ABCB4 p.Gln1181*
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[hide] ABCB4 mutations in adult patients with cholestatic... J Gastroenterol. 2015 Sep 1. Degiorgio D, Crosignani A, Colombo C, Bordo D, Zuin M, Vassallo E, Syren ML, Coviello DA, Battezzati PM
ABCB4 mutations in adult patients with cholestatic liver disease: impact and phenotypic expression.
J Gastroenterol. 2015 Sep 1., [PMID:26324191]
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BACKGROUND: The ABCB4 gene encodes the MDR3 protein. Mutations of this gene cause progressive familial intrahepatic cholestasis type 3 (PFIC3) in children, but their clinical relevance in adults remains ill defined. The study of a well-characterized adult patient series may contribute to refining the genetic data regarding cholangiopathies of unknown origin. Our aim was to evaluate the impact of ABCB4 mutations on clinical expression of cholestasis in adult patients. METHODS: We consecutively evaluated 2602 subjects with hepatobiliary disease. Biochemical evidence of a chronic cholestatic profile (CCP) with elevated serum gamma-glutamyltransferase activity or diagnosis of intrahepatic cholestasis of pregnancy (ICP) and juvenile cholelithiasis (JC) were inclusion criteria. The personal/family history of additional cholestatic liver disease (PFH-CLD), which includes ICP, JC, or hormone-induced cholestasis, was investigated. Mutation screening of ABCB4 was carried out in 90 patients with idiopathic chronic cholestasis (ICC), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), ICP, and JC. RESULTS: Eighty patients had CCP. PSC and ICC patients with PFH-CLD had earlier onset of disease than those without it (p = 0.003 and p = 0.023, respectively). The mutation frequency ranged from 50 % (ICP, JC) to 17.6 % (PBC). Among CCP patients, presence or absence of PFH-CLD was associated with ABCB4 mutations in 26.8 vs 5.1 % (p = 0.013), respectively; in the subset of ICC and PSC patients, the corresponding figures were 44.4 vs 0 % (p = 0.012) and 28.6 vs 8.7 % (p = 0.173). CONCLUSIONS: Cholangiopathies attributable to highly penetrant ABCB4 mutant alleles are identifiable in a substantial proportion of adults that generally have PFH-CLD. In PSC and ICC phenotypes, patients with MDR3 deficiency have early onset of disease.
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72 CCP chronic cholestatic profile, NCCP patients without chronic cholestatic profile, PBC primary biliary cirrhosis, PSC primary sclerosing cholangitis, ICP intrahepatic cholestasis of pregnancy, JC juvenile cholelithiasis, AIH autoimmune hepatitis, OS overlap syndrome between AIH and PBC or PSC, ICC idiopathic chronic cholestasis; a with (n = 14) or without (n = 23) other cholangiopathies in the personal/family history (see ''Methods``), b with (n = 9) or without (n = 15) other cholangiopathies in the personal/family history (see ''Methods``), c with (n = 2) or without (n = 2) other cholangiopathies in the personal/family history (see ''Methods``) Table 1 Heterozygous nucleotide changes within the ABCB4 gene identified in 18 adult patients with cholangiopathies and predicted impact on MDR3 Nucleotide changea Involved regions Type of mutation Mutant protein Location on the protein Degree of conservationb Reference genotypesc c.217C[G Exon 4 Missense p.(L73V) TM1 B 7, 21 c.475C[T Exon 6 Non-sense p.(R159X) ICD1 X 8, 14 c.523A[G Exon 6 Missense p.(T175A) ICD1 B 18, 21, 8, 25, 14 c.959C[T Exon 9 Missense p.(S320F) TM5 B 18, 8, 14 c.1529A[G Exon 13 Missense p.(N510S) N-ter NBD B 14 c.1531G[A Exon 13 Missense p.(A511T) N-ter NBD A 8, 14 c.1633C[T Exon 14 Missense p.(R545C) N-ter NBD A 21 c.1769G[A Exon 15 Missense p.(R590Q) N-ter NBD A 8, 13, 14, 25 c.1846G[A Exon 15 Missense p.(E616K) N-ter NBD A This study (JN392435) c.1901G[A Exon 16 Missense p.G634E Linker region B This study (JN392436) c.2431G[C Exon 20 Missense p.(G811R) ICD4 A This study (JN392437) c.2544_2548delATCAT Exon 21 Frameshift p.(S849YfsX24) TM9 X This study (JN392438) c.2576T[G Exon 21 Missense p.(L859W) TM10 B This study (JN392439) c.2844G[C Exon 23 Missense p.(M948I) TM11 B This study (JN392440) c.3541C[T Exon 27 Non-sense p.(Q1181X) C-ter NBD X This study (JN392441) TM transmembrane domain, ICD intracellular domain, N-ter NBD N-terminal nucleotide binding domain, C-ter NBD C-terminal nucleotide binding domain a The mutations were numbered according to GenBank NM_018849 and NP_061337.
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ABCB4 p.Gln1181* 26324191:72:1820
status: NEW141 p.(S320F) Yes JC/HIC 16 F PSC 55 p.(R590Q) Yes 7 M ICC 16 p.(R545C) Yes JC Father of patient 72 18a,b M ICC 34 p.(S849YfsX24) Yes JC Family history of JC 49 F ICC 32 p.(G811R) Yes ICP/JC Family history of JC 72 F ICC 12 p.(R545C) Yes ICP/JC Daughter of patient 72 68 F PBC 31 p.(T175A) No ICP 73a F PBC 58 p.(R590Q) Yes JC 75 F PBC 64 p.(L73V) No JC 38 M JC 18 p.(S320F) No 55 M JC 26 p.(Q1181X) Yes 81 F JC 39 p.(R590Q) ?
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ABCB4 p.Gln1181* 26324191:141:388
status: NEW