ABCB4 p.Arg144*
| ClinVar: |
c.430C>T
,
p.Arg144*
D
, Pathogenic
|
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[hide] Intrahepatic cholestasis of pregnancy: three novel... Aliment Pharmacol Ther. 2006 Jun 1;23(11):1649-53. Floreani A, Carderi I, Paternoster D, Soardo G, Azzaroli F, Esposito W, Variola A, Tommasi AM, Marchesoni D, Braghin C, Mazzella G
Intrahepatic cholestasis of pregnancy: three novel MDR3 gene mutations.
Aliment Pharmacol Ther. 2006 Jun 1;23(11):1649-53., [PMID:16696816]
Abstract [show]
BACKGROUND: The aetiology of intrahepatic cholestasis of pregnancy is unknown, but more than 10 different MDR3 gene mutations have recently been identified. AIM: To evaluate the genetic contribution of the MDR3 gene in the pathogenesis of intrahepatic cholestasis of pregnancy in Italian subjects. METHODS: We performed a multicentre prospective case-control study, enrolling 80 women with intrahepatic cholestasis of pregnancy at the third trimester of pregnancy and 80 pregnant women without intrahepatic cholestasis of pregnancy. Genomic DNA was extracted from peripheral venous blood leucocytes using standard procedures. The polymerase chain reaction was used to amplify exon 14 of the MDR3 gene and the polymerase chain reaction products were sequenced using a Big Dye Terminator Cycle Sequencing kit. RESULTS: Three novel non-synonymous heterozygous mutations in exon 14 were found (4%; E528D, R549H, G536R) among the 80 intrahepatic cholestasis of pregnancy patients, whereas the pregnant controls were all negative for exon 14 polymorphisms. The three patients involved had normal GGT and bilirubin, but high levels of both ALT and serum bile acids. One had cholesterol bile stones. The outcome of pregnancy was normal for two (with vaginal delivery), while foetal distress was recorded in the third. CONCLUSIONS: These three novel mutations add further information on the involvement of the MDR3 gene in intrahepatic cholestasis of pregnancy. As in other studies, we found only heterozygous mutations that could cause an impaired transport protein function, not its absence (which is responsible for more severe liver disease). Different genetic backgrounds might justify the presence of novel MDR3 gene mutations.
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No. Sentence Comment
35 MDR3 mutations reported in the literature Mutation (codon) Exon Reference (R144X) 6 Gendrot et al.5 481G>A (R150K) 6 Mu¨llenbach et al.6 426-432del (132) 6 DeVree et al.13 959C>T (S320F) 9 Rosmordurc et al.,14 Pauli-Magnus et al.9 (G535D) 14 Lucena et al.7 1669 C>A (A546D) 14 Dixon et al.4 1712 del T (571) 14 Jacquemin et al.8, 15 2285 G>A (G762E) 18 Pauli-Magnus et al.9 2901 C>T (R957X) 23 DeVree et al.13 conditions included an initial denaturation step at 94 °C for 5 min, followed by 40 cycles of denaturation at 94 °C for 30 s, annealing at 55 °C for 30 s and extension at 72 °C for 30 s.
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ABCB4 p.Arg144* 16696816:35:75
status: NEW[hide] A second heterozygous MDR3 nonsense mutation assoc... J Med Genet. 2003 Mar;40(3):e32. Gendrot C, Bacq Y, Brechot MC, Lansac J, Andres C
A second heterozygous MDR3 nonsense mutation associated with intrahepatic cholestasis of pregnancy.
J Med Genet. 2003 Mar;40(3):e32., [PMID:12624161]
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156 In the first patient, the sequence analysis showed a heterozygous substitution (CGA- TGA) in codon 144, which creates a stop codon (R144X) (fig 1).
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ABCB4 p.Arg144* 12624161:156:132
status: NEW162 The R144X mutation destroys a SalI restriction site and we used a PCR restriction test to search for this mutation in the control group.
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ABCB4 p.Arg144* 12624161:162:4
status: NEW163 No R144X mutation was detected in any of the 100 DNA samples.
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ABCB4 p.Arg144* 12624161:163:3
status: NEW166 This R144X mutation is the most proximal truncating mutation reported in this disease, unique to pregnancy (fig 1).
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ABCB4 p.Arg144* 12624161:166:5
status: NEW