PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-5 (5)
 

Clipboard (0)
None

Select a Filter Below

Journals
Year of Publication
Document Types
1.  Mutations in TJP2 cause progressive cholestatic liver disease 
Nature genetics  2014;46(4):326-328.
The elucidation of genetic causes of cholestasis has proved to be important in understanding the physiology and pathophysiology of the liver. Protein-truncating mutations in the tight junction protein 2 gene (TJP2) are shown to cause failure of protein localisation, with disruption of tight-junction structure leading to severe cholestatic liver disease. This contrasts with the embryonic-lethal knockout mouse, highlighting differences in redundancy in junctional complexes between organs and species.
doi:10.1038/ng.2918
PMCID: PMC4061468  PMID: 24614073
2.  ATP8B1 Gene Expression Is Driven by a Housekeeping-Like Promoter Independent of Bile Acids and Farnesoid X Receptor 
PLoS ONE  2012;7(12):e51650.
Background
Mutations in ATP8B1 gene were identified as a cause of low γ-glutamyltranspeptidase cholestasis with variable phenotype, ranging from Progressive Familial Intrahepatic Cholestasis to Benign Recurrent Intrahepatic Cholestasis. However, only the coding region of ATP8B1 has been described. The aim of this research was to explore the regulatory regions, promoter and 5′untranslated region, of the ATP8B1 gene.
Methodology/Principal Findings
5′Rapid Amplification of cDNA Ends using human liver and intestinal tissue was performed to identify the presence of 5′ untranslated exons. Expression levels of ATP8B1 transcripts were determined by quantitative reverse-transcription PCR and compared with the non-variable part of ATP8B1. Three putative promoters were examined in vitro using a reporter gene assay and the main promoter was stimulated with chenodeoxycholic acid. Four novel untranslated exons located up to 71 kb upstream of the previously published exon 1 and twelve different splicing variants were found both in the liver and the intestine. Multiple transcription start sites were identified within exon −3 and the proximal promoter upstream of this transcription start site cluster was proven to be an essential regulatory element responsible for 70% of total ATP8B1 transcriptional activity. In vitro analysis demonstrated that the main promoter drives constitutive ATP8B1 gene expression independent of bile acids.
Conclusions/Significance
The structure of the ATP8B1 gene is complex and the previously published transcription start site is not significant. The basal expression of ATP8B1 is driven by a housekeeping-like promoter located 71 kb upstream of the first protein coding exon.
doi:10.1371/journal.pone.0051650
PMCID: PMC3518472  PMID: 23251605
3.  Bile composition in Alagille Syndrome and PFIC patients having Partial External Biliary Diversion 
BMC Gastroenterology  2008;8:47.
Background
Partial External Biliary Diversion (PEBD) is a surgical intervention to treat children with Progressive Familial Intrahepatic Cholestasis (PFIC) and Alagille syndrome (AGS). PEBD can reduce disease progression, and examining the alterations in biliary lipid composition may be a prognostic factor for outcome.
Methods
Biliary lipid composition and the clinical course of AGS and PFIC patients were examined before and after PEBD.
Results
Pre-PEBD bile from AGS patients had greater chenodeoxycholic/cholic acid (CDCA/CA), bile salt, cholesterol and phospholipid concentrations than PFIC patients. AGS patients, and PFIC patients with familial intrahepatic cholestasis 1 (FIC1) genotype, responded better to PEBD than PFIC patients with bile salt export protein (BSEP) genotype. After successful PEBD, AGS patients have higher biliary lipid concentrations than PFIC patients and PEBD also increases biliary phospholipid concentrations in FIC1 patients.
Conclusion
Both AGS and FIC1 patients can benefit from PEBD, and preserved biliary phospholipid concentrations may be associated with better outcomes post-PEBD.
doi:10.1186/1471-230X-8-47
PMCID: PMC2585081  PMID: 18937870
4.  Differences in presentation and progression between severe FIC1 and BSEP deficiencies 
Journal of hepatology  2010;53(1):170-178.
Background & Aims
Progressive familial intrahepatic cholestasis (PFIC) with normal serum levels of gamma-glutamyltranspeptidase can result from mutations in ATP8B1 (encoding familial intrahepatic cholestasis 1 [FIC1]) or ABCB11 (encoding bile salt export pump [BSEP]). We evaluated clinical and laboratory features of disease in patients diagnosed with PFIC, who carried mutations in ATP8B1 (FIC1 deficiency) or ABCB11 (BSEP deficiency). Our goal was to identify features that distinguish presentation and course of these 2 disorders, thus facilitating diagnosis and elucidating the differing consequences of ATP8B1 and ABCB11 mutations.
Methods
A retrospective multi-center study was conducted, using questionnaires and chart review. Available clinical and biochemical data from 145 PFIC patients with mutations in either ATP8B1 (61 “FIC1 patients”) or ABCB11 (84 “BSEP patients”) were evaluated.
Results
At presentation, serum aminotransferase and bile salt levels were higher in BSEP patients; serum alkaline phosphatase values were higher, and serum albumin values were lower, in FIC1 patients. Elevated white blood cell counts, and giant or multinucleate cells at liver biopsy, were more common in BSEP patients. BSEP patients more often had gallstones and portal hypertension. Diarrhea, pancreatic disease, rickets, pneumonia, abnormal sweat tests, hearing impairment, and poor growth were more common in FIC1 patients. Among BSEP patients, the course of disease was less rapidly progressive in patients bearing the D482G mutation.
Conclusions
Severe forms of FIC1 and BSEP deficiency differed. BSEP patients manifested more severe hepatobiliary disease, while FIC1 patients showed greater evidence of extrahepatic disease.
doi:10.1016/j.jhep.2010.01.034
PMCID: PMC3042805  PMID: 20447715
cholestasis; genetics; transport protein; pediatrics; P-type ATPase; ATP binding cassette protein; ATP8B1; FIC1; ABCB11; BSEP
5.  Sinistral portal hypertension 
The Ulster medical journal  2006;75(3):175-177.
Sinistral, or left-sided, portal hypertension is a rare cause of upper gastrointestinal haemorrhage. There are many causes of sinistral portal hypertension. The primary pathology usually arises in the pancreas and results in compression of the pancreatic vein. This compression causes backpressure in the left portal venous system and subsequent gastric varices. Management is usually surgical to treat the underlying pathology and splenectomy to decompress the left portal venous system.
This paper presents four cases of sinistral portal hypertension followed by a literature review of the reported causes and management issues.
PMCID: PMC1891772  PMID: 16964806
Left-sided portal hypertension; Sinistral portal hypertension; Upper gastrointestinal haemorrhage; Gastric varices

Results 1-5 (5)