Gene/Protein Disease Symptom Drug Enzyme Compound
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The half-century of lipophobia in the United States may be abating with some return of sanity on the discussion of health and dietary fat [Taubes, 2001]. The youngest victims of this collective, decades long madness are those infants deprived for one reason or another of breast milk. They are unable to speak for themselves at a time of greatest need for cholesterol during growth, the most critical period of myelination of central and peripheral nervous system, formation of bone and bile, and of every steroid hormone. Some of the commercial formulas they are fed contain only 1 or 2 mg of cholesterol per 100 g edible portion contrasted with almost 14 mg in breast milk. One can only hope that the confidence in their endogenous ability to synthesize sufficient amounts of cholesterol is not misplaced. Pediatric pathology has learned that when this endogenous ability fails during embryogenesis on the basis of mutations in the postsqualene biosynthesis of cholesterol, a startling variety of developmental pathology may present itself ranging from lethal forms of "idiopathic" hydrops, microcephaly with cerebral dysgenesis and dysmyelinization, agenesis of corpus callosum, cerebellar vermis dysgenesis, cataracts, cleft palate, many different forms of congenital heart defect, pyloric stenosis and/or Hirschsprung dysganglionosis, adrenal (cortical) insufficiency, cholestatic liver disease, limb malformations, and genital ambiguity in genetic males. Population genetic considerations suggest a hypothetical birth prevalence of the RSH (so-called Smith-Lemli-Opitz) syndrome, the commonest of these Garrodian errors of cholesterol biosynthesis, of 1/2500; since only about 1/15,000 to 1/20,000 homozygotes are liveborn and biochemically confirmed, over 80% prenatal or perinatal mortality must occur and deserves the most discerning of services from birth attendants, perinatologists, neonatologists, and fetal/pediatric pathologists. An easy, reliable, economical biochemical test for the presence of 7-dehydrocholesterol is available and the commonest mutation, the IVS8-1G-->C mutation, is quickly and reliably tested for molecularly. Thus, the successful diagnosis, even after death, will contribute substantially to correct genetic counseling, carrier detection, prenatal diagnosis, and treatment in those known to be affected prenatally andplanned to be liveborn. Thus, developmental pathology plays an integral, vital role in preventive medicine.
Pediatr Pathol Mol Med
PMID:Cholesterol and development: the RSH ("Smith-Lemli-Opitz") syndrome and related conditions. 1194 34

Hepatitis B virus (HBV) is at the origin of severe liver diseases like chronic active hepatitis, liver cirrhosis and hepatocellular carcinoma. There are some groups of patients with high risk of generation of HBV mutants: infected infants, immunosuppressed individuals (including hemodialysis patients), patients treated with interferon and lamivudine for chronic HBV infection. These groups are the target for molecular investigations reviewed in this paper. The emergence of lamivudine- or other antiviral-resistant variants, rises concern regarding long term use of these drugs. Infection or immunization with one HBV subtype confers immunity to all subtypes. However, reinfection or reactivation of latent HBV infection with HBV mutants have been reported in patients undergoing transplant and those infected with HIV. Mutations of the viral genome which are not replicative incompetent can be selected in further course of infection or under prolonged antiviral treatment and might maintain the liver disease. Four open reading frames (ORF) which are called S-gene, C-gene, X-gene and P-gene were identified within the HBV genome. Mutations may affect each of the ORFs. Mutated S-genes were described to be responsible for HBV-infections in successfully vaccinated persons, mutated C-genes were found to provoke severe chronic liver diseases, mutated X-genes could cause serious medical problems in blood donors by escaping the conventional test systems and mutated P-genes were considered to be the reason for chemotherapeutic drug resistance. This paper reviews molecular, immunological and clinical aspects of the HBV mutants.
J Cell Mol Med
PMID:Molecular, immunological and clinical properties of mutated hepatitis B viruses. 1200 75

Gene therapy is an attractive approach for the treatment of liver disease. We demonstrate that a so-called third-generation human immunodeficiency virus (HIV)-derived vector system can govern the efficient delivery, integration, and stable expression of a transgene into primary human hepatocytes in the complete absence of cell division. We also show that rodent hepatocytes exhibit a significant degree of resistance to HIV vector-mediated transduction, a phenotype that is particularly pronounced in murine hepatocytes and that results from a block in the immediate-early phase of infection. We finally describe a methodology, that allows very high rates of transduction through minimal in vitro manipulation, in which hepatocytes are kept in suspension and reimplanted within a few hours of harvest with a fully preserved engraftment potential. These results have immediate implications for the treatment of liver diseases by the transplantation of genetically modified hepatocytes, an approach that could be applied to a number of hereditary and acquired hepatic disorders.
Mol Ther 2002 Aug
PMID:Highly efficient lentiviral vector-mediated transduction of nondividing, fully reimplantable primary hepatocytes. 1216 Nov 86

Detection of the prothrombin G20210A mutation was performed on the LightCycler Instrument (Roche Molecular Biochemicals, Mannheim, Germany) using commercially available primers and hybridization probes. Herein we report four cases from unrelated African American individuals where LightCycler analysis showed atypical melting curves. Sequence analysis of the four samples showed heterozygosity for a C to T mutation 1 bp upstream from the known 20210 mutation at position 20209. The clinical significance of this mutation is not known, but three patients in whom it was detected had a history of venous thrombosis or stroke. The fourth patient had severe liver disease, which may have masked thrombotic predisposition. Since most assays used to detect the G20210A mutation use a PCR/restriction digestion assay, which would not detect the C20209T mutation, this new mutation may be underrecognized when prothrombin gene mutation testing is performed by PCR/restriction digestion assay.
Diagn Mol Pathol 2002 Sep
PMID:Detection of a novel point mutation of the prothrombin gene at position 20209. 1221 54

Lamivudine has previously been found to be effective not only in patients with compensated liver disease due to hepatitis B virus (HBV) but also in those with hepatic decompensation. However, long-term follow-up of patients with hepatic encephalopathy (HE) has not been previously reported. We describe a patient with recurrent HE associated with decompensated liver cirrhosis due to hepatitis B. After the initiation of treatment with lamivudine, manifestation of HE has not been observed for about 2 years and liver function has improved as well. This experience suggests that improved liver function using lamivudine may contribute to prevention from recurrence of HE.
Int J Mol Med 2002 Nov
PMID:Additional benefit of lamivudine treatment as a preventive therapy for hepatic encephalopathy in patients with decompensated liver cirrhosis associated with hepatitis B. 1237 9

Mallory bodies (MBs) are cytoplasmic inclusions that contain keratin 8 (K8) and K18 and are present in hepatocytes of individuals with alcoholic liver disease, nonalcoholic steatohepatitis, or benign or malignant hepatocellular neoplasia. Mice fed long term with griseofulvin are an animal model of MB formation. However, the lack of a cellular model has impeded understanding of the molecular mechanism of this process. Culture of HepG2 cells with griseofulvin has now been shown to induce both the formation of intracellular aggregates containing K18 as well as an increase in the abundance of K18 mRNA. Overexpression of K18 in HepG2, HeLa, or COS-7 cells also induced the formation of intracellular aggregates that stained with antibodies to ubiquitin and with rhodamine B (characteristics of MBs formed in vivo), eventually leading to cell death. The MB-like aggregates were deposited around centrosomes and disrupted the microtubular array. Coexpression of K8 with K18 restored the normal fibrous pattern of keratin distribution and reduced the toxicity of K18. In contrast, an NH(2)-terminal deletion mutant of K8 promoted the formation of intracellular aggregates even in the absence of K18 overexpression. Deregulated expression of K18, or an imbalance between K8 and K18, may thus be an important determinant of MB formation, which compromises the function of centrosomes and the microtubule network and leads to cell death.
Mol Biol Cell 2002 Oct
PMID:Formation of Mallory body-like inclusions and cell death induced by deregulated expression of keratin 18. 1238 48

Niemann-Pick disease type C (NPC) is a neurodegenerative disorder with major visceral complications, including liver disease that can be fatal before onset of neurodegeneration. We have sought to determine the extent to which visceral disease contributes to neurodegeneration by making transgenic mice in which the wild-type NPC1 protein is expressed primarily in the CNS using the prion promoter. When the transgene was introduced into the npc1(-/-) animals neurodegeneration was prevented, a 'normal' lifespan occurred and the sterility of npc1(-/-) mice was corrected. The rescue did not provide complete neurological correction in the CNS as GM2 and GM3 gangliosides were observed to accumulate in some neurons and glia of transgenic animals. Two of three transgenic lines demonstrated some low-level ectopic expression resulting in correction of visceral phenotypes in liver and spleen. Interestingly, the third transgenic line continued to have moderate histocytosis in liver and spleen, yet had no detectable neurodegeneration. Thus, it is primarily the lack of NPC1 in the CNS and not the secondary effects of the visceral involvement that causes the neurological decline in NPC disease. In addition, the expression levels of NPC1 found in the CNS of transgenic animals were much greater than in normal littermates, demonstrating that overexpression of NPC1 is not harmful and allowing possibilities for genetic therapy interventions that utilize overexpression.
Hum Mol Genet 2002 Nov 15
PMID:Rescue of neurodegeneration in Niemann-Pick C mice by a prion-promoter-driven Npc1 cDNA transgene. 1241 32

Technetium-99m sestamibi has attracted interest for assessment of the function of P-glycoproteins, which are well expressed in the liver and have roles in biliary transport and the removal of chemotherapeutic drugs. To further examine the cross-reactivity of (99m)Tc-sestamibi for P-glycoprotein family members, we conducted studies in animals. Hepatobiliary secretion of (99m)Tc-sestamibi was determined in normal FVB/N mice, mutant mice with specific P-glycoprotein deficiencies in the FVB/N background, normal Long-Evans Agouti (LEA) rats, and Long-Evans Cinnamon (LEC) rats with abnormal copper transport and liver disease but intact P-glycoprotein expression. After intrasplenic injection, (99m)Tc-sestamibi was rapidly incorporated in the mouse and rat liver, with maximal accumulation after 102+/-31 and 109+/-16 s, respectively ( P=NS). In normal mice and rats, 55%+/-11% and 55%+/-6%, respectively, of the maximal sestamibi activity was retained in the liver after 1 h ( P=NS). In double knockout mice lacking both mdr1a and mdr1b homologs of the human MDR1 ( ABCB1) gene, 88%+/-11% of maximal sestamibi activity was retained in the liver after 1 h ( P<0.001). In knockout mice deficient in either mdr1a gene or mdr2 ( ABCB4) gene, biliary sestamibi excretion was also impaired, although this impairment was relatively less pronounced in ABCB4-deficient mice than in double knockout mice lacking both ABCB1 gene homologs ( P<0.03). Hepatobiliary sestamibi excretion in LEC rats was not different from that in control normal rats, despite the presence of significant liver disease in the former. Hepatobiliary sestamibi excretion requires P-glycoproteins and is unperturbed in chronic liver disease. Sestamibi appears to be a substrate for both ABCB1 and ABCB4 genes, although the former utilizes it far more efficiently. Assessment of P-glycoprotein activity with sestamibi should consider how regulation of ABCB1 and related family members might modulate sestamibi incorporation.
Eur J Nucl Med Mol Imaging 2003 Jul
PMID:Sestamibi is a substrate for MDR1 and MDR2 P-glycoprotein genes. 1253 46

CD40, a tumor necrosis factor receptor superfamily member, is up-regulated on intraheptatic endothelial cells (IHEC) and epithelial cells during inflammatory liver disease, and there is evidence that the functional outcome of CD40 ligation differs between cell types. Ligation of CD40 on cholangiocytes or hepatocytes results in induction of Fas-mediated apoptosis, whereas ligation of IHEC CD40 leads to enhanced chemokine secretion and adhesion molecule expression. We now report that differential activation of two transcription factors, nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1), in primary human hepatocytes or IHEC, is associated with and may explain, in part, the different responses of these cell types to CD40 ligation. CD40 ligation induced a rise in NF-kappaB activity in hepatocytes,which peaked at 2 h and returned to baseline by 24 h; however, IHEC CD40 ligation resulted in a sustained up-regulation of NF-kappaB (>24 h). In hepatocytes, CD40 ligation led to sustained up-regulation of AP-1 activity >24 h associated with increased protein levels of RelA (p65), c-Jun, and c-Fos, whereas no induction of AP-1 activity was observed in IHECs. Analysis of mitogen-activated protein kinase phosphorylation (phospho-extracellular signal-regulated kinase 1/2 and phospho-c-Jun NH(2)-terminal kinase 1/2) and expression of inhibitor kappaBalpha were entirely consistent, and thus confirmed the profiles of NF-kappaB and AP-1 signaling and the effects of the selective inhibitors assessed using electrophoretic mobility shift assay or Western immunoblotting. CD40 ligation resulted in induction of apoptosis in hepatocytes after 24 h, but on IHECs, CD40 ligation resulted in proliferation. Inhibition of (CD40-mediated) NF-kappaB activation prevented IHEC proliferation and led to induction of apoptosis. Selective extracellular signal-regulated kinase and c-Jun NH(2)-terminal kinase inhibitors reduced levels of apoptosis in (CD40-stimulated) hepatocytes by approximately 50%. We conclude that differential activation of these two transcription factors in response to CD40 ligation is associated with differences in cell fate. Transient activation of NF-kappaB and sustained AP-1 activation is associated with apoptosis in hepatocytes, whereas prolonged NF-kappaB activation and a lack of AP-1 activation in IHECs result in proliferation.
Mol Biol Cell 2003 Apr
PMID:Differential induction of nuclear factor-kappaB and activator protein-1 activity after CD40 ligation is associated with primary human hepatocyte apoptosis or intrahepatic endothelial cell proliferation. 1268 91

Aggresome formation in cells involves the failure of the ubiquitin-proteasome pathway to dispose of proteins destined for degradation by the 26S proteasome. UBB(+1) is present in Mallory bodies in alcoholic liver disease and in aggresomes formed in Alzheimer's desease. The present investigation focuses on the role that UBB(+1) plays in cytokeratin aggresome formation in Mallory bodies (MBs) in vitro. Immunoprecipitation with a monoclonal antibody to cytokeratin-8 (CK-8) was used. The immunoprecipitate was incubated for 24 h in the presence of different constituents involved in aggresome formation including ubiquitin, UBB(+1), the proteasome inhibitor PS341, an ATP generating energy source, a deubiquitinating enzyme inhibitor, a purified proteasome fraction, and an E(1-3) conjugating enzyme fraction. MB-like protein aggregates formed in the presence of ubiquitin, plus UBB(+1) or PS341. These aggregates stained positively for CK-8. UBB(+1), and a proteasome subunit Tbp7, as demonstrated on Western blots. A second approach was used to form MBs in vitro in cultured hepatocytes transfected with UBB(+1) protein using Chariot. The cells were double stained using CK-8 and ubiquitin antibodies. The two proteins colocalized in MB-like aggregates. The results support the possibility that aggresome formation is a complex multifactor process, which is favored by inhibition of the proteasome and by the presence of UBB(+1).
Exp Mol Pathol 2003 Apr
PMID:The mechanism of cytokeratin aggresome formation: the role of mutant ubiquitin (UBB+1). 1271 Sep 47


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