ABCB4 p.Ala953Asp
| Predicted by SNAP2: | C: N (72%), D: D (80%), E: D (80%), F: D (71%), G: N (53%), H: D (75%), I: D (66%), K: D (80%), L: D (71%), M: D (66%), N: D (71%), P: D (80%), Q: D (71%), R: D (75%), S: N (82%), T: N (53%), V: D (59%), 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: N, T: D, V: D, W: D, Y: D, |
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[hide] Expression and localization of hepatobiliary trans... Hepatology. 2005 May;41(5):1160-72. Keitel V, Burdelski M, Warskulat U, Kuhlkamp T, Keppler D, Haussinger D, Kubitz R
Expression and localization of hepatobiliary transport proteins in progressive familial intrahepatic cholestasis.
Hepatology. 2005 May;41(5):1160-72., [PMID:15841457]
Abstract [show]
Mutations of the bile salt export pump (BSEP) or the multidrug resistance P-glycoprotein 3 (MDR3) are linked to impaired bile salt homeostasis and lead to progressive familial intrahepatic cholestasis (PFIC)-2 and -3, respectively. The regulation of bile salt transporters in PFIC is not known. Expression of hepatobiliary transporters in livers of ten patients with a PFIC phenotype was studied by quantitative reverse transcription polymerase chain reaction, Western blotting, and immunofluorescence microscopy. PFIC was diagnosed by clinical and laboratory findings. All patients could be assigned to PFIC-2 or PFIC-3 by the use of BSEP- and MDR3-specific antibodies and by MDR3 gene-sequencing. Whereas in all PFIC-2 patients, BSEP immunoreactivity was absent from the canalicular membrane, in three PFIC-3 livers, canalicular MDR3 immunoreactivity was detectable. Serum bile salts were elevated to 276 +/- 233 and to 221 +/- 109 micromol/L in PFIC-2 and PFIC-3, respectively. Organic anion transporting polypeptide OATP1B1, OATP1B3, and MRP2 mRNA and protein levels were reduced, whereas sodium taurocholate cotransporting polypeptide (NTCP) was only reduced at the protein level, suggesting a posttranscriptional NTCP regulation. Whereas MRP3 mRNA and protein were not significantly altered, MRP4 messenger RNA and protein were significantly increased in PFIC. In conclusion, PFIC-2 may be reliably diagnosed by immunofluorescence, whereas the diagnosis of PFIC-3 requires gene-sequencing. Several mechanisms may contribute to elevated plasma bile salts in PFIC: reduced bile salt uptake via NTCP, OATP1B1, and OATP1B3, decreased BSEP-dependent secretion into bile, and increased transport back into plasma by MRP4. Upregulation of MRP4, but not of MRP3, might represent an important escape mechanism for bile salt extrusion in PFIC.
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No. Sentence Comment
38 Clinical and Laboratory Parameters of PFIC Patients Patients Clinical Parameters Laboratory Parameters Diagnosis Onset of Symptoms Age at LTx BS (<8 M) ␥GT (<25 U/l) Bilirubin (<1 mg/dL) MDR3-Mutation MDR3- IF BSEP- IF PFIC Type C1 F.A. 4 m 3 y 5 m 47 7 1.3 None detected ϩ - 2 C2 A.A. 3 m 2 y 5 m 144 19 22.6 None detected ϩ - 2 C3 S.H. 3 m 3 y 3 m 616 77 22.7 None detected ϩ - 2 C4 M.D. 6 m 10 y 7 m 160 7 5.4 None detected ϩ - 2 C5 T.A. 6 m 4 y 2 m 414 11 5.4 555 A 3 G/T175A Heterozygous ϩ - 2 C6 M.D. 4 m 7 y 9 m 163 26 11.2 1069 G 3 T/S346I ϩ ϩ 3 C7 S.F. birth 8 y 7 m 299 250 1.9 1069 G 3 T/8346I* ϩ ϩ 3 C8 K.Y. 6 m 3 y 10 m 85 277 0.5 2890 C 3 A/A953D ϩ ϩ 3 C9 K.B. 4 m 3 y 8 m 360 165 1.1 426-432 del† - ϩ 3 C10 B.D. 7 y 11 y 4 m 199 24 20.7 None detected - ϩ 3 NOTE.
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ABCB4 p.Ala953Asp 15841457:38:724
status: NEW109 Two different mutations were found in the three patients with detectable canalicular MDR3 immunoreactivity (S346I and A953D).
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ABCB4 p.Ala953Asp 15841457:109:118
status: NEW168 Normal canalicular MDR3 localization associated with this mutation was already reported for child C7.39 A second MDR3 mutation (A953D, C8) identified in this study has not been described so far.
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ABCB4 p.Ala953Asp 15841457:168:128
status: NEW[hide] Combined features of low phospholipid-associated c... Liver Int. 2010 Feb;30(2):327-31. Epub 2009 Oct 19. Poupon R, Barbu V, Chamouard P, Wendum D, Rosmorduc O, Housset C
Combined features of low phospholipid-associated cholelithiasis and progressive familial intrahepatic cholestasis 3.
Liver Int. 2010 Feb;30(2):327-31. Epub 2009 Oct 19., [PMID:19840255]
Abstract [show]
Adenosine triphosphate-binding cassette, subfamily B, member 4 (ABCB4) gene alterations can cause two distinct clinical entities: progressive familial intrahepatic cholestasis type 3 (PFIC3) and low phospholipid-associated cholelithiasis (LPAC). Based on the findings in two siblings and a review of the literature, we aimed to identify determinants of disease phenotypic traits associated with ABCB4 gene alterations. Two siblings presented, before the age of 30 years, recurrent symptomatic cholelithiasis and extensive biliary fibrosis that progressed towards portal hypertension and liver failure necessitating liver transplantation. We analysed the sequence of the ABCB4 gene and immunolocalization of the protein in the liver. Sequence analysis of ABCB11, potentially involved in similar symptoms, was also performed. Two heterozygous non-synonymous variants of ABCB4 were found in both siblings. One of them (c.959C>T; p.Ser320Phe) was previously implicated in LPAC and the second one (c.2858C>A; p.Ala953Asp) in PFIC3. Both patients were also heterozygous for the ABCB11 variant Val444Ala, which predisposes to cholestatic disorders. ABCB4 was normally detected at the canalicular membrane of hepatocytes. The review of ABCB4 gene variants reported so far shows that the vast majority of variants causing PFIC3 and LPAC are distinct. Also as a general rule, homozygous variants cause PFIC3 while heterozygous variants lead to LPAC. Combined PFIC3 and LPAC phenotype is a rare clinical event, which may be determined by the coexistence of ABCB4 variants related to both phenotypes and also potentially to the ABCB11 variant. Thus, most of the patients presenting with LPAC are not at a particular risk of developing PFIC3 features in adulthood.
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No. Sentence Comment
7 One of them (c.959C 4 T; p.Ser320Phe) was previously implicated in LPAC and the second one (c.2858C 4 A; p.Ala953Asp) in PFIC3.
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ABCB4 p.Ala953Asp 19840255:7:107
status: NEW89 Sequence ABCB4 gene analysis showed the presence of composite heterozygous double alterations affecting exon 9 (c.959C 4 T; p.Ser320Phe) and exon 23 (c.2858C4 A; p.Ala953Asp) in both siblings (Fig. 1, arrows).
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ABCB4 p.Ala953Asp 19840255:89:164
status: NEW111 The other one was located in exon 23, and resulted in a substitution of alanine for aspartic acid (p.Ala953Asp).
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ABCB4 p.Ala953Asp 19840255:111:101
status: NEW135 (Ala953Asp), previously reported in a homozygous state in PFIC3 (3) and one heterozygous missense mutation (Ser320Phe) previously reported in LPAC (5).
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ABCB4 p.Ala953Asp 19840255:135:1
status: NEW136 The Ser320Phe has never been described in PFIC3 (1-3) and the Ala953Asp has never been found in LPAC [(4, 5) and unpublished personal data].
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ABCB4 p.Ala953Asp 19840255:136:62
status: NEW[hide] ABCB4: Insights from pathobiology into therapy. Clin Res Hepatol Gastroenterol. 2014 Oct;38(5):557-63. doi: 10.1016/j.clinre.2014.03.001. Epub 2014 Jun 19. Falguieres T, Ait-Slimane T, Housset C, Maurice M
ABCB4: Insights from pathobiology into therapy.
Clin Res Hepatol Gastroenterol. 2014 Oct;38(5):557-63. doi: 10.1016/j.clinre.2014.03.001. Epub 2014 Jun 19., [PMID:24953525]
Abstract [show]
Adenosine triphosphate (ATP)-binding cassette, sub-family B, member 4 (ABCB4), also called multidrug resistance 3 (MDR3), is a member of the ATP-binding cassette transporter superfamily, which is localized at the canalicular membrane of hepatocytes, and mediates the translocation of phosphatidylcholine into bile. Phosphatidylcholine secretion is crucial to ensure solubilization of cholesterol into mixed micelles and to prevent bile acid toxicity towards hepatobiliary epithelia. Genetic defects of ABCB4 may cause progressive familial intrahepatic cholestasis type 3 (PFIC3), a rare autosomic recessive disease occurring early in childhood that may be lethal in the absence of liver transplantation, and other cholestatic or cholelithiasic diseases in heterozygous adults. Development of therapies for these conditions requires understanding of the biology of this transporter and how gene variations may cause disease. This review focuses on our current knowledge on the regulation of ABCB4 expression, trafficking and function, and presents recent advances in fundamental research with promising therapeutic perspectives.
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No. Sentence Comment
108 The A286 V mutation was inactive, the S320F was fully active but its expression reduced to 50%, and the A953D mutation affected both the expression and the activity of ABCB4.
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ABCB4 p.Ala953Asp 24953525:108:104
status: NEW