ABCMdb

ABCB11 p.Gln931Pro

Predicted by SNAP2:	A: N (82%), C: N (61%), D: N (87%), E: N (87%), F: N (57%), G: N (82%), H: N (93%), I: N (72%), K: N (97%), L: N (66%), M: N (78%), N: N (72%), P: D (59%), R: N (87%), S: N (87%), T: N (93%), V: N (66%), W: N (53%), Y: N (57%),
Predicted by PROVEAN:	A: N, C: D, D: N, E: N, F: D, G: D, H: N, I: D, K: N, L: D, M: N, N: N, P: D, R: N, S: N, T: N, V: D, W: D, Y: D,

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[hide] Diagnosis of ABCB11 gene mutations in children wit... Mol Med Rep. 2014 Sep;10(3):1264-74. doi: 10.3892/mmr.2014.2349. Epub 2014 Jun 20. Hu G, He P, Liu Z, Chen Q, Zheng B, Zhang Q
Diagnosis of ABCB11 gene mutations in children with intrahepatic cholestasis using high resolution melting analysis and direct sequencing.
Mol Med Rep. 2014 Sep;10(3):1264-74. doi: 10.3892/mmr.2014.2349. Epub 2014 Jun 20., [PMID:24969679]

Abstract [show]
Intrahepatic cholestasis represents a heterogeneous group of disorders that begin during childhood, most commonly manifesting as neonatal cholestasis, and lead to ongoing liver dysfunction in children and adults. For children, inherited pathogenic factors of cholestasis have gained increasing attention owing to the rapid development of molecular biology technology. However, these methods have their advantages and disadvantages in terms of simplicity, sensitivity, specificity, time required and expense. In the present study, an effective, sensitive and economical method is recommended, termed high-resolution melting (HRM) analysis and direct sequencing, based on general polymerase chain reaction, to detect mutations in diseasecausing genes. As one type of inherited intrahepatic cholestasis, progressive familial intrahepatic cholestasis type 2 (PFIC2) is caused by pathogenic mutations in the ABCB11 gene, HRM was used to detect mutations in the ABCB11 gene in the present study, and the diagnosis for PFIC2 was made by comprehensive analysis of genetic findings and clinical features. Furthermore, the characteristics of mutations and single nucleotide polymorphisms (SNPs) in the ABCB11 gene were elucidated. A total of 14 types of mutations/polymorphisms were identified in 20 patients from mainland China, including six missense mutations (p.Y337H, p.Y472C, p.R696W, p.Q931P, p.D1131V and p.H1198R), one nonsense mutation (p.R928X) and seven SNPs (p.D36D/rs3815675, p.F90F/rs4148777, p.Y269Y/rs2287616, p.I416I/rs183390670, p.V444A/rs2287622, p.A865V/rs118109635 and p.A1028A/rs497692). Five mutations were novel. The majority of the mutations were different from those detected in other population groups. A total of 4/20 patients (1/5) were diagnosed to be PFIC2 by combining genetic findings with the clinical features. Polymorphisms V444A and A1028A, with an allele frequency of 74.5 and 67.2%, respectively, were highly prevalent in the mainland Chinese subjects. No differences were found between the patients with cholestasis and the control subjects. Efficient genetic screening facilitates the clinical diagnosis of genetic disorders. The present study demonstrated that HRM analysis was efficient and effective in detecting mutations and expanded the known spectrum of ABCB11 gene mutations.

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7 A total of 14 types of mutations/polymorphisms were identified in 20 patients from mainland China, including six missense mutations (p.Y337H, p.Y472C, p.R696W, p.Q931P, p.D1131V and p.H1198R), one nonsense mutation (p.R928X) and seven SNPs (p.D36D/rs3815675, p.F90F/rs4148777, p.Y269Y/rs2287616, p.I416I/rs183390670, p.V444A/rs2287622, p.A865V/rs118109635 and p.A1028A/rs497692). Login to comment
112 Results MutationsandSNPsdetectedinpatients.Amongthe20 patients with cholestasis, 14 types of variants were detected, including seven mutations in the coding region (p.Y337H, p.Y472C, p.R696W, p.R928X, p.Q931P, p.D1131V and p.H1198R) and seven SNPs (p.D36D/rs3815675, p.F90F/rs4148777, p.Y269Y/rs2287616, p.I416I/rs183390670, p.V444A/rs2287622, p.A865V/rs118109635 and p.A1028A/rs497692). Login to comment
113 Missense mutations p.Y337H, p.R696W, p.Q931P, p.D1131V and p.H1198R were novel mutations identified in the study. Login to comment
118 Amino acid Carrier rate Variant Exon change RefSNP Patients and status in control (%) c.108T>C 4 D36D rs3815675 Heterozygous: P7, P11, P16 - c.270T>C 5 F90F rs4148777 Heterozygous: P6, P13 - c.807T>C 9 Y269Y rs2287616 Heterozygous: P7, P11, P16 - c.1009T>C 10 Y337H - Heterozygous: P5 0 c.1248C>A 12 I416I rs183390670 Heterozygous: P13 - c.1331T>C 13 V444A rs2287622 Heterozygous: P1, P5, P12, P16, P17, P19 94.5 Homozygous: P2, P3, P4, P6, P7, P8, P9, P10, P11, P14, P15, P18, P20 c.1415A>G 13 Y472C - Heterozygous: P3 0 c.2086C>T 18 R696W - Heterozygous: P11 0 c.2594C>T 21 A865V rs118109635 Heterozygous: P7, P17 - c.2782C>T 22 R928X - Heterozygous: P1 0 c.2792A>C 22 Q931P - Heterozygous: P4 0 c.3084A>G 24 A1028A rs497692 Heterozygous: P1, P8, P12, P13, P15, P16, P17, P20 90.5 Homozygous: P2, P3, P4, P5, P6, P7, P9, P10, P14, P18, P19 c.3392A>T 25 D1131V - Heterozygous: P3 0 c.3593A>G 26 H1198R - Heterozygous: P1 0 RefSNP refers to the reference SNP in the Single Nucleotide Polymorphism Database of NCBI. Login to comment
122 The results based on comprehensive evaluation of SIFT, PolyPhen-2, SNPs&GO and evolution conservation indicated that p.Y337H, p.Y472C, p.R696W, p.D1131V and p.H1198R were likely damaging, p.Q931P and p.A865V were possibly damaging and p.V444A was predicted to be benign. Login to comment
141 Variant SIFT PolyPhen-2 SNPs&GO EC/EN c.1009T>C (Y337H) 0.01 0.996 Disease EC c.1331T>C (V444A) 0.34 0.001 Neutral EC c.1415A>G (Y472C) 0 1.000 Disease EC c.2086C>T (R696W) 0.02 0.999 Disease EC c.2594C>T (A865V) 0.07 0.880 Disease EC c.2792A>C (Q931P) 0.02 0.178 Disease EN c.3392A>T (D1131V) 0 1.000 Disease EC c.3593A>G (H1198R) 0 1.000 Disease EC SIFT, Sorting Intolerant From Tolerant (mutation of residues with SIFT scores <0.05 are predicted to be deleterious); PolyPhen-2, Polymorphism Phenotyping version 2 (a score <0.2 denotes benign variants, between 0.2 and 0.85 is possibly damaging and >0.85 is highly likely damaging); SNPs&GO, a web tool to predict function of SNPs with a result of neutral or disease-related variants for human; EC, evolutionarily conserved; EN, evolutionarily non-conserved; SNP, single nucleotide polymorphism. Table VI. Login to comment
156 All the diseaseߛrelated mutations detected above were tested in 200 control subjects using HRM analysis to screen exon 10 (p.Y337H), exon 13 (p.Y472C), exon 18 (p.R696W), exon 22 (p.R928X), exon 22 (p.Q931P), exon 25 (p.D1131V) and exon 26 (p.H1198R). Login to comment
179 Among the seven mutations identified in the study, p.Y337H, p.R696W, p.Q931P, p.D1131V and p.H1198R are novel mutations according to data from The Human Gene Mutation Database (http://www. Login to comment
190 These mutations were evolutionarily conserved and an comprehensive analysis of the results of SIFT, PolyPhen-2, SNPs&GO revealed that they may be deleterious with the exception of p.Q931P. Login to comment