ABCMdb

ABCB4 p.Tyr1171Cys

Predicted by SNAP2:	A: D (80%), C: D (80%), D: D (91%), E: D (85%), F: N (53%), G: D (85%), H: D (85%), I: D (75%), K: D (91%), L: D (75%), M: D (75%), N: D (91%), P: D (91%), Q: D (91%), R: D (91%), S: D (85%), T: D (85%), V: D (80%), W: D (75%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: 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,

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[hide] Analysis of gene mutations in children with choles... J Pediatr Gastroenterol Nutr. 2010 Oct;51(4):488-93. Matte U, Mourya R, Miethke A, Liu C, Kauffmann G, Moyer K, Zhang K, Bezerra JA
Analysis of gene mutations in children with cholestasis of undefined etiology.
J Pediatr Gastroenterol Nutr. 2010 Oct;51(4):488-93., [PMID:20683201]

Abstract [show]
BACKGROUND: The discovery of genetic mutations in children with inherited syndromes of intrahepatic cholestasis allows for diagnostic specificity despite similar clinical phenotypes. Here, we aimed to determine whether mutation screening of target genes could assign a molecular diagnosis in children with idiopathic cholestasis. PATIENTS AND METHODS: DNA samples were obtained from 51 subjects with cholestasis of undefined etiology and surveyed for mutations in the genes SERPINA1, JAG1, ATP8B1, ABCB11, and ABCB4 by a high-throughput gene chip. Then, the sequence readouts for all 5 genes were analyzed for mutations and correlated with clinical phenotypes. Healthy subjects served as controls. RESULTS: Sequence analysis of the genes identified 14 (or 27%) subjects with missense, nonsense, deletion, and splice site variants associated with disease phenotypes based on the type of mutation and/or biallelic involvement in the JAG1, ATP8B1, ABCB11, or ABCB4 genes. These patients had no syndromic features and could not be differentiated by biochemical markers or histopathology. Among the remaining subjects, 10 (or approximately 20%) had sequence variants in ATP8B1 or ABCB11 that involved only 1 allele, 8 had variants not likely to be associated with disease phenotypes, and 19 had no variants that changed amino acid composition. CONCLUSIONS: Gene sequence analysis assigned a molecular diagnosis in 27% of subjects with idiopathic cholestasis based on the presence of variants likely to cause disease phenotypes.

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No. Sentence Comment
95 Gene sequence variants likely to cause disease phenotypes in subjects with CUEÃ Subject Age g-GTP Liver biopsy Gene Variant (allele frequency, if new) References CUE-1 1 mo 458 Not done JAG1 p.C251X New CUE-2 3.5 mo 632 Cholestasis, GCT, small bile ducts JAG1 p.V1086E New CUE-3 1.5 y 400 Pseudoacinar transformation, portal inflammation, moderate fibrosis ABCB4 p.Q945X/p.Y1171C (0%) New/new CUE-4 26 y 47 Cytoplasmic and canalicular cholestasis, portal fibrosis ATP8B1 p.N45T/p.I1050K (0%) (20)/new CUE-5 3.5 y 40 Electron microscopy consistent with Byler disease ATP8B1 c.1819þ1g>a/p.R930X Newy /(27) CUE-6 1.5 y 20 Canalicular cholestasis, portal inflammation ATP8B1 g.92918del565/g.92918del565 (13) CUE-7 1 y 44 GCT, portal inflammation, and fibrosis ABCB11 p.R928X/p.R1090X (13,28) CUE-8 2.5 y 62 Canalicular cholestasis, periportal inflammation, portal fibrosis ABCB11 p.I541T/p.I541T (12) CUE-9 5.5 y 54 Cholestasis, GCT, ductopenia, bridging fibrosis ABCB11 p.E297G/E297G (22) CUE-10 11 y 9 Minimal cholestasis; insufficient representation of portal tracts ABCB11 p.R948C/p.E1223D (0%) (12)/new CUE-11 6 mo 64 Cytoplasmic and canalicular cholestasis, GCT, fibrosis ABCB11 p.C68Y (0%)/p.R832H (0%) New, new CUE-12 2 y 42 Not done ABCB11 c.3770delA/c.3770delA Newy /newy CUE-13 19 y 29 Marked cholestasis, portal fibrosis. Login to comment
64 This patient had 1 sequence variant that introduced a premature stop codon (p.Q945X) in ABCB4 and a second missense variant predicted to be damaging to the encoded protein (p.Y1171C; Table 3 and Fig. 2), which together are likely to result in MDR3 deficiency. Login to comment