ABCB11 p.His1198Arg
| Predicted by SNAP2: | A: D (63%), C: D (63%), D: D (53%), E: D (71%), F: D (59%), G: D (63%), I: D (59%), K: N (61%), L: D (59%), M: D (63%), N: N (53%), P: D (85%), Q: D (59%), R: D (75%), S: N (57%), T: D (59%), V: D (66%), W: N (53%), Y: N (61%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, 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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No. Sentence Comment
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).
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ABCB11 p.His1198Arg 24969679:7:184
status: NEW112 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).
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ABCB11 p.His1198Arg 24969679:112:225
status: NEW113 Missense mutations p.Y337H, p.R696W, p.Q931P, p.D1131V and p.H1198R were novel mutations identified in the study.
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ABCB11 p.His1198Arg 24969679:113:61
status: NEW118 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.
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ABCB11 p.His1198Arg 24969679:118:993
status: NEW122 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.
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ABCB11 p.His1198Arg 24969679:122:159
status: NEW135 Age of onset/ GGT TBA TBIL/DBIL ALT/AST Mutation Patient gender Symptoms (U/l) (&#b5;mol/l) (&#b5;mol/l) (U/l) Mutation origin P1 1 m/M Persistent jaundice, 49 101.3 162.5/130.4 432/606 Compound R928X, hepatosplenomegaly heterozygous maternal; p.R928X/p.H1198R H1198R, paternal.
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ABCB11 p.His1198Arg 24969679:135:296
status: NEWX
ABCB11 p.His1198Arg 24969679:135:303
status: NEW141 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.
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ABCB11 p.His1198Arg 24969679:141:355
status: NEW156 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).
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ABCB11 p.His1198Arg 24969679:156:249
status: NEW179 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.
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ABCB11 p.His1198Arg 24969679:179:93
status: NEW[hide] Hypothyroidism Associated with ATP8B1 Deficiency. J Pediatr. 2015 Dec;167(6):1334-1339.e1. doi: 10.1016/j.jpeds.2015.08.037. Epub 2015 Sep 15. Li L, Deheragoda M, Lu Y, Gong J, Wang J
Hypothyroidism Associated with ATP8B1 Deficiency.
J Pediatr. 2015 Dec;167(6):1334-1339.e1. doi: 10.1016/j.jpeds.2015.08.037. Epub 2015 Sep 15., [PMID:26382629]
Abstract [show]
OBJECTIVE: To examine whether hypothyroidism is an extrahepatic feature of ATPase, aminophospholipid transporter, class I, type 8B, member 1 (ATP8B1) deficiency. STUDY DESIGN: Children with normal gamma-glutamyltransferase cholestasis (n = 47; 13 patients with ATP8B1 deficiency, 19 with ATP-binding cassette, subfamily B (MDR/TAP), member 11 (ABCB11) deficiency, and 15 without either ATP8B1 or ABCB11 mutations) were enrolled. Clinical information and thyroid function test results were retrospectively retrieved from clinical records and compared. Hypothyroidism was diagnosed by clinical-biochemistry criteria (thyroid function test results). RESULTS: Three out of 13 patients with ATP8B1 deficiency were diagnosed as hypothyroid and 2 as subclinically hypothyroid. The frequency of hypothyroidism and subclinical hypothyroidism was significantly higher than in patients with ABCB11 deficiency (5/13 vs 0/19, P = .006) and in patients without ATP8B1 or ABCB11 mutations (5/13 vs 0/15, P = .013). Thyroid function test results normalized after hormone replacement in all 5 patients, with no relief of cholestasis. CONCLUSIONS: As hypothyroidism can be another extrahepatic feature of ATP8B1 deficiency, thyroid function should be monitored in these patients.
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71 ABCB11 mutations and immunostaining in patients with ABCB11 mutations Patient ID Sex Nucleotide change Amino acid change Mutation origin BSEP expression GGT expression 244 Female c.145C>T/- p.Q49X/- Paternal/- Absent Normal 653 Female c.1197+1G>T/c.1197+1G>T -/- Paternal/maternal Not assessed Not assessed 727 Male c.2782C>T/c.3593A>G p.R928X/p.H1198R Maternal/paternal Not assessed Not assessed 889 Female c.3457C>T/c.3623A>G p.R1153C/p.Y1208C Paternal/maternal Absent Normal 919 Female c.1493T>C/c.1493T>C p.I498T/p.I498T Paternal/maternal Not assessed Not assessed 996 Male c.612-2_4 CTA>TT/- -/- Maternal/- Absent Normal 1022 Male c.212T>A/c.677C>T p.L71H/p.S226L Paternal/maternal Absent Normal 1131 Male c.409G>A/c.2216delC p.E137K/p.P740QfsX6 De novo/paternal Absent Normal 1134 Male c.1760C>G/c.3677G>C p.S587X/p.R1226P Maternal/paternal Absent Absent 1139 Female c.2935A>G/c.3746T>G p.N979D/p.L1249X Not assessed Not assessed Not assessed 1140 Male c.542G>T/c.1370_1372dupGTG p.R181I/p.V458dup Maternal/paternal Not assessed Not assessed 1219 Female c.872T>C/c.3691C>T p.V291A/p.R1231W Maternal/paternal Not assessed Not assessed 334* Female c.2944G>A/- p.G982R/- Not assessed Normal Normal 802* Female c.3458G>A/- p.R1153H/- Not assessed Not assessed Not assessed 862* Male c.634G>A/c.849A>C/c.1638G>T p.A212T/p.E283D/p.Q546H Maternal/maternal/de novo Not assessed Not assessed 864* Male c.1727A>G/- p.N576S/- Paternal/- Normal Normal 1165* Male c.1583T>C/c.1583T>C p.I528T/p.I528T Not assessed Not assessed Not assessed 1167* Male c.334A>G/c.3233T>C p.I112V/p.I1078T Not assessed Not assessed Not assessed 1242* Male c.2783G>A/- p.R928Q/- Not assessed Not assessed Not assessed Bold: Novel mutation.
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ABCB11 p.His1198Arg 26382629:71:346
status: NEW