ABCMdb

ABCB4 p.Arg47Gln

ClinVar:	c.140G>A , p.Arg47Gln ? , Uncertain significance
Predicted by SNAP2:	A: D (53%), C: D (53%), D: D (80%), E: D (71%), F: D (63%), G: D (66%), H: D (63%), I: D (66%), K: N (87%), L: D (66%), M: N (57%), N: D (63%), P: D (71%), Q: N (78%), S: N (61%), T: N (53%), V: D (63%), W: D (75%), Y: D (66%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: N, L: D, M: D, N: D, P: D, Q: D, S: D, T: D, V: D, W: D, Y: D,

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[hide] Aspects of liver pathology in adult patients with ... Virchows Arch. 2012 Mar;460(3):291-8. Epub 2012 Feb 14. Wendum D, Barbu V, Rosmorduc O, Arrive L, Flejou JF, Poupon R
Aspects of liver pathology in adult patients with MDR3/ABCB4 gene mutations.
Virchows Arch. 2012 Mar;460(3):291-8. Epub 2012 Feb 14., [PMID:22331132]

Abstract [show]
The aims of this study were to describe the histological liver lesions in adult patients with MDR3/ ABCB4 mutation and to study the usefulness of MDR3 immunostaining as a diagnostic tool. All adult patients from our institution with an MDR3/ABCB4 mutation and a liver histology were included (n = 13). Eleven patients had a single heterozygous gene mutation and two patients had two heterozygous mutations. Two patients had no liver lesions. Eight patients had a mild ductular reaction and portal fibrosis. One patient had a few fibrous septa and two patients had biliary cirrhosis. In three cases intraductal lipid crystals were identified. Two patients had biliary fibroobliterative lesions with no sclerosing cholangitis on cholangiography. Biliary dysplasia was identified in hepatectomy specimens from two patients, one of whom developed an intrahepatic cholangiocarcinoma. One patient with biliary cirrhosis developed a hepatocellular carcinoma. MDR3 immunostainings performed on formalin-fixed paraffin-embedded sections showed a strong canalicular staining in all patients except in one. To conclude, the predominant histological features were ductular reaction with no or mild fibrosis without cholangitis. Liver lesions previously unreported in association with MDR3/ABCB4 gene mutations (biliary dysplasia, cholangiocarcinoma, small duct sclerosing cholangitis) were also found. Lipid crystals in bile ducts may be suggestive of MDR3/ABCB4 mutation. MDR3 immunostaining on formalin-fixed paraffin-embedded sections does not seem to be sensitive for the diagnosis of heterozygous MDR3/ABCB4 mutations.

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No. Sentence Comment
107 Location and nucleotide change Effect on protein Status of variant Mutation category 1 c.1328dup p.Arg444Glu fsX4, truncating Heterozygous Insertion 2 c.1584 G > C p.Glu528Asp Heterozygous Missense 3 c.101 C > T p.Thr34Met Heterozygous Missense 4 c.1553delT p.Leu518Tyr fsX16, truncating Heterozygous Deletion 5 c.139 C > G p.Arg 47 Gly Heterozygous Missense 6 c.1217 G > A p.Arg 406 Gln Heterozygous Missense c.140 G > A p.Arg47Gln Heterozygous, compound Missense 7 c.857 C > T p.Ala 286 Val Heterozygous Missense 8 c.2324 C > T p.Thr775Met Heterozygous Missense c.2836 G > A p.Ala946Thr Heterozygous Missense 9 c.523A > G p.Thr175Ala Heterozygous Missense 10 c.1005 + 5 G > A p.? Login to comment
106 Location and nucleotide change Effect on protein Status of variant Mutation category 1 c.1328dup p.Arg444Glu fsX4, truncating Heterozygous Insertion 2 c.1584 G > C p.Glu528Asp Heterozygous Missense 3 c.101 C > T p.Thr34Met Heterozygous Missense 4 c.1553delT p.Leu518Tyr fsX16, truncating Heterozygous Deletion 5 c.139 C > G p.Arg 47 Gly Heterozygous Missense 6 c.1217 G > A p.Arg 406 Gln Heterozygous Missense c.140 G > A p.Arg47Gln Heterozygous, compound Missense 7 c.857 C > T p.Ala 286 Val Heterozygous Missense 8 c.2324 C > T p.Thr775Met Heterozygous Missense c.2836 G > A p.Ala946Thr Heterozygous Missense 9 c.523A > G p.Thr175Ala Heterozygous Missense 10 c.1005 + 5 G > A p.? Login to comment

[hide] [44-year-old woman with elevated liver enzymes and... Internist (Berl). 2011 Oct;52(10):1234-7. doi: 10.1007/s00108-010-2775-2. Hopf C, Beuers U, Bikker H, Denk GU, Rust C
[44-year-old woman with elevated liver enzymes and a family history for cholelithiasis].
Internist (Berl). 2011 Oct;52(10):1234-7. doi: 10.1007/s00108-010-2775-2., [PMID:21161147]

Abstract [show]
"Low phospholipid associated cholelithiasis" (LPAC) syndrome is an important differential diagnosis in younger patients with biliary symptoms after cholecystectomy and concomitant elevated serum liver tests. Typical symptoms include recurrence of biliary colics after cholecystectomy, echogenic material in the intrahepatic bile ducts, intrahepatic cholestasis of pregnancy or cholestasis under hormonal contraception and a family history of gallstone disease. Patients with LPAC syndrome can be successfully treated with ursodeoxycholic acid.

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39 Diskussion LPAC-Syndrom Das LPAC-Syndrom ist gekennzeichnet durch [7]: F eine symptomatische Cholezystolithiasis vor dem 40.Êf;Lebensjahr, Abb. 1ߙ8ߙDie Oberbauchsonographie zeigt intrahepatisch echoreiche Foki, teilweise mit dorsalem Schallschatten (rote Pfeile), ohne intra- oder extrahe- patische Cholestase p.Gly319Glu p.Arg47Gln p.Arg47Gln p.Gly319Glu p.Arg47Gln p.Gly319Glu Keine Mutation Abb. 2ߙ8ߙStammbaum der betroffenen Familie, die Indexpatientin ist mit einem Stern gekennzeichnet. Login to comment

[hide] Reversal of advanced fibrosis after long-term urso... Ann Hepatol. 2015 Sep-Oct;14(5):745-51. Frider B, Castillo A, Gordo-Gilart R, Bruno A, Amante M, Alvarez L, Mathet V
Reversal of advanced fibrosis after long-term ursodeoxycholic acid therapy in a patient with residual expression of MDR3.
Ann Hepatol. 2015 Sep-Oct;14(5):745-51., [PMID:26256905]

Abstract [show]
INTRODUCTION: Progressive familial intrahepatic cholestasis type 3 (PFIC-3) is a severe liver disorder associated with inherited dysfunction of multidrug resistance protein 3 (MDR3/ABCB4), which functions as a phospholipid floppase, translocating phosphatidylcholine from the inner to the outer hemileaflet of the canalicular membrane of hepatocytes. MDR3 deficiency results in a disbalanced bile which may damage the luminal membrane of cells of the hepatobiliary system. We evaluated clinical, biochemical and histological improvement in a genetically proven PFIC-3 patient after long-term ursodeoxycholic acid (UDCA) administration. MATERIAL AND METHODS: A PFIC-3 patient and a relative with cholestatic liver disease were studied. Hepatic MDR3 expression was analyzed by immunohistochemistry and ABCB4 mutations were identified. The effect of the mutations on MDR3 expression and subcellular localization was studied in vitro. RESULTS: A 23-year-old man presented cholestasis with severe fibrosis and incomplete cirrhosis. Canalicular staining for MDR3 was faint. Sequence analysis of ABCB4 revealed two missense mutations that reduce drastically protein expression levels. After 9 years of treatment with UDCA disappearance of fibrosis and cirrhosis was achieved. CONCLUSION: These data indicate that fibrosis associated with MDR3 deficiency can be reversed by long-term treatment with UDCA, at least when there is residual expression of the protein.

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71 Site-directed mutagenesis The substitutions R47Q and T82N were introduced into the plasmid pReceiver-M02-MDR3 (Capital Biosciences, Rockville, MD, USA), which contains the full open reading frame of ABCB4, by site-directed mutagenesis using the QuickChange II system (Stratagene, La Jolla, CA, USA). Login to comment
72 Primers used for mutagenesis were as follows (top strand shown; mutated nucleotides are in lowercase): R47Q, 5`-CATTGTT- TCaATACTCCGATTGGC-3`; T82N, 5`-GGAGAGAT- GAaTGACAAATTTG-3`. Login to comment
110 Effects of R47Q and T82N mutations on MDR3 subcellular localization and expression. Login to comment
120 Genetic analysis Sequence analysis revealed that P1 was a compound heterozygote for two missense mutations in exon 4 of ABCB4: c.140G > A and c.245C > A, (p.R47Q and p.T82N respectively; the first of them located in a cytoplasmic domain and the latter in an extracellular domain). Login to comment
123 In vitro studies of ABCB4 mutations In order to determine whether these substitutions affected subcellular localization or expression of MDR3, MDCKII and HEK293T cells were transfected with expression vectors containing wild-type or the mutated versions of MDR3 (R47Q and T82N) and were analyzed by either immunofluorescence or Western blot. Login to comment
127 Thus, R47Q and T82N mutations do not alter MDR3 localization, but lead to reduced protein levels. Login to comment
129 In this disorder, the severity of cholestasis, the time of presentation and the favourable response to UDCA therapy seems to depend on the degree of penetrance of the genetic defect.4,6 The phenotypic characterization of the mutations found in our patient confirms this assumption, since R47Q and T82N do not impair the canalicular expression of MDR3, but they result in a dramatic reduction in the levels of the protein, a finding that correlates with data from the immunohistochemical analysis of the liver biopsy. Login to comment
131 However, it was reported that mutations at R47 impair phosphorylation of N-terminal domain of MDR3, which is determinant for PC secretion.14 It was reported that R47G mutated protein has similar localization and stability to wild-type protein, but PC secretion activity B A KDa 200 150 100 MDR3 Na/K-ATPase Mock WT R47Q T82N Wild-type R47Q T82N resulted markedly decreased because of this lack of phosphorylation of neighboring residues, either Thr44 or Ser49. Login to comment