ABCMdb

PMID: 24914347

Jirsa M, Bronsky J, Dvorakova L, Sperl J, Smajstrla V, Horak J, Nevoral J, Hrebicek M
ABCB4 mutations underlie hormonal cholestasis but not pediatric idiopathic gallstones.
World J Gastroenterol. 2014 May 21;20(19):5867-74. doi: 10.3748/wjg.v20.i19.5867., [PubMed]

Sentences

No. Mutations Sentence Comment

25 ABCG8 p.Asp19His ABCB11 p.Val444Ala ABCB4 p.Thr175Ala ABCB4 p.Arg652Gly In our previous study[10] we focused on the role of the common variants c.523A>G (p.Thr175Ala) and c.1954A>G (p.Arg652Gly) in ABCB4, c.1331T>C (p.Val444Ala) in ABCB11 and c.55 G>C (p.Asp19His) in ABCG8 in pediatric gallstone disease. Login to comment 26 ABCB11 p.Val444Ala ABCB4 p.Thr175Ala ABCB4 p.Arg652Gly In our previous study[10] we focused on the role of the common variants c.523A>G (p.Thr175Ala) and c.1954A>G (p.Arg652Gly) in ABCB4, c.1331T>C (p.Val444Ala) in ABCB11 and c.55 G>C (p.Asp19His) in ABCG8 in pediatric gallstone disease. Login to comment 72 ABCB4 p.Pro741Leu In patient 31, a novel heterozygous variation was found (c.2222C>T, leading to predicted conservative amino acid substitution p.Pro741Leu in the extracellular loop between transmembrane domains 7 and 8). Login to comment 73 ABCB4 p.Pro741Leu In patient 31, a novel heterozygous variation was found (c.2222C>T, leading to predicted conservative amino acid substitution p.Pro741Leu in the extracellular loop between transmembrane domains 7 and 8). Login to comment 74 ABCB4 p.Gly773Val Another predicted amino acid substitution (p.Gly773Val, localized in transmembrane domain 8 and caused by the novel mutation c.2318G>T) was found in a heterozygous state in patient 32. Login to comment 75 ABCB4 p.Gly773Val Another predicted amino acid substitution (p.Gly773Val, localized in transmembrane domain 8 and caused by the novel mutation c.2318G>T) was found in a heterozygous state in patient 32. Login to comment 77 ABCB4 p.Arg652Gly None of these changes is reportedly associated with hepatobiliary disease, with the possible exception of c.1954A>G (p.Arg652Gly), found previously in a heterozygous state in subjects 4, 8 and 26[10] . Login to comment 78 ABCB4 p.Arg652Gly None of these changes is reportedly associated with hepatobiliary disease, with the possible exception of c.1954A>G (p.Arg652Gly), found previously in a heterozygous state in subjects 4, 8 and 26[10] . Login to comment 79 ABCB4 p.Thr175Ala Families with suspect LPAC Two of the five probands carried a single heterozygous nonsense mutation, two were heterozygotes for the missense mutation c.523A>G (p.Thr175Ala, rs58238559), and one was a compound heterozygote for the same missense mutation (c.523A>G) and for the frameshift mutation c.1371delG (p.Gln458Argfs*7) (Figure 2). Login to comment 80 ABCB4 p.Thr175Ala Families with suspect LPAC Two of the five probands carried a single heterozygous nonsense mutation, two were heterozygotes for the missense mutation c.523A>G (p.Thr175Ala, rs58238559), and one was a compound heterozygote for the same missense mutation (c.523A>G) and for the frameshift mutation c.1371delG (p.Gln458Argfs*7) (Figure 2). Login to comment 81 ABCB4 p.Thr175Ala While the number of patients was too low to make the result fully convincing, this observation suggests that p.Thr175Ala at least confers susceptibility to hepatobiliary disease. Login to comment 82 ABCB4 p.Thr175Ala While the number of patients was too low to make the result fully convincing, this observation suggests that p.Thr175Ala at least confers susceptibility to hepatobiliary disease. Login to comment 84 ABCB11 p.Val444Ala Two probands were homozygous and the other three probands were heterozygous for the low-expression ABCB11 variant c.1331T>C (p.Val444Ala) (Figure 2). Login to comment 85 ABCB11 p.Val444Ala Two probands were homozygous and the other three probands were heterozygous for the low-expression ABCB11 variant c.1331T>C (p.Val444Ala) (Figure 2). Login to comment 88 ABCB4 p.Thr175Ala This indicates that the null mutations in familiesߙIߙ- III and even the missense mutation leading to p.Thr175Ala in families IV and ࡴ all are likely sufficient in a heterozygous state to promote the LPAC phenotype. Login to comment 89 ABCB4 p.Thr175Ala This indicates that the null mutations in familiesߙIߙ- III and even the missense mutation leading to p.Thr175Ala in families IV and ࡴ all are likely sufficient in a heterozygous state to promote the LPAC phenotype. Login to comment 93 ABCB4 p.Gly773Val Table 2 Known variations in ABCB4, ABCB11 and ABCG8 found in 35 pediatric subjects with idiopathic gallstones in pediatric patients with idiopathic gallstones who met clinical criteria for the diagnosis of LPAC was the variation c.2318G>T (p.Gly773Val ) found in a heterozygous state in only one affected subject. Login to comment 94 ABCB4 p.Arg652Gly ABCB4 p.Gly773Val Table 2 Known variations in ABCB4, ABCB11 and ABCG8 found in 35 pediatric subjects with idiopathic gallstones in pediatric patients with idiopathic gallstones who met clinical criteria for the diagnosis of LPAC was the variation c.2318G>T (p.Gly773Val ) found in a heterozygous state in only one affected subject. Login to comment 95 ABCB4 p.Arg652Gly The nucleotide change c.1954A>G found in 3 other pediatric gallstone subjects is common in the European, Caucasian, and African general population, but it has also been found in a patient with LPAC and low biliary phospholipid in whom its predicted consequence p.Arg652Gly was hypothesized to be conditionally penetrant, leading to clinical symptoms only under certain circumstances, such as pregnancy, or when combined with another mutation[18] . Login to comment 98 ABCB4 p.Thr175Ala Interestingly, the ABCB4 variation c.523A>G (p. Thr175Ala), found in three index patients with LPAC, Patient. Login to comment 99 ABCG8 p.Asp19His ABCB11 p.Val444Ala ABCB4 p.Thr175Ala ABCB4 p.Arg652Gly Interestingly, the ABCB4 variation c.523A>G (p. Thr175Ala), found in three index patients with LPAC, Patient. Login to comment 100 ABCB11 p.Val444Ala ABCB4 p.Arg652Gly ID Variations in the coding sequence of ABCB4 ABCB11 low expression allele ABCG8 variation c.147C>T c.175C>T c.459T>C c.504C>T c.711A>T c.1954A>G c.1331T>C c.55G>C Ser49Ser Leu59Leu Phe153Phe Asn168Asn Ile237Ile Arg652Gly Val444Ala Asp19His rs8187789 rs2302387 rs2230027 rs1202283 rs2109505 rs2230028 rs2287622 rs11887534 1 CC CC TT TT AA AA CC GG 2 CC CC TT CT AA AA TC GG 3 CC CC TT CT AA AA TC GG 4 CC CC TT CT AT AG TC GG 5 CC CC TT TT AA AA CC GG 6 CC CC TT CC AA AA TC GG 7 CC CC TT CT AA AA TC GG 8 CC CC TT CC AA AG TC GG 9 CC CC TT TT AA AA TT GG 10 CC CC TT TT AA AA CC GG 11 CC CC TT TT AA AA TC GG 12 CC CC TT TT AA AA CC GG 13 CC CC TT CT AA AA TC GG 14 CC CC TT CC AA AA CC GG 15 CC CC TT TT AA AA TC GC 16 CC CC TT CC AA AA TC GC 17 CC CC TT CC AA AA TC GG 18 CC CC TT TT AA AA TC GC 19 CC CC TT CT AA AA TC GC 20 CC CC TT CT AA AA TT GG 21 CC CC TT TT AA AA TC GG 22 CC CC TT CT AA AA TT GG 23 CC CC TT CT AA AA TT GG 24 CC CT TT CC AT AA CC GG 25 CC CC TT CC AA AA TC GG 26 CT CT TC CC AA AG TC GG 27 CC CC TT TT AA AA TC GG 28 CC CC TT TT AA AA TT GG 29 CC CC TT CT AA AA TT GG 30 CC CC TT TT AA AA CC GC 31 CC CC TT CT AA AA TT GC 32 CC CC TT CT AA AA TT GG 33 CC CC TT TT AA AA TC GG 34 CC CC TT CC AA AA TT GG 35 CC CC TT TT AA AA CC GG Allelic frequency of variant alleles in patients with gallstones, HapMap populations and Czech population controls Allele T T C T T G C G Gallstone patients 0.014 0.029 0.014 0.571 0.029 0.043 0.471 0.086 HapMap CEU 0 0.112 01 0.664 0.175 0.075 0.408 0.085 HapMap HCB 0 0.167 01 0.344 0.222 0.023 0.333 0.022 HapMap JPT 0 0.273 01 0.442 0.300 0.023 0.261 0.011 HapMap YRI 0.042 0.525 0.11 0 0.362 0.392 0.425 0.042 Czech controls (n = 150) n.d. n.d. n.d. n.d. n.d. 0.090 0.400 0.0672 1 Results from corresponding populations studied in Environmental Genome Project (NIEHS ES15478 project). Login to comment 106 ABCB4 p.Thr175Ala The substitution p.Thr175Ala, predicted uniformly to impair protein function by SIFT, PMut, PolyPhen-2 and MutationTaster is thus considered a disease-associated mutation[3] with incomplete penetrance. Login to comment 107 ABCB4 p.Thr175Ala The substitution p.Thr175Ala, predicted uniformly to impair protein function by SIFT, PMut, PolyPhen-2 and MutationTaster is thus considered a disease-associated mutation[3] with incomplete penetrance. Login to comment 124 ABCB4 p.Thr175Ala His DNA sample was not available for analysis; however, he is most likely a heterozygous carrier of c.523A>G (p.Thr175Ala) as depicted. Login to comment 125 ABCB4 p.Thr175Ala His DNA sample was not available for analysis; however, he is most likely a heterozygous carrier of c.523A>G (p.Thr175Ala) as depicted. Login to comment 127 ABCB4 p.Thr175Ala ABCB4 p.Thr175Ala ABCB4 p.Thr175Ala c.1331T|T c.55G|G c.1331T|T c.55G|G c.1331T|T c.55G|G c.1331C|C c.55G|G c.1331C|C c.55G|G c.1331C|C c.55G|G c.1331C|C c.55G|G c.1331T|C c.55G|G c.1331T|C c.55G|G c.1331C|C c.55G|G c.1331C|C c.55G|G c.1331C|C c.55G|G c.1331C|C c.55G|G c.1331T|C c.55G|G c.1331T|C c.55G|G c.1331T|C c.55G|G c.1331T|C c.55G|C c.1331T|C c.55C|C c.1331T|C c.55G|C c.1331T|T c.55G|C I II III IV ࡴ n.a. n.a. p.Ser1203X F1-1 F2-1 F1-1 n.a. F3-1 F3-2 F1-2 F2-1 p.Thr175Ala p.Gln458Argfs*7 LPAC phenotype p.Thr175Ala p.Thr175Ala p.Glu501X young adults[26] , together with the decreased biliary secretion rate of phosphatidylcholine in carriers of mutations in ABCB4, shifts the cholesterol-solubility equilibrium to the borderline. Login to comment 128 ABCB4 p.Thr175Ala ABCB4 p.Thr175Ala ABCB4 p.Thr175Ala c.1331T|T c.55G|G c.1331T|T c.55G|G c.1331T|T c.55G|G c.1331C|C c.55G|G c.1331C|C c.55G|G c.1331C|C c.55G|G c.1331C|C c.55G|G c.1331T|C c.55G|G c.1331T|C c.55G|G c.1331C|C c.55G|G c.1331C|C c.55G|G c.1331C|C c.55G|G c.1331C|C c.55G|G c.1331T|C c.55G|G c.1331T|C c.55G|G c.1331T|C c.55G|G c.1331T|C c.55G|C c.1331T|C c.55C|C c.1331T|C c.55G|C c.1331T|T c.55G|C I II III IV ࡴ n.a. n.a. p.Ser1203X F1-1 F2-1 F1-1 n.a. F3-1 F3-2 F1-2 F2-1 p.Thr175Ala p.Gln458Argfs*7 LPAC phenotype p.Thr175Ala p.Thr175Ala p.Glu501X young adults[26] , together with the decreased biliary secretion rate of phosphatidylcholine in carriers of mutations in ABCB4, shifts the cholesterol-solubility equilibrium to the borderline. Login to comment 131 ABCB4 p.Thr175Ala In contrast, two patients heterozygous for the missense MDR3 variant p.Thr175Ala tolerated long-term administration of oral contraceptives after cholecystectomy without apparent worsening in hepatobiliary disease. Login to comment 132 ABCB4 p.Thr175Ala In contrast, two patients heterozygous for the missense MDR3 variant p.Thr175Ala tolerated long-term administration of oral contraceptives after cholecystectomy without apparent worsening in hepatobiliary disease. Login to comment