotypes, including single heterozygous mutations, were generally associated with less severe disease and, often, absence of symptoms. CONCLUSIONS: ABCB4 mutations are responsible for a chronic liver disease in more than one-third of patients with chronic intrahepatic cholestasis and elevated gamma-GT activity. In patients with severe ABCB4 genotype, the disease is often progressive with risk of developing cirrhosis and liver failure during the first 2 decades of life. Patients with mild genotypes, including single heterozygous mutations, have variable expressions of liver disease that may be influenced by comorbidity factors and modulated by still unknown genetic modifiers.
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107 Nucleotidechange (effectonprotein) Predictionscoresby PolyPhenanalysis Nucleotidechange (effectonprotein) Predictionscoresby PolyPhenanalysis Referencefor eachgenotype 1[1-I]c.475C>T(p.R159X)XUnknownUnknown20 1[1-II]c.475C>T(p.R159X)XUnknownUnknownThisstudy 2[2-I]c.523A>G(p.T175A)0.774c.1069T>C(p.F357L)þc.2324C>T(p.T775M)1.079þ0.59720 3[3-I]c.1135_1136insAA(p.S379KfsX413)Xc.2102T>C(p.L701P)2.22620 4[4-I]c.2662G>T(p.E888X)Xc.748G>C(p.A250P)Rc.1888A>G(p.M630V)1.871R1.67720 5[5-I]c.959C>T(p.S320F)1.287c.857C>T(p.A286V)1.40820 6[6-I]c.377G>A(p.G126E)1.998c.1531G>A(p.A511T)2.1720 6[6-II]c.377G>A(p.G126E)1.998c.1531G>A(p.A511T)2.1720 7[7-I]c.2176C>A(p.P726T)2.086c.1769G>A(p.R590Q)þc.2284G>T(p.G762X)2.623RX20 8[8-1]c.1091C>T(p.A364V)1.343c.2210C>T(p.A737V)0.21720 9[9-I]c.1777A>G(p.T593A)2.044UnknownUnknown20 10[10-I]c.2144C>T(p.T715I)0.383UnknownUnknown20 11[11-I]c.2519C>A(p.A840D)1.803c.1424T>C(p.V475A)2.60320 12[12-I]c.1672G>A(p.E558K)2.486c.2168G>A(p.G723E)Rc.3577G>A(p.A1193T)1.548þ2.34120 12[12-II]c.1672G>A(p.E558K)2.486c.2168G>A(p.G723E)Rc.3577G>A(p.A1193T)1.548þ2.34120 13[13-I]c.2860G>A(p.G954S)0.245c.2860G>A(p.G954S)0.24520 14[14-I]c.523A>G(p.T175A)0.774UnknownUnknown20 15[15-I]c.959C>T(p.S320F)1.287c.837T>A(p.Y279X)X20 16[16-I]c.523A>G(p.T175A)0.774UnknownUnknown20 17[17-I]c.2169_2170insG(p.L724AfsX744)Xc.2169_2170insG(p.L724AfsX744)X20 17[17-II]c.2169_2170insG(p.L724AfsX744)Xc.2169_2170insG(p.L724AfsX744)X20 18[18-I]c.1207T>C(p.Y403H)2.798c.1207T>C(p.Y403H)2.79820 19[19-I]c.208G>C(p.G70R)þc.1769G>A(p.R590Q)1.497þ2.623c.959C>T(p.S320F)1.287Thisstudy 19[19-II]c.208G>C(p.G70R)þc.1769G>A(p.R590Q)1.497þ2.623c.959C>T(p.S320F)1.287Thisstudy 19[19-III]c.208G>C(p.G70R)þc.1769G>A(p.R590Q)1.497þ2.623c.959C>T(p.S320F)1.287Thisstudy 20[20-I]c.217C>G(p.L73V)0.489UnknownUnknown22,thisstudy 21[21-I]c.959C>T(p.S320F)1.287c.959C>T(p.S320F)1.28716,thisstudy 22[22-I]c.1207T>C(p.Y403H)2.798UnknownUnknownThisstudy Xidentifiesmutationsthatpredictprematureterminationoftranslation.PolyPhenpredictionwithPSICscoredifferencesbelow1.5definebenignsubstitutions;PSICscoredifferencesencompassing between1.5and2.0(bold)definesubstitutionspossiblydamaging,whereasabove2.0(underlined)definesubstitutionsprobablydamaging.
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ABCB4 p.Ala364Val 21119540:107:745
status: NEW