MDR3 mutations associated with intrahepatic and gallbladder cholesterol cholelithiasis: an update

Mbongo-Kama, Elvire; Harnois, Florence; Mennecier, D; Leclercq, E; Burnat, P.; Ceppa, F.

doi:10.1016/s1665-2681(19)31919-2

Cited by 8 publications

(3 citation statements)

References 22 publications

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“…ABCB1 extrudes a wide variety of drugs and is responsible for multidrug resistance of cancer cells. Since the identification of ABCB4‐associated diseases, a growing number of mutations have been reported 16–18. However, it remains unclear how mutations identified from genetics studies affect ABCB4 expression.…”

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confidence: 99%

Correlates of screening sigmoidoscopy use among men in a large nonprofit health plan

Haque

Quinn

Habel

et al. 2007

Cancer

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Although basic research on human embryonic stem cells (hESCs) at the laboratory bench has progressed with enviable speed there has been little head way in terms of its clinical application. A look at the Internet however shows several stem cell clinics worldwide offering direct transplantation of undifferentiated hESCs to patients for the cure of a variety of diseases before bona fide evidence‐based results can be demonstrated from large controlled studies. This raises concern because reliable protocols have to be first developed to resolve the three major hurdles delaying clinical trials such as inadequate cell numbers, immunorejection and tumorigenesis. Cell expansion methods using bioreactors, rotary culture and mitotic agents have now been developed to generate stem cell derivatives in large numbers. The problem of immunorejection can now be overcome with the development of indirect and direct reprogramming protocols to personalize tissues to patients (human induced pluripotent stem cells, hiPSCs; nuclear transfer stem cells, NTSCs; induced neuronal cells, iN). However, hESC, hiPSC, and NTSCs being pluripotent have the disadvantage of teratoma formation in vivo which has to be carefully addressed so as to provide safe stem cell based therapies to the patient. This review addresses the issue of tumorigenesis and discusses approaches by which this concern may be overcome and at the same time emphasizes the need to concurrently explore alternative stem cell sources that do not confer the disadvantages of pluripotency but are widely multipotent so as to yield safe desirable tissues for clinical application as soon as possible. J. Cell. Biochem. 111: 769–781, 2010. © 2010 Wiley‐Liss, Inc.

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confidence: 99%

Correlates of screening sigmoidoscopy use among men in a large nonprofit health plan

Haque

Quinn

Habel

et al. 2007

Cancer

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“…Correlation between MDR3 gene mutation and PNAC in premature infants will become a prominent research topic. Studies have demonstrated that exon 6 of MDR3 gene mutations is associated with cholestasis ( 35 , 36 ). The aim of the present study was to investigate the correlation between exon 6 of MDR3 and premature infants with PNAC.…”

Section: Discussionmentioning

confidence: 99%

Correlation between mutation of MDR3 gene exon 6 and parenteral nutrition-associated cholestasis of preterm infants

Yang

Liu

2014

Experimental and Therapeutic Medicine

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The aim of this study was to investigate the association between the mutation of multidrug resistance 3 (MDR3) exon 6 and parenteral nutrition-associated cholestasis (PNAC) in preterm infants. A total of 41 preterm infants with PNAC formed the experimental group, and 56 preterm infants receiving total parenteral nutrition (TPN) for >14 days but without cholestasis formed the control group. Genomic DNA was extracted from peripheral venous blood leukocytes. Polymerase chain reaction was used to amplify exon 6 of the MDR3 gene. The target band of MDR3 gene exon 6 was identified in all blood samples from all cases. We identified five cases with C. 504 C>T heterozygous mutations of exon 6 of the MDR3 gene and 14 cases with C. 504 C>T homozygous mutations in the experimental group. In the control group, we identified seven cases with the C. 504 C>T homozygous mutation and six cases with the C. 504 C>T heterozygous mutation. The distribution of the T/C allele frequency of C. 504 in exon 6 of the MDR3 gene between the experimental group and control group was statistically significant (P<0.05). Further analysis revealed the odds ratio of the T/C allele frequency of the C. 504 mutation in exon 6 of the MDR3 gene between the experimental group and control group to be 0.316. Point mutation C. 485 T>A was detected in one case in the experimental group. The C. 504 C>T and C. 485 T>A MDR3 mutations in exon 6 are possibly responsible for the development of PNAC in infants. C. 504 C>T may not be the only risk factor of neonatal PNAC. In order to further confirm the association between exon 6 of the MDR3 gene and PNAC, a large-sample multicenter study should be carried out.

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“…Moreover, in a group of Japanese patients with a significant reduction in expression of ABCB4 mRNA and protein in the liver, the concentration of phospholipids in gallbladder bile is dramatically decreased such that they suffer from cholesterol gallstones and cholesterol-rich brown pigment stones in the intrahepatic bile ducts [ 118 , 119 ]. These studies indicate that reduced phospholipid concentrations in bile caused by either ABCB4 mutations and variations or reduced expression can promote the formation of intrahepatic stones, regardless of whether the patient is European or Asian [ 112 , 120 , 121 , 122 ]. This concept is further supported by findings from another study revealing that a subgroup of patients with cholesterol microlithiasis show a significant reduction in mean percent molar concentrations of phospholipids in duodenal bile [ 123 ].…”

Section: Role Of Abcb4 In the Pathogenesis Of Low Phospholipid-associ...mentioning

confidence: 99%

Genetic Analysis of ABCB4 Mutations and Variants Related to the Pathogenesis and Pathophysiology of Low Phospholipid-Associated Cholelithiasis

Wang

Portincasa

Liu

et al. 2022

Genes

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Clinical studies have revealed that the ABCB4 gene encodes the phospholipid transporter on the canalicular membrane of hepatocytes, and its mutations and variants are the genetic basis of low phospholipid-associated cholelithiasis (LPAC), a rare type of gallstone disease caused by a single-gene mutation or variation. The main features of LPAC include a reduction or deficiency of phospholipids in bile, symptomatic cholelithiasis at <40 years of age, intrahepatic sludge and microlithiasis, mild chronic cholestasis, a high cholesterol/phospholipid ratio in bile, and recurrence of biliary symptoms after cholecystectomy. Needle-like cholesterol crystals, putatively “anhydrous” cholesterol crystallization at low phospholipid concentrations in model and native bile, are characterized in ABCB4 knockout mice, a unique animal model for LPAC. Gallbladder bile with only trace amounts of phospholipids in these mice is supersaturated with cholesterol, with lipid composition plotting in the left two-phase zone of the ternary phase diagram, consistent with “anhydrous” cholesterol crystallization. In this review, we summarize the molecular biology and physiological functions of ABCB4 and comprehensively discuss the latest advances in the genetic analysis of ABCB4 mutations and variations and their roles in the pathogenesis and pathophysiology of LPAC in humans, based on the results from clinical studies and mouse experiments. To date, approximately 158 distinct LPAC-causing ABCB4 mutations and variants in humans have been reported in the literature, indicating that it is a monogenic risk factor for LPAC. The elucidation of the ABCB4 function in the liver, the identification of ABCB4 mutations and variants in LPAC patients, and the exploration of gene therapy for ABCB4 deficiency in animal models can help us to better understand the cellular, molecular, and genetic mechanisms underlying the onset of the disease, and will pave the way for early diagnosis and prevention of susceptible subjects and effective intervention for LPAC in patients.

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MDR3 mutations associated with intrahepatic and gallbladder cholesterol cholelithiasis: an update

Cited by 8 publications

References 22 publications

Correlates of screening sigmoidoscopy use among men in a large nonprofit health plan

Correlates of screening sigmoidoscopy use among men in a large nonprofit health plan

Correlation between mutation of MDR3 gene exon 6 and parenteral nutrition-associated cholestasis of preterm infants

Genetic Analysis of ABCB4 Mutations and Variants Related to the Pathogenesis and Pathophysiology of Low Phospholipid-Associated Cholelithiasis

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