ABCMdb

ABCB4 p.Arg47*

ClinVar:

c.140G>A , p.Arg47Gln ? , Uncertain significance

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Publications
[hide] Chinese children with chronic intrahepatic cholest... J Pediatr Gastroenterol Nutr. 2012 Aug;55(2):150-6. Fang LJ, Wang XH, Knisely AS, Yu H, Lu Y, Liu LY, Wang JS
Chinese children with chronic intrahepatic cholestasis and high gamma-glutamyl transpeptidase: clinical features and association with ABCB4 mutations.
J Pediatr Gastroenterol Nutr. 2012 Aug;55(2):150-6., [PMID:22343912]

Abstract [show]
OBJECTIVE: The aims of the present study was to study the significance of ABCB4 mutations in mainland Chinese children with chronic intrahepatic cholestasis and to correlate genetic findings with clinical features and response to ursodeoxycholic acid (UDCA) therapy. METHODS: Thirteen patients with chronic intrahepatic cholestasis and elevated serum gamma-glutamyl transpeptidase activity of unknown cause were enrolled in a single pediatric center. All of the encoding exons and flanking areas of ABCB4 were sequenced. Available liver biopsy specimens were immunostained for multidrug resistance protein 3. The clinical features, biochemical parameters, and responses to therapy were compared with patients with or without ABCB4 mutation(s). RESULTS: Six different ABCB4 mutations were identified in 3 patients; each patient was a compound heterozygote. Apart from c.139C>T (p.R47X), all were novel, including c.344+2_+3insT, c.1376A>G (p.D459G), c.1745G>A (p.R582Q), c.2077_2078delC (p.P693HfsX698), and c.3825_3826delA (p.M1276WfsX1308). Absent or reduced multidrug resistance protein 3 canalicular immunostaining was demonstrated in patients with ABCB4 mutations. Serum total bile acid levels were higher in patients with ABCB4 mutations than in patients without ABCB4 mutations (352.5 +/- 97.0 vs 55.9 +/- 50.4 mumol/L, P = 7.32E-05). There was no difference in other biochemical parameters between patients with and without ABCB4 mutations. After oral UDCA administration in 3 patients with ABCB4 mutations, pruritus disappeared, growth improved, spleen size decreased, and platelet counts increased. In the 10 patients without ABCB4 mutations, an inconsistent response to UDCA therapy was observed. CONCLUSIONS: In mainland Chinese children, some cases of chronic intrahepatic cholestasis with high gamma-glutamyl transpeptidase could be attributed to ABCB4 mutations. UDCA administration partially improved clinical symptoms and liver function.

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No. Sentence Comment
6 Apart from c.139C>T (p.R47X), all were novel, including c.344þ2_þ3insT, c.1376A>G (p.D459G), c.1745G>A (p.R582Q), c.2077_2078delC (p.P693HfsX698), and c.3825_3826delA (p.M1276WfsX1308). Login to comment
76 Apart from c.139C>T (p.R47X) (19), they were novel; they included c.344þ2_þ3insT, c.1376A>G (p.D459G), c.1745G>A (p.R582Q), c.2077_2078delC (p.P693HfsX698), and c.3825_3826delA (p.M1276WfsX1308). Login to comment
79 Translation would generate a truncated protein (p.R47X) including only the first intracellular domain. Login to comment
92 MDR3 staining was completely absent with compound heterozygous mutations c.139C>T (p.R47X) and c.1745G>A (p.R582Q) (case 13, Fig. 1E). Login to comment
144 Normal MDR3 staining (A) and normal BSEP staining (B) in control liver specimen; normal MDR3 staining (C) and normal BSEP staining (D) in case 6 without ABCB4 mutation; absence of MDR3 staining (E) and normal BSEP staining (F) in case 13 with compound heterozygous ABCB4 mutations c.139C>T (p.R47X) and c.1745G>A (p.R582Q); faint MDR3 staining (G) and normal BSEP staining (H) in case 11 with compound heterozygous ABCB4 mutations c. Login to comment

[hide] ABCB4 heterozygous gene mutations associated with ... Gastroenterology. 2008 Jul;135(1):131-41. Epub 2008 Mar 26. Ziol M, Barbu V, Rosmorduc O, Frassati-Biaggi A, Barget N, Hermelin B, Scheffer GL, Bennouna S, Trinchet JC, Beaugrand M, Ganne-Carrie N
ABCB4 heterozygous gene mutations associated with fibrosing cholestatic liver disease in adults.
Gastroenterology. 2008 Jul;135(1):131-41. Epub 2008 Mar 26., [PMID:18482588]

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BACKGROUND & AIMS: Adenosine triphosphate-binding cassette subfamily B, member 4 (ABCB4) mutations have not been investigated in patients with unexplained cholestasis. We aimed to investigate ABCB4 mutations in adult patients with unexplained anicteric cholestasis and to describe liver injury associated with ABCB4 mutations. METHODS: Between February 2004 and March 2007, all adults with unexplained cholestasis despite multiple investigations including liver biopsy and 124 healthy volunteers had ABCB4 sequencing. Fibrosis, bile duct lesions, inflammatory infiltrate, activation of myofibroblasts and multidrug-resistant P-glycoprotein 3 (MDR3) immunostaining were assessed on patients' liver biopsy specimens. RESULTS: Thirty-two patients were included (23 females, 16-69 years of age). Eight different ABCB4 heterozygous mutations were found in 11 patients (34%). Seven of these mutations (exons 4, 6, 14, 18, 23) were never detected in the control group. One mutation (exon 15) was detected in 4 patients (12.5%) and 4 controls (3%). At the time of liver biopsy, the main clinical and biologic characteristics were similar in the 32 patients regardless of ABCB4 mutation. The histologic pattern in patients with a mutation consisted of portal fibrosis with ductular reaction and strong macrophagic infiltrate of portal tracts without significant periportal and lobular necroinflammatory lesions or cholangitis. Fibrosis score and macrophagic infiltration of portal tracts were significantly increased in patients with ABCB4 mutation (P = .01). Absence or reduced MDR3 canalicular immunostaining was demonstrated in all patients with ABCB4 mutations tested. CONCLUSIONS: Heterozygous ABCB4 mutations were detected in 34% of adults with unexplained cholestasis, for the most part without biliary symptoms, and could result in significant liver fibrosis.

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No. Sentence Comment
56 As described in Figure 1, 3 (T175A, R590Q, A934T) have been previously described in patients with LPAC or ICP.8,13 Conversely, 5 (R47X, V526F, A539T, R545G, I738L) have not been previously described.20 The frequency of each mutation is indicated in Figure 1. Login to comment
91 Clinical Characteristics at the Time of Liver Biopsy and ABCB4 Heterozygous Point Mutations Identified in 11 Patients With Unexplained Anicteric Cholestasis Case Sex Age Cholelithiasis symptoms (age at the onset) Recurrence of cholelithiasis after cholecystectomy Intrahepatic hyperechogenic foci, sludge, or microlithiasis ICPa or steroid sexual triggered cholestasisb ABCB heterozygous mutation Exon Location and nucleotide changes Amino acid changes 1 F 23 No __ No Yesa Nonsense 4c c. 139CϾT R47X Missense 6 c. 523AϾG T175A 2 F 16 No - No Yesb Nonsense 4c c. 139CϾT R47X Missense 6 c. 523AϾG T175A 3 F 50 No - No No Missense 18c c. 2212AϾC I738L 4 M 53 Yes (53 y) No Yes - Missense 14c c. Login to comment
92 1615GϾA A539T Missense 15 c. 1769GϾA R590Q 5 F 47 No - No No Missense 23 c. Login to comment
57 As described in Figure 1, 3 (T175A, R590Q, A934T) have been previously described in patients with LPAC or ICP.8,13 Conversely, 5 (R47X, V526F, A539T, R545G, I738L) have not been previously described.20 The frequency of each mutation is indicated in Figure 1. Login to comment