Heterozygous non-sense mutation of the MDR3 gene in familial intrahepatic cholestasis of pregnancy

Jacquemin, Emmanuel; Cresteil, Danièle; Manouvrier, Sylvie; Boute, Odile; Hadchouel, Michelle

doi:10.1016/s0140-6736(05)77221-4

Cited by 355 publications

(233 citation statements)

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“…For example, although mutations in ATP8B1 and ABCB11 have been reported for subjects with severe forms of PFIC with low serum levels of gamma-glutamyltranspeptide (γGTP), specific mutations within each gene have also been associated with milder clinical phenotypes. 15,17,[24][25][26][27][28][29][30] Equally notable is the phenotypic pleomorphism of mutations in ABCB4, which ranges from high γGTP-PFIC (or PFIC3), to intrahepatic cholestasis of pregnancy, and gallstone formation, 19,25,[31][32][33][34][35][36] and an array of mutations in JAG1 in subjects with liver and/or non-hepatic malformations (e.g. : cardiovascular and renal defects).…”

Section: Discussionmentioning

confidence: 99%

Novel Resequencing Chip Customized to Diagnose Mutations in Patients With Inherited Syndromes of Intrahepatic Cholestasis

et al. 2007

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Background and Aims-Inherited syndromes of intrahepatic cholestasis commonly result from mutations in the genes SERPINA1 (α1-antitrypsin deficiency), JAG1 (Alagille syndrome), ATP8B1 (Progressive Familial Intrahepatic Cholestasis type 1/PFIC1), ABCB11 (PFIC2), and ABCB4 (PFIC3). However, the large gene sizes and lack of mutational hotspots make it difficult to survey for disease-causing mutations in clinical practice. Here, we aimed to develop a technological tool that reads out the nucleotide sequence of these genes rapidly and accurately.

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Section: Discussionmentioning

confidence: 99%

Novel Resequencing Chip Customized to Diagnose Mutations in Patients With Inherited Syndromes of Intrahepatic Cholestasis

et al. 2007

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“…Mutations in MDR3 have been reported in patients with progressive familial intrahepatic cholestasis type 3 (PFIC3) with high serum ␥-glutamyltransferase activity, 41,42 intrahepatic cholestasis of pregnancy (ICP), 25,43,44 and "adolescent cholelithiasis with recurrent intrahepatic cholestasis of pregnancy followed by adulthood biliary cirrhosis". 44 Almost all mutations found in patients with PFIC3 and ICP were frame-shift mutations due to deletion or nonsense mutations, introducing stop codons downstream and leading to the production of inactive truncated proteins.…”

mentioning

confidence: 99%

“…Interestingly, patients with PFIC3 and ICP, who had these frame-shift or nonsense mutations, showed similar clinical manifestations, such as inheritance, early onset in childhood, and clinical severity. 25,[41][42][43] On the other hand, the patient with "adolescent cholelithiasis with intrahepatic cholestasis of pregnancy followed by adulthood biliary cirrhosis" had a heterozygous missense mutation of MDR3 and showed less severe clinical manifestations with middle-aged onset. The relatively mild MDR3 dysfunction due to missense mutations allowed for a slower progression of biliary cirrhosis.…”

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confidence: 99%

Single-nucleotide polymorphism analysis of the multidrug resistance protein 3 gene for the detection of clinical progression in Japanese patients with primary biliary cirrhosis

Ohishi¹,

Nakamura²,

Iio³

et al. 2008

Hepatology

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Primary biliary cirrhosis (PBC) is a multifactorial disease in which genetic factors rather than environmental factors may predominantly contribute to the pathogenesis. In order to identify the genetic determinants of the disease severity and progression of PBC, we examined an association of seven tag single-nucleotide polymorphisms (SNPs) in the multidrug resistance protein 3 (MDR3/ABCB4) gene in 148 Japanese PBC patients and 150 age-and sex-matched healthy control subjects. SNPs were detected via polymerase chain reaction (PCR) restriction fragment length polymorphism and PCR direct DNA sequencing methods. Subsequently, haplotypes were constructed from three tag SNPs (rs31658, rs31672, and rs1149222) that were significantly associated with progression of PBC. Logistic regression analyses revealed that a Hap 2 haplotype and its homozygous diplotype, Hap 2/Hap 2, in MDR3 were closely associated with the susceptibility to jaundice-type progression of PBC [P ‫؍‬ 0.004, odds ratio (

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“…Existen otros tipos de mutación localizada en diferentes segmentos del cromosoma 7 en las que la inmunotinción es normal, pero probablemente el MDR3 identificado carece de actividad transportadora 14 . Por esta razón la técnica de inmunotinción es de poco valor en el diagnóstico de esta enfermedad 15 .…”

Section: Discussionunclassified

Colestasia Intrahepática Familiar Progresiva Tipo 3: Presentación de Casos Clínicos y Actualización de Tema

2009

Rev. chil. pediatr.

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Familial Intrahepatic Cholestasis (FIC) includes a heterogeneous group of recessive autosomic alterations characterized by hepatocellular cholestasis secondary to the interruption of the normal process of synthesis of bilis. Objective: A description of FIC in 3 of 5 children of an index family. Clinical case: a 5 y.o. child with hepatosplenomegaly increased serum hepatic enzymes and biliary acids. Abdominal echography showed alterations compatible with hepatic fibrosis. Biopsy showed bridge fibrosis, duct proliferation, minimal chronic cholestasis. These findings were compatible with a phenotype FIC-3 with elevate levels of Gamma-glutamyl transferase. A mutation of MDR3 gene is responsible for the absence of biliary phospholipids, allowing a detergent effect of biliary acids upon the duct epithelium, developing cholangitis, fibrosis and later cirrhosis. Among four brothers, the mutation was found in two twin sisters. Three affected brothers were treated with ursodeoxicolic acid, 30 mg/Kg. Excellent results were obtained in the twin girls not in the index boy. The clinical expression of this illness is variable, and an elevation of aminotransferase must call attention to this possibility. Early diagnostic and treatment could avoid the development of hepatic damage and cirrhosis.

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Heterozygous non-sense mutation of the MDR3 gene in familial intrahepatic cholestasis of pregnancy

Cited by 355 publications

References 4 publications

Novel Resequencing Chip Customized to Diagnose Mutations in Patients With Inherited Syndromes of Intrahepatic Cholestasis

Novel Resequencing Chip Customized to Diagnose Mutations in Patients With Inherited Syndromes of Intrahepatic Cholestasis

Single-nucleotide polymorphism analysis of the multidrug resistance protein 3 gene for the detection of clinical progression in Japanese patients with primary biliary cirrhosis

Colestasia Intrahepática Familiar Progresiva Tipo 3: Presentación de Casos Clínicos y Actualización de Tema

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