ABCMdb

ABCB11 p.Arg303Lys

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Publications

PMID: 18692205 [PubMed] Chen HL et al: "Diagnosis of BSEP/ABCB11 mutations in Asian patients with cholestasis using denaturing high performance liquid chromatography."

No. Sentence Comment

3 Results Seven mutations in 4 of 16 patients with PFIC from different families were detected by DHPLC, including M183V, V284L, R303K, R487H, W493X, G1004D, and 1145delC. Login to comment
46 Age of onset Bil T (␮mol/L) Bil D (␮mol/L) GGT (U/L) AST (U/L) ALT (U/L) Liver pathology Mutations found Exon Predicted effect Outcome 1 1 mo 169.3 121.4 56 518 244 IC, GCT c.850GϾC c.1145delC 9 11 p. Val284Leu p.Ala382AlafsX16 Death, 5 y 2 1 mo 100.9 51.3 30 88 66 IC, GCT, bridging fibrosis c.850GϾC c.1145delC 9 11 p. Val284Leu p.Ala382AlafsX16 Alive 5 y, chronic cholestasis, Failure to thrive 3 2 wk 119.7 58.1 36 500 341 IC, GCT c.547AϾG c.908GϾA 7 9 p.Met183Val p.Arg303Lys Death, 8 mo 4 1 mo 179.6 138.5 68 186 150 GCT, fibrosis c.1478GϾA c.3011GϾA 14 23 p.Trp493X p.Gly1004Asp Death, 2 yr 5 birth 237.7 155.6 47 1184 653 - c.1460GϾA 14 p.Arg487His Death, 1 y 6 2 mo 360.8 251.4 132 884 352 Lobular disarray NF Death, 9 mo 7 1 mo 119.7 109.4 25 54 49 IC, bridging fibrosis NF Alive, 7 y 8 2 mo 401.9 273.6 51 251 252 GCT, cell ballooning NF Death 1 y 6mo 9 3 mo 442.9 256.5 54 556 217 - NF Death, 7 mo 10 1 mo 157.3 90.6 20 606 828 GCT, hepatocyte ballooning, confluent necrosis NF Death, 9 mo 11 1 mo 193.2 136.8 52 523 345 GCT, focal necrosis NF Death 4 mo 12 2 mo 165.9 94.1 99 298 202 GCT, portal inflammation, ductal proliferation NF Death 8 mo 13 2 wk 277.0 194.9 64 1054 825 GCT, necrosis NF OLT, 6 mo 14 2 mo 413.8 229.1 51 625 665 GCT, biliary cirrhosis NF OLT, 9 mo 15 birth 371.1 271.9 68 584 400 GCT NF Alive, 10 mo 16 birth 176.1 145.4 57 352 249 GCT, bridging fibrosis NF Death, 9 mo 17 birth 136.8 46.2 47 29 117 GCT NF Alive, 5 y 18 32 y 143.6 63.3 24 105 91 Centrilobular canalicular cholestasis, hemosiderosis c.3011GϾA 23 p.Gly1004Asp Alive, 35 y, recurrent cholestasis IC, Intrahepatic cholestasis; GCT, giant-cell transformation; OLT, orthotopic liver transplantation; NF, mutations not found. Login to comment
80 RESULTS Mutations Detected in Patients with PFIC Of 17 patients with low-GGT PFIC, mutations in ABCB11 were found in 5 patients, including a sibling pair (patients 1 and 2) with compound heterozygous c.850GϾC (p.V284L) and c.1145delC (p.Ala382AlafsX16) mutations.12 Patient 3 had compound heterozygous c.547AϾG (p.M183V)/c.908GϾA (p.R303K) mutations. Login to comment
88 R303K had been reported in 1 family of Central Asian/Arab background.13 R487H had previously been reported to occur in a Japanese patient.11 No mutational hot spots were identified in our patients. Login to comment
102 Analysis of Mutations in Normal Controls All the missense mutations detected above were tested in 80 normal control subjects (160 alleles), using DHPLC for M183V (exon 7), V284L (exons 9), R303K (exon 9), R487H (exon 14), L827I (exon 21), and G1004D (exon 23). Login to comment
105 R303K and R487H had previously been reported to occur in patients with PFIC, further supporting their disease-causing roles.11,13 Figure 1. Login to comment
109 The PolyPhen results indicated that V284L and G1004D are possibly damaging, and M183V, R303K, R487H, and L827I were predicted to be benign (Table IV). Login to comment
122 In our study, G1004D was found in 1 patient with PFIC and in 1 patient with BRIC.12 R303K, which was found in our patient, had been reported in a family of central Asian/Arab background.13 Further investigations are therefore required to confirm whether these mutations are found more commonly in Asian patients. Login to comment
128 Prediction of functional consequences of nonsynonymous mutations and polymorphisms in ABCB11 found in Asian patients Amino acid change SIFT PolyPhen (PSIC score) EC/EU M183V 0.02 1.45 EC V284L 0.02 1.87 EC R303K 0.00 0.38 EC V444A 0.76 0.60 EC R487H 0.01 0.65 EC L827I 0.01 1.23 EC A865V 0.10 0.76 EC G1004D 0.00 1.97 EC SIFT, Sorting intolerant from tolerant (SIFT scores Ͻ0.05 indicate evolutionarily conserved amino acids, and mutation of these residues are predicted to be deleterious); PolyPhen, polymorphism phenotyping (a PSIC score Ͻ0.5 denotes benign variants, between 1.5 and 2 is possibly damaging, and Ͼ2 is probably damaging); EC, evolutionarily conserved; EU, evolutionarily unconserved. Login to comment

PMID: 18853996 [PubMed] Chen ST et al: "Prenatal diagnosis of progressive familial intrahepatic cholestasis type 2."

No. Sentence Comment

6 Results: We report on two families of PFIC2 with inherited compound heterozygous mutations of ABCB11 (M183V and R303K in Family 1, V284L and 1145delC in Family 2) from the parents. Login to comment
66 In Family 1, compound heterozygous missense mutations M183V and R303K were found in the patient. Login to comment
71 Genetic analysis from amniotic DNA showed a heterozygous mutation of M183V, but not R303K. Login to comment
96 (a) Case 1, an affected male with compound heterozygous M183V and R303K mutations; cases 2 and 4, an unaffected sibling and mother with a heterozygous M183V mutation; case 3, an unaffected father with a heterozygous R303K mutation. Login to comment

PMID: 19750581 [PubMed] Treepongkaruna S et al: "Novel ABCB11 mutations in a Thai infant with progressive familial intrahepatic cholestasis."

No. Sentence Comment

90 Chen et al[13] have reported seven BSEP mutations (M183V, V284L, R303K, R487H, W493X, G1004D and 1145delC) in four PFIC patients of Chinese descent; none of these mutations has been described in Caucasian patients. Login to comment

PMID: 19845854 [PubMed] Liu LY et al: "ABCB11 gene mutations in Chinese children with progressive intrahepatic cholestasis and low gamma glutamyltransferase."

No. Sentence Comment

87 All of them, except for R303K, were different from those reported in other population groups. Login to comment
119 R303K found in Central Asian, Arab and Taiwan Chinese is shown in green. Login to comment

PMID: 20214736 [PubMed] Ananthanarayanan M et al: "PFIC2 and ethnicity-specific bile salt export pump (BSEP, ABCB11) mutations: where do we go from here?"

No. Sentence Comment

28 Mutations reported in this study except one (R303K) were unique to this population Liver International (2010) c 2010 John Wiley & Sons A/S 777 Liver International ISSN 1478-3223 group. Login to comment

PMID: 18395098 [PubMed] Strautnieks SS et al: "Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families."

No. Sentence Comment

220 Four different changes occurred at, or adjacent to, the 5= splice site of intron 9: R303K, c.908af9;1delG,1,33 c.908af9;1Gb0e;T,28 and c.908af9;1Gb0e;A. Login to comment

PMID: 22795478 [PubMed] Kubitz R et al: "The bile salt export pump (BSEP) in health and disease."

No. Sentence Comment

185 PFIC BRIC/NFC ICP Other liver diseases Genetic variants without disease association Missense mutations M1V C336S D549V L1055P E135K E137K T87R V43I S701P G19R W342G G556R C1083Y E137K L198P M123T S56L L712L L50S A382G G562D A1110E E186G E297G S194P Q121K A865D M62K R387H A570T S1114R L198P R415Q L198P R128H A865G C68Y A390P L581F G1116E E297G V444A G260D I206V S874P C107R G410D A588V G1116F G374S D482G E297K V284A I939M I112T L413W S593R G1116R A390P N591S V444A G295C R958Q W114R I420T I627T S1120N R432T T655I T510T G295R F959C Y157C D440E E636G R1128C V444A T655I G295S F959V A167T G455E R698C S1144R I498T D676Y R299K T965S A167V K461E S699P R1153C A570T P710P R303K F971L I182K T463I E709K R1153H T586I L827I L339V F971Y M183T Q466K G758R S1154P G648V G855R H423R L1006F M183V R470Q G766R N1173D T655I E1186K V444A N1009H G188W Y472C Y818F T1210P T923P V444D K1145N M217R V481E R832C N1211D A926P V444G I1183T R223C D482G R832H V1212F R948C A459V S226L R487H T859R R1231Q G1004D I468I G238V R487P A865V R1231W R1050C R487L T242I N490D Q869P L1242I G1116R Q546K A257G I498T G877R D1243G R1128H Q558H V284L G499E S901R R1268Q L1197G E592Q E297G I512T R948C A1283V R1231Q V597M R303G N515T N979D G1292V R616G R303K R517H G982R G1298R T619A Q312H F540L G1004D M677L R313S I541L T1029K M677V G327E I541T G1032R R696Q W330R F548Y A1044P R698H Nonsense mutations (premature stop-codons) S25X Y472X Y772X R1090X E96X W493X Q791X V1147X W330X R520X R928X Q1215X Y354X I528X Y1041X R1235X R415X R575X R1057X E1302X R470X Q702X Q1058X Table 1 (Continued) PFIC BRIC/NFC ICP Other liver diseases Genetic variants without disease association Splice site mutations 76 + 3G > T 908 + 1delG 2178 + 1G > T 3057-2A > G Q159Q 77-1G > C 908 + 1G > T 2179-2A > G 3213 + 1delG Q361Q 99-1G > T 908 + 1G > A 2343 + 1G > T 3213 + 4A > G 150 + 3A > C 1435-13 -8del 2343 + 2T > C 3213 + 5G > A 390-1G > A 2012-8T > G 2611-2A > T 611 + 1G > A 2178 + 1G > A R1001R Deletions/insertions/frame shifts Q101Dfs8X L380Wfs18X G648Vfs5X Q1058Hfs38X F959Hfs1X T127Hfs6X A382 A388del K700Sfs12X I1061Vfs34X F959Gfs48X N199Ifs14X P456Pfs24X T919del L1165del L232Cfs9X H484Rfs5X K930Efs92X A1192Efs50X R303Sfs17X I528Sfs21X K930Efs79X T1256Tfs40X V368Rfs27X I610Qfs45X K969 K972del Synonymous variants without disease association R33R F90F L232L I416I G557G I876I A1028A K1145K D36D I134I Y269Y G418G V597V G937G K1070K R52R S136S Q312Q F427F A804A Y981Y T1086T D58D V195V G319G E395E A535A G817G G1004G A1110A The overview shows ࣈ 290 known variants of BSEP on the protein level, except splice site mutations, which are shown on cDNA level. Login to comment