Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038002 (splenomegaly)
 9,873 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tangier disease (also known as familial HDL-deficiency) is characterized by very low high density lipoprotein (HDL) plasma levels, splenomegaly, and massive cholesteryl ester accumulation in the cytoplasm of various cell types. Since this phenotype may in part be caused by a defect in the pathway mediating cholesterol efflux from peripheral cells, we investigated the HDL3-mediated mobilization of cholesterol synthesized de novo from [14C]-mevalonolactone in cultivated fibroblasts from two patients with Tangier disease. Our results indicate that the HDL3-induced translocation of [14C]-cholesterol from intracellular pools to the plasma membrane and its subsequent secretion into the extracellular medium was approximately 50% less in the cells from the patients than in controls. The same result was also obtained with artificial apolipoprotein A-I-containing phospholipid vesicles. By contrast, no significant difference in HDL3-induced cholesterol efflux was observed when plasma membrane was labeled with exogenous [14C]-cholesterol. We conclude that inefficient cholesterol efflux in Tangier disease is primarily caused by impaired HDL3-induced activation of cholesterol translocation from intracellular pools to the plasma membrane.
 ...
PMID:The high density lipoprotein- and apolipoprotein A-I-induced mobilization of cellular cholesterol is impaired in fibroblasts from Tangier disease subjects. 799 22

Tangier disease is one of the most severe forms of familial high-density lipoprotein (HDL) deficiency. Since its discovery it has been diagnosed in about 100 patients and is characterized by severe plasma deficiency or absence of HDL, apolipoprotein A-I (apoA-I, the major HDL apolipoprotein) and by accumulation of cholesteryl esters in many tissues throughout the body. The biochemical signs of this condition are plasma HDL concentrations less than 5 mg/dL, low total plasma cholesterol (below 150 mg/dL), and normal or high plasma triglycerides. Tangier disease is caused by mutations in the 'ATP-Binding Cassette transporter A1' (ABCA1) gene, which encodes the membrane transporter ABCA1. This transporter plays a key role in the first step of reverse cholesterol transport, through which the efflux of free cholesterol from peripheral cells is transferred to lipid-poor apoA-I. The Tangier disease clinical phenotype is inherited as an autosomal recessive trait, the biochemical phenotype is inherited as an autosomal co-dominant trait. Nearly all the children affected by Tangier disease were identified on the basis of large, yellow-orange tonsils, while half of the adult patients affected by Tangier disease came to medical attention because of symptoms of neuropathy. Diagnosis in the remaining subjects was related to the clinical features of hepatomegaly, splenomegaly, premature myocardial infarction (about 30% of Tangier disease cases) or stroke, thrombocytopenia, anemia, gastrointestinal disorders, corneal opacities, hypocholesterolemia, low HDL cholesterol, or following a familial screening of Tangier patients. To date there is no specific treatment for Tangier disease. Old and recently designed drugs, known to increase HDL levels, have been shown to be ineffective in Tangier patients. The possible and more realistic therapeutic strategy should be designed to obtain a selective increase of mature HDL concentration to restore cholesterol efflux. Recently designed drugs like the cholesteryl ester transfer protein (CETP) inhibitors dalcetrapib and anacetrapib and reconstituted forms of HDL could be considered until the development of gene therapy.
 ...
PMID:Tangier disease: epidemiology, pathophysiology, and management. 2291 75