Gene/Protein Disease Symptom Drug Enzyme Compound
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Mutations in the human ferrochelatase gene (FECH) are the primary cause of the inborn disorder erythropoietic protoporphyria (EPP). While the majority of the EPP patients exhibit only photosensitivity, a small percentage of patients (approximately 2%) develop liver complications in addition to the cutaneous symptoms. In this study, the FECH gene of an Israeli EPP patient who suffered from EPP-related liver complications was sequenced. A splicing defect IVS10+1, g-->t, which is known to cause the deletion of exon 10, was identified in the index patient as well as in his symptomatic older sister and his asymptomatic mother. Like the other 12 known FECH mutations associated with liver complications, IVS10+1, g-->t is a "null-allele" mutation. Although the two siblings with overt EPP share an identical genotype with respect to both the mutation on one FECH allele and three intragenic single nucleotide polymorphisms, -251G, IVS1-23T, and IVS3-48C on the other allele, the sister of the index patient has so far shown no signs of liver involvement, suggesting that additional factors might account for the liver disease in EPP.
Blood Cells Mol Dis
PMID:A "null allele" mutation is responsible for erythropoietic protoporphyria in an Israeli patient who underwent liver transplantation: relationships among biochemical, clinical, and genetic parameters. 1273 48

Hepatitis C virus (HCV) is a major cause of liver disease throughout the world. The genome of this virus consists of approximately 10,000 bp and codes for 10 mature polypeptides. Genome sequence comparison has revealed the existence of six major genotypes and a large number of subtypes. The genotypes can be distinguished by whole genome or genome fragment sequencing, genotype specific amplification of a genomic region or PCR amplification, followed by hybridization or restriction digestion, among other methods. There is a markedly heterogeneous geographical distribution of the HCV genotypes in the world. Different genotypes have been linked to distinct clinical outcomes and to differences in the susceptibility of the virus to interferon treatment. Several studies have been conducted to determine the distribution of HCV genotypes among different groups of individuals in Brazil. Most of these studies indicate a higher prevalence of genotype 1, followed by genotypes 3 and 2. Differences in genotypes can affect serological detection as well as the clinical outcome of the disease and sensibility to interferon treatment. Further studies need to be conducted to determine the degree of differentiation of circulating HCV genotypes in different patient groups in Brazil.
Genet Mol Res 2003 Mar 31
PMID:Molecular epidemiology of the hepatitis C virus in Brazil. 1291 8

Cumulative evidence has shown that a delicate balance between serine proteases and their inhibitors is crucial for normal functioning of several biological pathways. The importance of proteases and their inhibitors is well documented in several human diseases. Among them, the best documented are hemophilia B, a genetic deficiency of the serine protease coagulation factor IX and serpinophathies. Alpha-1-antitrypsin deficiency (MIM 107400), is associated with early-onset emphysema and liver disease, while hereditary angioedema (HANE; MIM 106100) is caused by mutations in the C1 inhibitor, a serpin involved in the regulation of the complement cascade. Recently, two human genetic diseases of the central nervous system have been related to mutations in components of extracellular proteolytic systems. Here, we review the recent advances in this field.
Hum Mol Genet 2003 Oct 15
PMID:Extracellular proteases and their inhibitors in genetic diseases of the central nervous system. 1292 75

Despite the availability of safe and effective prophylactic vaccines, hepatitis B viral disease has remained a tenacious scourge, ranking ninth globally among all causes of mortality (up to 1 million deaths annually). Approximately 6% of the global population--more than 350 million people--have failed to resolve viral infection and become chronic carriers, eventually placing between 15 and 25% of such individuals at risk for end-stage liver disease. Until recently, the immunomodulator interferon-alpha and especially the nucleoside analog lamivudine (Epivir) have been the treatments of choice for chronic hepatitis B viral infection. However, the inexorable development of drug resistance to lamivudine has been a major clinical impediment to the long-term use of such treatment. Herein, the current and future diagnostic methods for early detection of emerging drug resistance to the hepatitis B virus is reviewed. Given the recent approval of adefovir dipivoxil (Hepsera) and the possibility that other nucleoside and nucleotide analogs could soon become part of the hepatitis B virus therapeutic arsenal, the clinical ramifications for co-ordinated use of diagnostic tests together with new antihepadenaviral agents for optimal patient management is also discussed.
Expert Rev Mol Diagn 2003 Sep
PMID:Early detection of hepatitis B drug resistance: implications for patient management. 1451 Jan 75

The TNFalpha receptor super-family consists of several members sharing a sequence homology in a unique function domain, the death domain, which is located in the intracellular portion of the receptor. These so-called death receptors, including Fas, TNF-R1 and TRAIL-R1/TRAIL-R2, are expressed on hepatocytes. When stimulated by their ligands, FasL, TNFalpha or TRAIL, respectively, the death receptors can activate multiple death domain-initiated apoptosis programs, including both extrinsic and intrinsic pathways. A cascade of caspases is activated, which cleave proteins important for the cell structure and function. Activation of the intrinsic pathway also leads to mitochondrial release of several apoptotic proteins and mitochondrial dysfunction, which kill the cell through both caspase-dependent and caspase-independent mechanisms. Death receptor-induced hepatocyte apoptosis contributes to the development of a number of liver diseases, including viral hepatitis, inflammatory hepatitis, Wilson's disease, alcoholic liver disease, endotoxiemia-induced liver failure and ischemia/reperfusion-induced liver damage. This article comprehensively reviews the mechanisms of induction and regulation of death receptor-initiated apoptosis in hepatocytes, examines how these molecular events affect our understanding of the pathogenesis of these diseases and further discusses the potential therapeutic application of the knowledge. We hope we can provide a cohesive and integrated perspective on the many aspects of these complicated processes.
Curr Mol Med 2003 Sep
PMID:Death receptor activation-induced hepatocyte apoptosis and liver injury. 1452 81

Among seven human hepatitis viruses (A to E, G and TT virus), hepatitis B (HBV) and C (HCV) viruses are able to persist in the host for years and principally contribute to the establishment of chronic hepatitis. During the course of persistent infection, continuous intrahepatic inflammation maintains a cycle of liver cell destruction and regeneration that often terminates in hepatocellular carcinoma (HCC). While the expression and retention of viral proteins in hepatocytes may influence the severity and progression of liver disease, the mechanisms of liver injury in viral hepatistis are defined to be due not to the direct cytopathic effects of viruses, but to the host immune response to viral proteins expressed by infected hepatocytes. In the process of liver injury, hepatocellular death (apoptosis) induced by the proapoptotic molecules of T cells activated following antigen recognition triggers a cascade of antigen nonspecific effector systems and causes necroinflammatory disease. Accordingly, the regulation of the immune response, e.g., via the cell death pathways, in chronically infected patients should prevent the development of HCC.
Curr Mol Med 2003 Sep
PMID:Mechanisms of viral hepatitis induced liver injury. 1452 85

Erythropoietic protoporphyria (EPP) is characterized by excess accumulation of protoporphyrin, which is due to deficient activity of the enzyme ferrochelatase (FECH). This results in photosensitivity and in some patients liver disease which may necessitate liver transplantation. The aim of this study was to delineate the abnormalities in the FECH gene which cause phenotypic expression in EPP. We identified 43 individuals from 25 North American families with EPP who were heterozygous for various FECH mutations, but the mutations did not adequately explain the variable phenotype. We also examined the presence of an intron polymorphism (IVS3-48c) in the FECH gene which was shown to cause the formation of aberrantly spliced FECH mRNA. FECH DNA analysis demonstrated that 94% of 31 symptomatic individuals with FECH mutations were heterozygous for IVS3-48c, whereas 12 asymptomatic individuals with FECH mutations were homozygous for IVS3-48t. Haplotype analysis in four families showed that symptomatic members had the IVS3-48c polymorphism in the non-mutant FECH allele. Sequencing of the proximal FECH gene promoter showed no additional changes which might affect gene expression. The levels of normal FECH mRNA, measured by relative quantitative RT-PCR, and FECH enzyme activity were correspondingly lower in the cultured lymphoblasts of family members with the IVS3-48c polymorphism. These results indicate that symptomatic disease in most North American patients with EPP is explained by the inheritance of a mutation in one FECH allele which causes a structural alteration in the protein, together with a low expressing non-mutant FECH allele which is caused by the IVS3-48c polymorphism.
Mol Genet Metab
PMID:Genotypic determinants of phenotype in North American patients with erythropoietic protoporphyria. 1456 69

Retinoids influence the pathogenesis of alcohol liver disease (ALD). To analyze the impact of retinoid X receptor alpha (RXRalpha) on ALD, alcohol-induced hepatotoxicity was studied using mice fed ethanol intragastrically for 25 days. Alcohol-induced microvesicular fat around the central vein and drug-induced morphological changes (loss of rough endoplasmic reticulum, pinkish cytoplasm, and enlarged hepatocyte) in the pericentral area were observed in the liver of wild-type mice. In the hepatocyte RXRalpha-deficient mouse liver, alcohol induced fat accumulation, mitosis, acute inflammation, and necrosis. The histology score after alcohol treatment was significantly higher in mutant mice than in wild-type mice. However, drug-induced morphological changes were not apparent in alcohol-treated hepatocyte RXRalpha-deficient mice. Northern analysis showed that the basal and alcohol-induced CYP2B, CYP2A, and CYP3A mRNA levels were lower in hepatocyte RXRalpha-deficient mice than in wild-type mice, which in turn may protect mutant mice from morphological changes. Compared with wild-type mice, hepatocyte RXRalpha-deficient mice have significant lower levels of S-adenosylmethionine and glutathione, which is further reduced after alcohol treatment, and that may account for severe liver injury induced by alcohol. The overall result suggests an important role of RXRalpha in preventing alcohol-induced liver injury.
Exp Mol Pathol 2003 Dec
PMID:RXRalpha-regulated liver SAMe and GSH levels influence susceptibility to alcohol-induced hepatotoxicity. 1461 10

A mass screening in 1990 of H town in Japan demonstrated a high prevalence of hepatitis C virus (HCV) infection in our previous studies. The purpose of the present study was to evaluate the prognosis and natural history of liver disease among the same residents after 12 years. Of 509 residents, 69 people had died, and 55 people had moved to other regions. In all, 139 persons of the remaining 385 residing in H town were examined for liver function tests, antibodies to HCV (anti-HCV), serum HCV RNA, and hepatitis B virus surface antigen (HBsAg). The data of 14 of these 385 people were collected from medical records. The cause of death of the 69 individuals was investigated. The prognosis of liver disease could be clarified after 12 years in 222 of the 509 residents. Most of the residents with liver disease had an advanced stage of disease. Of the 69 persons who died, the mortality rate caused by liver cirrhosis or hepatocellular carcinoma (HCC) was 44 and 53%, respectively, among 25 persons with positive anti-HCV, and 19 with positive HCV RNA. One person with positive HBsAg died of HCC. Persons with chronic HCV or HBV infection had significantly higher mortality rates from liver cirrhosis and HCC than those without infection (P<0.00001). The present study suggests that early detection and treatment for HCC should be carried out as HCV carriers age. Furthermore, persistent HCV carriers should receive therapy for suppression of the development of HCC. The eradication of HCC should be considered a national goal.
Int J Mol Med 2004 Feb
PMID:A cohort study of chronic liver disease in an HCV hyperendemic area of Japan: a prospective analysis for 12 years. 1471 32

Autosomal recessive polycystic kidney disease (ARPKD) is a severe form of inherited childhood nephropathy ( approximately 1:20,000 live births) characterized by fusiform dilatation of collecting ducts and congenital hepatic fibrosis. Up to 30% die as neonates due to respiratory insufficiency and the majority of surviving infants develop hypertension. Progression to end stage renal disease occurs in 20-45% of cases within 15 years but a proportion maintain renal function into adulthood where complications of liver disease predominate. The ARPKD disease gene, PKHD1, has recently been identified through analysis of an orthologous animal model, the PCK rat. PKHD1 is a large gene ( approximately 470 kb) with 67 exons from which multiple transcripts may be generated by alternative splicing. It is highly expressed in kidney, with lower levels in liver and pancreas. The ARPKD protein, fibrocystin (4074 aa and 447 kDa), is predicted to be an integral membrane, receptor-like protein containing multiple copies of an Ig-like domain (TIG). Fibrocystin is localized to the branching ureteric bud, collecting and biliary ducts, consistent with the disease phenotype, and often absent from ARPKD tissue. In common with other PKD-related proteins, fibrocystin is localized to the primary cilia of renal epithelial cells, reinforcing the link between ciliary dysfunction and cyst development. Screens of PKHD1 have revealed 119 different mutations of various types spread throughout the gene. Several ancestral changes have been described, some localized to specific geographic populations. The majority of patients are compound heterozygotes and preliminary genotype/phenotype studies associate two truncating mutations with severe disease. The complexities of PKHD1, marked allelic heterogeneity and high level of missense changes complicate gene-based diagnostics.
Mol Genet Metab 2004 Feb
PMID:Molecular genetics of autosomal recessive polycystic kidney disease. 1474 Nov 87


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