ABCMdb

PMID: 20414253

Shapiro R, Anikster Y, Yardeni T, Korem S, Hartman K, Shamir R, Broide E, Levine A, Bujanover Y, Bercovich D
DHPLC screening for mutations in progressive familial intrahepatic cholestasis patients.
J Hum Genet. 2010 May;55(5):308-13. Epub 2010 Apr 23., [PubMed]

Sentences

No. Mutations Sentence Comment

5 ABCB11 p.Ser226Leu ABCB11 p.Gly19Arg ABCB11 p.Gly877Arg Using denaturing high-performance liquid chromatography (DHPLC), five different mutations were identified in four affected families: three novel mutations in BSEP (G19R-g181c, S226L-c803t and G877R-g2755a), one novel mutation in MDR3 (IVS14+6 t/c) and one heterozygous mutation in ATP8B1 (R600W, in a family with the PFIC1/PFIC2 phenotype). Login to comment 61 ABCB11 p.Ser226Leu ABCB11 p.Gly19Arg Screening this family`s DNA yielded two novel heterozygous mutations in BSEP (G19R-g181c and S226L-c803t). Login to comment 64 ABCB11 p.Gly877Arg Family 2 was found to harbor a novel mutation, G877R-g2755a, in a homozygous state (Figure 3). Login to comment 69 ABCB11 p.Gly877Arg ABCB11 p.Gly877Arg In addition, DNA screening for MDR3 mutations in families 11, 12 and 13 yielded one heterozygous novel splice-site Table 2 Results from the screening of the five candidate genes Family DNA ATP8B1 BSEP MDR3 FXR NTCP 1 1-patient WT WT - WT WT 1-M WT WT - WT WT 2 2-patient WT G877R - WT WT 2-M WT G877R/N - WT WT 3 3-patient WT G19R/N; S226L/N - WT WT 3-B WT S226L/N - WT WT 3-patient WT G19R/N; S226L/N - WT WT 3-M WT S226L/N - WT WT 3-F WT G19R/N - WT WT 4 4-patient WT WT - WT WT 4-M WT WT - WT WT 4-B WT WT - WT WT 5 5-patient W.T WT - WT WT 5-patient WT WT - WT WT 5-M WT WT - WT WT 5-F WT WT - WT WT 6 6-patient WT WT - WT WT 6-M WT WT - WT WT 6-F WT WT - WT WT 7 7-patient WT WT - WT WT 7-patient WT WT - WT WT 7-M WT WT - WT WT 8 8-patient WT WT - WT WT 8-M WT WT - WT WT 9 9-patient R600W/N WT - WT WT 9-F WT WT - WT WT 9-M R600W/N WT - WT WT 9-S R600W/N WT - WT WT 9-S WT WT - WT WT 10 10-patient WT WT - WT WT 10-F WT WT - WT WT 11 11-patient - - WT WT - 11-M - - WT WT - 11-F - - WT WT - 12 12-patient - - IVS14+6t/c/N WT - 12-F - - W.T WT - 13 13-patient - - WT WT - 13-M - - WT WT - 13-F - - WT WT - 14 14-patient - - WT WT - 14-M - - WT WT - 14-F - - WT WT - 14-B - - WT WT - 14-S - - WT WT - Abbreviations: B, brother; BSEP, bile salt export pump; F, father; FXR, farnesoid X receptor; M, mother; NTCP, Na+-dependent taurocholic co-transporting polypeptide; S, sister; WT, wild type. Login to comment 73 ABCB11 p.Ser226Leu ABCB11 p.Gly19Arg ABCB11 p.Gly877Arg In total, five mutations were discovered in the ATP8B, BSEP and MDR3 genes; that is, three novel mutations in BSEP (G19R-g181c, S226L-c803t and G877R-g2755a), one novel mutation in MDR3 (IVS14+6 t/c) and only one heterozygous mutation in ATP8B1 (R600W). Login to comment 75 ABCB11 p.Ser226Leu ABCB11 p.Gly877Arg ABCB4 p.Gly19Arg The patients from family 3 were compound heterozygotes for two mutations in BSEP-G19R and S226L-and the patient from family 2 had a hemizygous mutation in BSEP-G877R. Login to comment 76 ABCB11 p.Ser226Leu ABCB11 p.Gly877Arg S226L and G877R are missense mutations at the conserved and active sites of the proteins (ConSeq; http://conseq.tau.ac.il; Figure 5), and G19R is located at the N-terminal region of the BSEP protein. Login to comment 83 ABCB11 p.Ser226Leu ABCB11 p.Ser226Leu ABCB11 p.Ser226Leu ABCB11 p.Gly19Arg ABCB11 p.Gly19Arg ABCB11 p.Gly19Arg ABCB11 p.Gly19Arg Sequence at S226LSequence at S226L Sequence at S226L-Normal Sequence at S226LSequence at G19R Sequence at G19R-Normal Sequence at G19R Sequence at G19RSequence at G19R-Normal Sequence at S226L Figure 2 DHPLC analysis and sequence of mutations in family 3. Login to comment 105 ABCB11 p.Gly877Arg ABCB11 p.Gly877Arg ABCB11 p.Gly877Arg G877R-Hetrozigote G877R -Homozygote unknown Figure 3 Sequence analysis of the G877R (2755g4a) missense mutations of the BSEP gene in family 2. Login to comment 116 ABCB11 p.Ser226Leu ABCB11 p.Gly877Arg The two mutations (S226L and G877R) are in the functional regions of the protein. Login to comment 117 ABCB11 p.Gly19Arg One mutation (G19R) is in the N-terminal region. Login to comment