ABCMdb

ABCB4 p.Arg159*

None has been submitted yet.

Publications

PMID: 17726488 [PubMed] Degiorgio D et al: "Molecular characterization and structural implications of 25 new ABCB4 mutations in progressive familial intrahepatic cholestasis type 3 (PFIC3)."

No. Sentence Comment

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. Login to comment
80 Nonsense mutations The four novel nonsense mutations identified in this study are p.R159X, p.Y279X, p.G762X and p.E888X (Table 2). Login to comment
82 The patient carrying the p.R159X mutation is heterozygous and the second mutated allele is still unknown; the other three cases show one nonsense mutation associated with three distinct missense mutations (Table 3). Login to comment
84 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. Login to comment

PMID: 21119540 [PubMed] Colombo C et al: "Clinical features and genotype-phenotype correlations in children with progressive familial intrahepatic cholestasis type 3 related to ABCB4 mutations."

No. Sentence Comment

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. Login to comment

PMID: 26324191 [PubMed] Degiorgio D et al: "ABCB4 mutations in adult patients with cholestatic liver disease: impact and phenotypic expression."

No. Sentence Comment

72 CCP chronic cholestatic profile, NCCP patients without chronic cholestatic profile, PBC primary biliary cirrhosis, PSC primary sclerosing cholangitis, ICP intrahepatic cholestasis of pregnancy, JC juvenile cholelithiasis, AIH autoimmune hepatitis, OS overlap syndrome between AIH and PBC or PSC, ICC idiopathic chronic cholestasis; a with (n = 14) or without (n = 23) other cholangiopathies in the personal/family history (see ''Methods``), b with (n = 9) or without (n = 15) other cholangiopathies in the personal/family history (see ''Methods``), c with (n = 2) or without (n = 2) other cholangiopathies in the personal/family history (see ''Methods``) Table 1 Heterozygous nucleotide changes within the ABCB4 gene identified in 18 adult patients with cholangiopathies and predicted impact on MDR3 Nucleotide changea Involved regions Type of mutation Mutant protein Location on the protein Degree of conservationb Reference genotypesc c.217C[G Exon 4 Missense p.(L73V) TM1 B 7, 21 c.475C[T Exon 6 Non-sense p.(R159X) ICD1 X 8, 14 c.523A[G Exon 6 Missense p.(T175A) ICD1 B 18, 21, 8, 25, 14 c.959C[T Exon 9 Missense p.(S320F) TM5 B 18, 8, 14 c.1529A[G Exon 13 Missense p.(N510S) N-ter NBD B 14 c.1531G[A Exon 13 Missense p.(A511T) N-ter NBD A 8, 14 c.1633C[T Exon 14 Missense p.(R545C) N-ter NBD A 21 c.1769G[A Exon 15 Missense p.(R590Q) N-ter NBD A 8, 13, 14, 25 c.1846G[A Exon 15 Missense p.(E616K) N-ter NBD A This study (JN392435) c.1901G[A Exon 16 Missense p.G634E Linker region B This study (JN392436) c.2431G[C Exon 20 Missense p.(G811R) ICD4 A This study (JN392437) c.2544_2548delATCAT Exon 21 Frameshift p.(S849YfsX24) TM9 X This study (JN392438) c.2576T[G Exon 21 Missense p.(L859W) TM10 B This study (JN392439) c.2844G[C Exon 23 Missense p.(M948I) TM11 B This study (JN392440) c.3541C[T Exon 27 Non-sense p.(Q1181X) C-ter NBD X This study (JN392441) TM transmembrane domain, ICD intracellular domain, N-ter NBD N-terminal nucleotide binding domain, C-ter NBD C-terminal nucleotide binding domain a The mutations were numbered according to GenBank NM_018849 and NP_061337. Login to comment
139 Sex Main diagnosis Age at onset (years) Heterozygous mutation Radical mutationc Concomitant cholangiopathy Notes 20 M PSC 47 p.(G634E) No 39 M PSC 27 p.(R159X) Yes JC 40 M PSC 30 p.(R590Q) Yes JC 24a,b F PSC 23 p.(A511T) ? Login to comment